Ethnomedicinal Uses, Phytochemistry, Pharmacological Activities, and Toxicology of the Subfamily Gomphrenoideae (Amaranthaceae): A Comprehensive Review

Article type: Review Article

Keywords: bioactivity, gomphrenoideae, phytochemistry, toxicology, traditional use

Authors: Dayanna Isabel Araque Gelves ⚬, Giulia Cristina de Andreoli Souza, Alvaro Jose Hernandez Tasco, Marcos José Salvador

Affiliations: Department of Plant Biology University of Campinas (UNICAMP) São Paulo Brazil; Department of Industrial Microbiology Universidad de Santander (UDES) Bucaramanga Colombia

License: © 2025 The Author(s). Chemistry & Biodiversity published by Wiley‐VHCA AG. CC BY 4.0 This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Article links: DOI: 10.1002/cbdv.202500530  |  PubMed: 40273036  |  PMC: PMC12435438

Relevance: Moderate: mentioned 3+ times in text

Full text: PDF (6.3 MB)

Introduction

Amaranthaceae is an important family of plants and includes species of economic interest; many are marketed as ornamental plants or to be used as food or healthcare based on traditional medicinal knowledge. However, several species are also known as invasive or parasitic plants and are even listed among the worst weeds. Amaranthaceae is placed in the order Caryophyllales Juss. ex Bercht. & J. Presl. and comprises about 163–195 genera and approximately 2215–3805 species, according to The Plant List database (www.theplantlist.org), including those formerly treated as the family Chenopodiaceae [ref. 1, ref. 2, ref. 3, ref. 4, ref. 5, ref. 6, ref. 7, ref. 8, ref. 9].

The Amaranthaceae family has recently become the subject of intensive systematics research. Results of the molecular genetic studies suggest that the traditional classification based on morphological and anatomical characters often did not reflect phylogenetic relationships. The family Amaranthaceae (in their narrow circumscription) is classified into two subfamilies, Amaranthoideae and Gomphrenoideae, and contains about 65 genera and 900 species [ref. 1, ref. 7].

The subfamily Gomphrenoideae comprises about 480 accepted species distributed in 15 genera (Scheme 1) (GBIF), with the majority of its members being annual and perennial herbs, with some shrubs or small trees and climbing plants that have adapted to salty soils, arid environments, and human settlements [ref. 4, ref. 6, ref. 8].

Members of the Gomphrenoideae subfamily are widely used in traditional medicine in Asia, America, and Africa, making them a focus of interest for researchers. Scientists seek to verify their medicinal properties through studies of the chemical and pharmacological profile, with the goal of finding new chemical compounds that could lead to the development of new, more efficient, and safer drugs.

This article provides a comprehensive review that consolidates all available information on members of this subfamily. A wide range of topics are covered, including traditional uses, reported phytochemical profiles, biological activities of interest, and safety and/or toxicity of the extracts studied up until April 2024. Additionally, it concludes with a comparison of traditional uses and activities verified under laboratory conditions and perspectives and research directions.

This review aims to highlight the biotechnological potential of the members of this subfamily, proposing them as a promising source of bioactive molecules. It also emphasizes the importance of studying the relationship among traditional uses, chemical profiles, biological activities, and safety; additionally, it seeks to demonstrate the effect of biotic and abiotic factors on the chemical profile, among which it can mention location, climatic conditions, available nutrients, exposure to UV light, interaction with other living beings, and even the plant genotype; this highlights the need for new research strategies that allow for controlled growth conditions, enabling the optimization and standardization of metabolite production in plants. As a sustainable alternative, the use of in vitro plant tissue cultures is suggested.

Methodology

To gather relevant literature, a comprehensive search was conducted using widely recognized scientific libraries. The search focused on keywords such as names of accepted genera or their synonyms, and the literature search was limited to sources in English. Chemical structures were drawn using ChemSketch, and their names, structures, and classifications were confirmed via the PubChem and ChemSpider websites. The information was summarized in different sections in the form of tables and figures for a better understanding. Scheme 2 outlines the methodology and work plan followed to develop this review. All plant names were consulted in “Global Biodiversity Information Facility” (www.gbif.org), “Plants of the World Online” (www.plantsoftheworldonline.org), “The Plant List” (www.theplantlist.org), “The World Flora Online” (http://www.worldfloraonline.org), MPNS (http://mpns.kew.org), on July 14, 2023 and May 20, 2024.

Traditional Medicinal Uses

Ethnomedicine plays a significant role in both research and society, with 80% of the population relying on traditional medicine for healthcare. The evidence of the pharmaceutical potential of commonly used plants has increased since 2013. By 2020, the WHO indicated that over 20 000 species of plants are utilized in medicine, with 13 000 plants having been studied. Furthermore, various sources indicate that 25%–50% of modern medicine is based on compounds derived from plants [ref. 10, ref. 11, ref. 12, ref. 13, ref. 14, ref. 15].

Currently, many drug development studies are based on traditional medicine, among which can be cited aspirin, atropine, curare alkaloids, ephedrine, cortisone, digoxin, morphine, penicillin, and tubocurarine [ref. 11, ref. 15, ref. 16].

In Africa, America, Asia, Europe, and Antarctica, different members of this subfamily have been used to treat a wide variety of conditions, including chronic diseases, infectious diseases, skin diseases, respiratory issues, gastrointestinal disorders and sexually transmitted diseases, urinary disorders, malaria, diabetes, cancer, hypertension, burns, wounds, snake bites, and scorpion stings, among others. The main uses of some of the members of this subfamily are summarized in Table 1. It is important to note that some plants listed in Table 1 are included in Ayurveda, Unani, Siddha, Homeopathy, Chinese Pharmacopoeia, and “Zhonghua Bencao.”

It is noteworthy that among the 15 genera of this subfamily, the traditional use of only eight (8) has been documented in the literature, accounting for 53.33%. Most of these plants have been used to treat infections, inflammation, pain and gastrointestinal, respiratory, and skin diseases. In this regard, conducting multidisciplinary research to verify whether these plants really have the potential to treat these conditions, as shown in Scheme 3. To date, only some species belonging to the subfamily have been studied in terms of chemical profile and biotechnological potential, as described in detail in the following sections.

Phytochemistry

Medicinal plants produce secondary metabolites or phytochemicals, which are responsible for their biological and pharmacological activity [ref. 12, ref. 85, ref. 88].

The production, quality, and quantity of phytochemical compounds are influenced by the biotic and abiotic factors present in the environment. Consequently, the phytochemical profile of a plant can vary significantly based on the location and growing conditions.

Furthermore, the concentration of secondary metabolites differs among the different parts of the plant, with the leaves typically exhibiting the highest concentration of phytochemicals [ref. 16, ref. 129, ref. 130].

Different natural products and their derivatives have been studied, revealing therapeutic potential for various diseases with fewer side effects than synthetic drugs [ref. 14, ref. 131]. In this context, 109 compounds identified within this subfamily have been evaluated for various biological activities, demonstrating significant activity in most instances. Notably, phenolic compounds are the most widely studied, with antimicrobial activity being the most assessed.

In the case of this subfamily until 2024, 512 compounds have been reported, including phenolic compounds, terpenoids, alkaloids, lipid compounds, and other minor compounds, demonstrating the wide chemical diversity present in the members of this subfamily.

A comprehensive review of the bioactive secondary metabolites isolated from Gomphrenoideae, including their sources, structures, and biological properties, is presented below and summarized in Tables 2, 3, 4, 5, 6 and Figure 1. The structures of compounds 63, 286, 287, and 334 are not provided, as there is no available literature presenting them, nor sufficient information to determine them.

Currently, only 8.22% of the members of Gomphrenoideae have a documented phytochemical profile. Notably, Gomphrena globosa L. has been found to contain 107 compounds, representing 20.94% of the total compounds reported in Gomphrenoideae, including phenolic compounds, terpenoids, alkaloids, lipid compounds, carboxylic acids, and tocopherols. Similarly, Alternanthera brasiliana (L.) Kuntze exhibits a remarkable phytochemical profile with 91 secondary metabolites, including phenolic compounds, terpenoids, alkaloids, lipid compounds, tocopherols, vitamins, among other compounds. In contrast, for other species, fewer than 10 chemical compounds have been reported, examples include Alternanthera paronychioides A.St.‐Hil. (24, 149), Alternanthera repens (Synm. Alternanthera caracasana Kunth) (159, 239–242), Gomphrena boliviana Moq. (6, 7, 9, 10, 17, 54), Gomphrena claussenii Moq. (13, 19, 20, 23–24, 66, 96), Gomphrena macrocephala A.St.‐Hil. (243–247), Gomphrena marginata Seub. (494), Gomphrena martiana Gillies ex Moq. (6–7, 9–10, 17–18, 38, 53–54), Pfaffia townsendii Pedersen (67, 106), and Tidestromia oblongifolia (S. Watson) Standl. (Synm. Tidestromia suffruticosa var. oblongifolia (S. Watson) Sánch.Pino & Flores Olv.) (179, 192, 194, 391, 408, 410).

However, no studies have been conducted on the phytochemical profile of species within the genera Froelichiella, Guilleminea, Hebanthodes, Pedersenia, Pseudoplantago, Quaternella, and Xerosiphon, leaving them chemically unexplored.

Determining the chemical profile of a plant is crucial, as it allows for the deduction of its biological activity, safety, and toxicity. Additionally, it facilitates the study of how internal and external factors influence the production of secondary metabolites and, consequently, biological activity. Research has demonstrated that plants of the same species collected from different locations or at different times, as well as subspecies, can exhibit different phytochemical profiles.

In accordance with the above, it is also worth mentioning that in many cases, the compounds identified in the chemical profile of a plant are produced by its endophytic microorganisms or by the interaction plant‐microorganisms. This association has become a new area of multidisciplinary research of high biotechnological interest.

It is important to emphasize that, to date, there are no studies that evaluate the effect of biotic and abiotic factors on the chemical profile of the members of this subfamily. Additionally, there are no reports on the endophytic communities present in these plants and their effect on the production of secondary metabolites.

Phenolic Compounds

Phenolic compounds are the most numerous and ubiquitously distributed group of secondary plant metabolites [ref. 73]. This group includes all substances that contain phenolic functions linked to aromatic or aliphatic structures [ref. 187].

These compounds exhibit a broad range of biological effects mainly related to their antioxidant capacity due to the presence of hydrogen‐donating hydroxyl groups [ref. 73, ref. 77, ref. 90, ref. 188]. Previous studies have reported that these compounds inhibit cellular DNA mutagenicity and possess antimicrobial and anti‐inflammatory activities [ref. 73, ref. 85, ref. 188].

To date, 173 phenolic compounds have been isolated from the Gomphrenoideae subfamily. In this review, these compounds have been classified into two categories: flavonoids and their glycosides (1–133) and non‐flavonoid phenolic compounds (134–173), as detailed in Sections 4.1.1 and 4.1.2, Table 2, and Figure 1.

Some of these compounds have been subjected to in vivo and in vitro studies to evaluate their biological activity, aiming to propose them as potential therapeutic agents for various diseases.

In terms of antimicrobial activity, compounds 5,7‐dihydroxy‐3,6‐dimethoxyflavone (6), oroxilin A (7), baicalein 5,6‐dimethyl ether (9), 3,5‐dimethoxy‐6,7‐methylenedioxyflavone (10), and 3,5,6,7‐tetramethoxyflavone (17) were evaluated against Mycobacterium phlei, Staphylococcus aureus ATTC 12600, and Enterococcus faecalis ATCC 19433. All were more active against M. phlei, with compounds 6 and 7 presenting the highest activity, with an MIC of 15 µg/mL [ref. 75]. Likewise, these compounds were evaluated against Aspergillus niger, Candida albicans, and Saccharomyces cerevisiae at concentrations of 125–4000 µg/mL and showed MICs ranging from 250 to 1000 µg/mL [ref. 75]. Compounds kaempferol (20), quercetin (24), quercetin 3‐methyl ether (3‐methoxy quercetin) (25), acacetin 8‐C‐[α‐l‐rhamnopyranosyl‐(1 → 2)‐β‐d‐glucopyranoside (34), 2″‐O‐β‐d‐glucopyranosyl‐vitexin (43), 2″‐O‐rhamnopyranosyl‐vitexin (72), and vitexin (88) were assessed against 15 gram‐positive and 4 gram‐negative bacteria, 7 yeast, and 4 dermatophytes at concentrations of 50–500 µg/mL. All these compounds showed activity against at least 3 microorganisms, with compound 24 showing the broadest spectrum, exhibiting activity against 19 of the 30 microorganisms evaluated [ref. 142].

Compounds (E)‐3′‐O‐β‐d‐glucopyranosyl‐4,5,6,4′‐tetrahydroxy‐7,2′‐dimethoxyaurone (33) and kaempferol 3‐O‐β‐d‐(6‐O‐p‐E‐coumaroyl)‐glucopyranoside (tiliroside) or kaempferol‐3‐O‐(6‐p‐coumaroyl)‐glucoside (106) were tested against 19 bacteria but only showed activity against four microorganisms in a concentration range of 0.02–0.5 mg/mL [ref. 2]. Compound 3,5,3′‐trihydroxy‐4′‐methoxy‐6,7‐methylenedioxyflavone (80) was evaluated against 15 microorganisms and showed activity against 7 microorganisms, with the lowest MIC observed against Streptococcus mutans 11.22.1 (20 µg/mL) and the highest in S. aureus ATCC 6538 (1250 µg/mL) [ref. 151]. Compounds kaempferol (20), kaempferol‐3‐O‐(6″‐O‐(E)‐p‐coumaroyl)‐β‐d‐glucopyranoside (107), kaempferol‐3‐O‐(6″‐O‐(Z)‐p‐coumaroyl)‐β‐d‐glucopyranoside (108), and kaempferol 3‐O‐β‐d‐(6″‐feruloylglucopyranoside) (109) were evaluated against Pseudomonas aeruginosa. Among these, compound 20 showed the highest activity with an MIC of 0.008 mg/mL, which was lower than that of ceftriaxone sodium [ref. 144].

The compound vanillic acid (156) was evaluated against five (5) bacteria at a concentration of 0.2 mg/disc and showed activity against two (2) of these microorganisms [ref. 157]. The compound 7‐methoxycoumarin (159), identified in A. caracasana, was evaluated in vitro for antimicrobial activity against Bacillus subtilis, S. aureus ATCC 12398, Staphylococcus epidermidis, Sarcina lutea, and Vibrio cholerae No. 01 ATCC 35971, showing MIC between 0.5 and 0.75 mg/mL, highlighting that this compound demonstrated an MCB of 1 mg/mL against V. cholerae No. 01 ATCC 35971 [ref. 33].

Compounds chrysoeriol‐6‐C‐β‐d‐boivinopyranoside (39), chrysoeriol‐6‐C‐β‐d‐boivinopyranosyl‐4′‐O‐β‐d‐glucopyranoside (40), luteolin‐6‐C‐β‐d‐boivinopyranoside (58), luteolin‐6‐C‐β‐d‐boivinopyranosyl‐3′‐O‐β‐d‐glucopyranoside (59), and luteolin‐6‐C‐β‐d‐boivinopyranosyl‐4′‐O‐β‐d‐glucopyranoside (60) were evaluated for antiviral activity. It was evident that compounds 40, 59, and 60 blocked the secretion of HBsAg, as detailed in subsequent sections [ref. 40]. The compound (80) was evaluated as an antiparasitic against Trypanosoma cruzi and Leishmania amazonensis at concentrations between 4 and 500 µg/mL, but they showed a low reduction in viability [ref. 151].

The results described show that the phenolic compounds exhibit antimicrobial activity at the laboratory level. Most were evaluated against bacteria, followed by yeasts, fungi, viruses, and, to a lesser extent, parasites, highlighting the potential of these compounds as a promising source of antimicrobials.

The isolated phenolic compounds of this subfamily have also been assessed for antioxidant activity. Compounds patuletin 3‐O‐β‐d‐glucopyranoside (67) and kaempferol‐3‐O‐(6″‐O‐(E)‐p‐coumaroyl)‐β‐d‐glucopyranoside (106), as well as a mixture of these two, were evaluated using the DPPH and ORAC assays, both compound 67 and the mixture exhibited relevant activity [ref. 127]. Compounds quercetin (24), quercetin 3‐methyl ether (3‐methoxy quercetin) (25), acacetin 8‐C‐[α‐l‐rhamnopyranosyl‐(1 → 2)‐β‐d‐glucopyranoside (34), 2″‐O‐β‐d‐glucopyranosyl‐vitexin (43), isorhamnetin 3‐O‐α‐l‐rhamnosyl‐(1 → 6)‐β‐d‐glucopyranoside (50), 2″‐O‐rhamnopyranosyl‐vitexin (72), and quercetin 3‐O‐α‐l‐rhamnosyl‐(1 → 6)‐β‐d‐glucopyranoside (129) were evaluated using chemiluminescent assays, showing activity, with compounds 24 and 25 exhibiting greater activity [ref. 145]. Similarly, compounds 34, 43, 70, and 88 were evaluated using ORAC, demonstrating their antioxidant potential, where compound 88 showed the best activity with 0.96 relative TE [ref. 143]. Although there have been few studies focused on studying the antioxidant potential of the phenolic compounds identified and isolated from this subfamily, the research conducted to date demonstrates that they are a promising source of antioxidant compounds.

Regarding cytotoxic activity against cancer cell lines, the mixture of compounds 5,7‐dihydroxy‐3,6‐dimethoxyflavone (6), oroxilin A (7), 3,5‐dimethoxy‐6,7‐methylenedioxyflavone (10), and 3,5,6,7‐tetramethoxyflavone (17) presented an ED₅₀: 27.5 µg/mL against KB cell [ref. 100]. The compounds alternanthin (35) and alternanthin B (36) were evaluated against HeLa cells at concentrations of 10 and 30 µg/mL, showing inhibition percentages between 8.9% and 55.9% [ref. 36]. Likewise, the mixture of flavonoids (6, 7, 10, and 17) was evaluated in vivo, resulting in an increase in the survival of the mice and a reduction in the size of the tumor [ref. 100].

Furthermore, compounds quercetin (24), quercetin 3‐methyl ether (3‐methoxy quercetin) (25), acacetin 8‐C‐[α‐l‐rhamnopyranosyl‐(1 → 2)‐β‐d‐glucopyranoside (34), 2″‐O‐β‐d‐glucopyranosyl‐vitexin (43), isorhamnetin 3‐O‐α‐l‐rhamnosyl‐(1 → 6)‐β‐d‐glucopyranoside (50), 2″‐O‐rhamnopyranosyl‐vitexin (72), and quercetin 3‐O‐α‐l‐rhamnosyl‐(1 → 6)‐β‐d‐glucopyranoside (129) were evaluated as immunomodulators, and it was evidenced that at 50 µmol/L, they do not induce significant release of LDH and are not cytotoxic against PMNL [ref. 145].

For some compounds, the effect on the nervous system has been evaluated. Compounds demethyltorosaflavone D (5), alternanthin (35), alternanthin B (36), chrysoeriol 7‐O‐rhamnoside or chrysoeriol 7‐rhamnoside (41), and torosaflavone E (79) were evaluated as antidepressants and antidementia agents. In the first case, the inhibition of MAO‐A and MAO‐B enzymes was evaluated, whereas in the second, the reduction in β‐amyloid (Aβ) aggregation was assessed. The authors report that the compounds were able to inhibit MAO‐A and MAO‐B, as well as reduce the formation of the Aβ‐aggregation, highlighting that compound 36 presents the greatest inhibition of toxic Aβ plaques [ref. 38, ref. 135]. These results show that the phenolic compounds isolated from this family also have promising activity in the nervous system.

Additionally, the analgesic and anti‐inflammatory activity in vivo was evaluated for compounds 2″‐O‐β‐d‐glucopyranosyl‐vitexin (43) and 2″‐O‐rhamnopyranosyl‐vitexin (72). In both cases, the compounds inhibited hyperalgesia, edema formation, and reduced leukocyte migration [ref. 34, ref. 67]. Likewise, compounds patuletin 3‐O‐β‐d‐glucopyranoside (67) and tiliroside (106) were evaluated for anti‐inflammatory activity in vivo, demonstrating a reduction in the edema formation and leukocyte migration [ref. 127]. These results show that phenolic compounds have potential as analgesic compounds.

Hypoglycemic activity was also evaluated in cleomiscosin A (162) and dictyoceratin C (166), but their activity was low [ref. 84].

Besides the above, it should be noted that some phenolic compounds such as caffeic acid (132) and ferulic acid (137), which have been isolated from members of this subfamily, can become candidates for drugs with dual activity (anti‐inflammatory and antimicrobial activity), which would provide an advantage from the pharmacoeconomic point of view [ref. 71].

A total of 36 out of 173 phenolic compounds identified in this subfamily have been researched in terms of biological activity, showing promising effects such as antimicrobial, antiviral, antioxidant, anticancer, immunomodulatory, antidepressant, antidementia, analgesic, and anti‐inflammatory. Compounds 43 and 72 are particularly noteworthy, as they have demonstrated antimicrobial, immunomodulatory, anti‐inflammatory, and analgesic activity, highlighting their biotechnological potential.

Flavonoids and Their Glycosides

Flavonoids are phenolic compounds commonly found in nature, known for their diverse biological activities. They exhibit antioxidant, analgesic, anti‐inflammatory, anticancer, antipyretic, antiallergic, antidiabetes, antiulcer, antimicrobial, antiprotozoal, antiplatelet, antiatherogenic, antiestrogenic, cardioprotective, neuroprotective, hepatoprotective, and radioprotective activities [ref. 28, ref. 77, ref. 85, ref. 90, ref. 187, ref. 188, ref. 189, ref. 190].

Currently, 133 flavonoids (Table 2) have been reported in members of Gomphrenoideae (Table 2 and Figure 1), consisting of 57 flavone glycosides (34–90), 43 flavonol glycosides (91–133), 15 flavones (3–17), 10 flavonols (18–27), 5 iso‐flavones (28–32), 2 flavan‐3‐ols (1–2), and an aurone (33). It should be noted that quercetin (24), kaempferol (20), and rutin (130) are the most commonly isolated flavonoids from these plants.

Some important aspects of the discovery of flavonoids are described below. In 1992, Pomilio reported the occurrence of an isorhamnetin glycoside (54) for the first time in G. boliviana Moq. [ref. 75]. Later, in 2003, Oliveira first reported the isolation of the symmetrically glycosylated methylene bioflavonoid 8,8‴‐methylene bis(spinacetin 3‐O‐robinobioside) (118) from the ethanol extract of Blutaparon portulacoides (A.St.‐Hil.) Mears leaves. In 2004, Ferreira discovered a new hepta‐substituted (E)‐aurone glucoside (33) in the ethanol extract of Gomphrena agrestis Mart. [ref. 2]. In 2011, Valentová isolated a new isoflavone (32) from the aerial parts of Iresine diffusa f. herbstii (Hook.) Pedersen, characterized by the presence of a methoxy group in position two of the isoflavanone skeleton [ref. 111].

In 2011, Ferreres reported a tetrahydroxymethylenedioxyflavone derivative (77) for the first time in natura [ref. 94]. In 2014, Felipe reported the presence of flavonoids (103, 106, 126) in the inflorescences of Pfaffia glomerata (Spreng.) Pedersen for the first time [ref. 154]. In 2017, Deladino reported the isolation of pentosyl‐vitexin (70) and pentosyl‐isovitexin (69) in A. brasiliana and Alternanthera tenella (Synm. Alternanthera sessilis (L.) R.Br. ex DC. and Alternanthera pungens Kunth) for the first time [ref. 28].

Quercetin (24) has been reported in various species, including Alternanthera bettzickiana (Regel) G. Nicholson, A. brasiliana, Alternanthera maritima (Mart.) A.St.‐Hil. (Synm. Alternanthera littoralis Beauv. ex Moq.), A. paronychioides, Alternanthera philoxeroides (Mart.) Griseb., A. sessilis (L.) R.Br. ex DC., A. tenella Moq. (Synm. A. sessilis (L.) DC. and Alternanthera ficoidea (L.) P. Beauv.), G. agrestis, Gomphrena celosioides Mart., G. claussenii, Gomphrena globosa, and Iresine angustifolia Euphrasén. Quercetin is one of the most abundant flavonoids in the nature and is known for its therapeutic application in allergies, cancer, inflammation, obesity, arthritis, asthma, diabetes, prostate adenocarcinoma, immunity, and infections, as well as its gastroprotective and analgesic properties [ref. 189].

On the other hand, it is noteworthy that G. globosa, with 50 flavonoids (13, 19–20, 24, 27, 46–48, 50–52, 55, 71, 77, 83–87, 92–95, 97–105, 107–110, 112–114, 116, 120–126, 128, 130, 132), is the plant with the highest number of flavonoid‐type compounds reported to date.

Non‐Flavonoid Phenolic Compounds

Currently, only 40 non‐flavonoid phenolic compounds have been reported. These include 14 hydroxycinnamic acids (143–156), 9 benzoic acids (134–142), 2 derivatives of gallic acid (157–158), 2 lignans (160–161), 2 phenylpropanoids (163–164), a coumarin (159), a coumarinolignoid (162), a glycosylated phenylpropionate (165), a sesquiterpene phenol (166), and 7 other phenolic compounds (167–173) (Table 2 and Figure 1).

G. celosioides has the highest number of non‐flavonoid phenolic constituents, with 12 compounds (140, 143–144, 149, 156, 160–162, 166, 168, 170–171). Ferulic acid (149) is the most abundant non‐flavonoid phenolic compound distributed among the species of Gomphrenoideae, having been reported in A. brasiliana, A. paronychioides, A. philoxeroides, A. sessilis, A. tenella, B. portulacoides, G. celosioides Mart, G. globosa, and I. angustifolia.

Terpenoids

Among the terpenes are found monoterpenes, triterpenes, sesquiterpenes, and triterpenoid saponins. These compounds exhibit different biological activities, including antioxidant, antimicrobial, antimalarial, anti‐HIV, anti‐inflammatory, antitumor, antimutagenic, anticancer, antipruritic, antidiabetic, anti‐atherosclerotic, antiallergic, cytotoxic, hemolytic, hypotensive, hepatoprotective, immunomodulatory, and nutraceutical activities, as well as inhibition of cardio‐cerebral vascular diseases, playing an important role in the pharmaceutical industry [ref. 4, ref. 9, ref. 77, ref. 131, ref. 191].

To date, the production of 95 different terpenes in this subfamily has been reported (Table 3 and Figure 1), including 31 triterpenoid saponins (234–264), 31 triterpenes (203–233), 19 sesquiterpenes (179–197), 5 diterpenoids (198–202), 4 monoterpenes (174–177), 3 carotenoids (265–267), a glycoside monoterpene (178), and a drimene (268).

Phytol (202), oleanolic acid (221), pfaffic acid (226), and pfaffosides A–F (255–260) are the most abundant terpenoid compounds distributed among the species of Gomphrenoideae.

In 1984, Nishimoto was the first to isolate the nortriterpene glucuronides called pfaffosides A–C (255–257) from the roots of Pfaffia paniculata (Mart.) Kuntze (Synm. Hebanthe eriantha (Poir.) Pedersen) [ref. 125]. That same year, Nakai reported the isolation of three additional nortriterpenoids, pfaffosides D–F (258–260), from the roots of P. paniculata [ref. 164]. In 2005, Rios identified three new drimenes (268, 195, 196) from the acetone extract of aerial parts of I. diffusa Humb. & Bonpl. ex Willd. [ref. 105]. In 2006, Kuroda reported for the first time the isolation of a taraxane glycoside (245) from a natural source, the roots of G. macrocephala [ref. 99].

In 2008, Chaudhary reported the presence of drimanes in the Amaranthaceae family for the first time, with the isolation of 11,12‐acetonide of 11,12,13‐trihydroxydrimene (179) and 11,12,13‐trihydroxydrimene (194) from the acetone extract of the aerial parts of T. oblongifolia (S. Watson) Standl. (Synm. T. suffruticosa var. oblongifolia (S. Watson) Sánch.Pino & Flores Olv.). Notably, this remains the only phytochemical study conducted on any Tidestromia species [ref. 128]. In 2010, 26 years after Nishimoto’s discovery, Li reported the isolation of two new nortriterpenoids, pfaffine A and B (227–228), from the root of P. paniculata [ref. 123]. In 2018, Han reported the isolation of three new norolean‐type triterpenes (215, 216, 224) from the root of P. glomerata [ref. 115].

With 24 compounds (212–213, 215–216, 221, 223–226, 229–230, 234–235, 237–238, 248, 253–260), P. glomerata has the highest number of terpenoid compounds. It is worth noting that in 2014, Felipe was the first to report the presence of glomeric acid (212), oleanonic acid (223), pfameric acid (229), chikusetsusaponin IV (237), and ginsenoside R₀ (248) in this plant [ref. 154].

As mentioned, terpenes exhibit various pharmaceutical activities, which has led to research on compounds isolated from this subfamily. However, their antimicrobial activity (antiparasitic, antibacterial, and antifungal activity) was not extensively studied. To date, only pfaffic acid (226) has been evaluated against T. cruzi, showing an IC₅₀ of 44.78 ± 7.83 µg/mL [ref. 177].

Antiviral activity has been assessed solely for chikusetsusaponin IVa (238) against 11 viruses, demonstrating efficacy against enveloped viruses (Table S1), and this compound was also evaluated in vivo in mice infected with HSV‐2, revealing a reduction in viral titer, symptom alleviation, and increased survival (Table 10) [ref. 41].

The cytotoxicity of pfaffoside A (255), pfaffoside C (257), pfaffoside D (258), pfaffoside E (259), and pfaffoside F (260) was evaluated against B‐16 cells, with inhibitory concentrations between 30 and 120 µg/mL as seen in Table S2 [ref. 125, ref. 164]. Philoxeroideside A (261), philoxeroideside B (262), philoxeroideside C (263), and philoxeroideside D (264) were evaluated against HL60 and SK‐N‐SH cell lines, with IC₅₀ values ranging from 37.29 to 271.45 µg/mL. Compound 264 exhibited the highest activity, with IC₅₀ values of 45.93 and 37.29 µg/mL, respectively [ref. 37].

Additionally, compounds 11α,12α‐epoxy‐3β‐[(O‐β‐d‐galactopyranosyl‐(1 → 3)‐O‐[β‐d‐glucopyranosyl‐(1 → 2)]‐β‐d‐glucuronopyranosyl)‐oxy]olean‐28,13‐olide (243), 11α,‐12α‐epoxy‐3β‐[(O‐β‐d‐glucuronopyranosyl)oxy]olean‐28,13‐olide (244), 11α,‐12α‐epoxy‐3β‐[(O‐β‐d‐glucuronopyranosyl)oxy]taraxer‐14‐en‐28‐oic acid β‐d‐glucopyranosyl ester (245), 11α,12α‐epoxy‐3β‐hydroxyolean‐28,13‐olide (246), and 11α,12α‐epoxy‐3β‐hydroxytaraxer‐14‐en‐28‐oic acid (247) were evaluated against HSC‐2, but only compounds 246 and 247 showed activity, with IC₅₀ values of 20 µM [ref. 99]. These results confirm the potential of most terpenoid‐type compounds as anticancer agents.

Hypoglycemic activity was evaluated in ilimaquinone (187) and neodactyloquinone (190), showing different levels of activity, with the compound 187 showing the highest efficacy [ref. 84].

Pfaffianol A (225), boussingoside A₂ (235), pfaffiaglycosides B (254), and pfaffoside C (257) were evaluated for their effects on melanogenesis inhibition. The results indicated that only compounds 225 and 257 had a significant effect, even greater than that of arbutin [ref. 161], as shown in Table 9.

The studies described above provide evidence of antiparasitic, antiviral, and cytotoxic activity against carcinogenic cell lines, as well as hypoglycemic activity and antimelanosis properties in 21 out of the 95 compounds identified in this family. This suggests that the members of this subfamily serve as a reservoir of terpenoid compounds with pharmacological activity.

Alkaloids

Alkaloids possess a wide range of biological activities, including inhibition of malignant cell growth and proliferation, as well as antioxidant, anti‐inflammatory, antiviral, antibacterial, and immunomodulatory effects [ref. 77, ref. 84, ref. 151].

To date, 62 alkaloids have been isolated (Table 4 and Figure 1), including 48 betalains (276–323), 2 guanidine alkaloids (269–270), 2 indole alkaloids (271–272), 2 tricyclic alkaloids (274–275), a pyridine alkaloid (273), and other alkaloids (324–330). Among these, the betacyanins amaranthine (276), isoamaranthine (288), betanin (295), and isobetanin (297) are the most abundant alkaloids found in species of Gomphrenoideae, being reported all in A. bettzickiana, A. brasiliana, A. ficoidea Griseb. (Synm. A. littoralis Beauv. ex Moq.), A. tenella, G. globosa, I. herbstii, and Iresine lindenii Van Houtte.

G. globosa has the highest number of alkaloid compounds, with 33 compounds (276, 278–280, 288–290, 294–313, 316, 318–321, 323).

In 2020, Killian reported the isolation of two new, unusual guanidine alkaloids (269–270) from the ethanol extract of aerial parts of I. diffusa [ref. 165], being the first time that this type of compound was isolated from a Gomphrenoideae species.

On the other hand, aurantiamide (326) has been found to possess antioxidant, anti‐inflammatory, antiviral, antibacterial, and immunomodulating properties [ref. 84]. This compound has been reported in the extract of the whole plant G. celosioides [ref. 83–ref. 85, ref. 89]. The presence of betalains in this subfamily is noteworthy, as these compounds are exclusively produced by plants belonging to the order Caryophyllales and have demonstrated significant biological activity.

Of the 62 identified alkaloids, 16 have been studied for their biological activity. For instance, the antimicrobial activity of compound aurantiamide acetate (327) was evaluated against 19 bacteria and 3 yeasts, showing activity against only 5 bacteria, as detailed in Table S1 [ref. 2]. In 2018, Spórna‐Kucab evaluated extracts, seven fractions (mixtures of alkaloids), and individual alkaloid‐type compounds for antimicrobial activity (bacteria and yeast). The study demonstrated that the isolated compounds exhibited better activity than the fractions, whereas the fractions showed better activity than the extracts. The compounds evaluated included cis‐isomer of gomphrenin II (298), cis‐isomer of gomphrenin III (299), cis‐isomer of isogomphrenin II (300), cis‐isomer of isogomphrenin III (301), gomphrenin II (304), gomphrenin III (305), isogomphrenin II (309), isogomphrenin III (310), isosinapoyl‐gomphrenin I (311), and sinapoyl‐isogomphrenin I (313) [ref. 173]. These findings are intriguing, as they suggest that the combination of these compounds may produce an antagonistic effect on antibacterial activity, which is not always the case. In many instances, fractions and extracts exhibit greater activity than isolated compounds due to compound synergism. This research highlights the importance of studying extracts, fractions, and isolated compounds in the search for substances of biotechnological interest.

Additionally, antiparasitic and antioxidant activities were evaluated for compounds alternamide A (7,8‐dihydroxy‐1,2,4,5‐tetrahydro‐3H‐1,5‐ethano[c]azepin‐3‐one) (274), alternamide B (6,7‐dihydroxy‐3,4‐dihydroquinoline‐1‐one) (275), alternamine A ((R)‐1‐(3,4‐dihydroxyphenyl)‐1,2,3,4‐tetrahydroisoquinoline‐6,7‐diol) (324), and alternamine B (4‐(2‐aminoethyl)benzene‐1,2‐diol‐4‐(2‐aminoethyl)benzene‐1,2‐diol‐b‐d‐glucopyranose) (325). These compounds showed different degrees of activity, as detailed in Tables S1 and S2, with compound 324 exhibiting promising antiparasitic activity [ref. 8].

Regarding anticancer activity, only compounds celosiadine A (269) and celosiadine B (270) have been evaluated in vitro, showing activity against LNCaP but not PC3 cells. Hypoglycemic activity was evaluated in bruceolline F (271), but it showed no activity [ref. 84].

The studies evaluating the bioactivity of alkaloid compounds from this subfamily have confirmed their antimicrobial, antioxidant, anticancer, and hypoglycemic properties, demonstrating the potential of this subfamily as a source of biologically active compounds. However, there is still a vast area for investigation, as there have been limited studies to ascertain the biotechnological potential of the betalains identified in this subfamily.

Betalains

Betalains are classified into betacyanins (red‐violet) and betaxanthins (yellow) based on their structure. In plants, they serve protective functions against pathogens and various environmental conditions, aiding in plant propagation. Once isolated, betalains can be utilized as colorants and exhibit a wide range of biological activities, including antioxidants, anticancer, radioprotective, antilipidemic, antihypoglycemic, anti‐inflammatory, and antimicrobial (antibacterial, antifungal, and antiviral) effects. They are also used in the treatment of hypertension, diabetes, anemia, thalassemia, high cholesterol levels, calcium deficiency disorders, and liver‐related issues. Additionally, betalains demonstrate chemopreventive properties and have positive effects on metabolism, cardiovascular health, and gastrointestinal health in humans. Importantly, betalains are non‐toxic and do not exhibit mutagenic or allergic reactions [ref. 29, ref. 96, ref. 130, ref. 174].

To date, 48 types of betalains have been reported in this subfamily. These include 18 belonging to the amaranthin group (276–293), 16 to the gomphrenin group (298–313), 8 types of betaxanthine (316–323), 4 belonging to the betanin group (294–297), and 2 other betalains (314–315). Deladino’s 2017 study indicates that it was the first report of amaranthine (276), isoamaranthine (288), betanin (295), and isobetanin (297) in Alternanthera species, although these compounds are commonly isolated from Amaranthus species [ref. 28]. However, it is important to note that these compounds were previously reported by Cai in A. bettzickiana and A. ficoidea, making Cai’s study the first to report these compounds [ref. 166].

As mentioned above, G. globosa showed the broadest phytochemical profile in terms of betalains. It is also worth noting that 22 betalains (276, 277, 281–282, 284–289, 291–293, 295, 297, 304–305, 309–312, 314) have been reported in I. herbstii and 17 (276, 278, 281–282, 284–285, 288–289, 291–293, 295, 297, 305, 310, 314–315) have been reported in I. lindenii. Among the compounds isolated in this subfamily, Betanin (295) is known to combat oxidative stress and reduce tumors in the lung, skin, colon, liver, and esophageal in various animal models. It also shows activity against tumors in the prostate, breast, and pancreas in humans and inhibits the proliferation of various human cancer cell lines [ref. 130]. Additionally, gomphrenin (302) has been found to have chemopreventive activity, whereas celosianin (278) and iresin (283) exhibit antioxidant potential [ref. 130].

Spórna‐Kucab in 2020 proposed new tribal names for some betalains. Among the proposed changes was renaming gomphrenina II (304) to globosin, gomphrenina III (305) to basellin (due to its presence in Basella alba), 2″‐OE‐sinapoyl‐amaranthin (289) to lindenin (because of its presence in I. lindenii), sinapoyl‐gomphrenin I (312) to gandolin (due to its presence in Gandola nigra), celosianin I (277) to argentianin, and celosianin II (278) to celosianin [ref. 110].

Compounds of Lipid Nature

Currently, 35 compounds have been reported in members of this subfamily. These include 33 fatty acids (331–363), a fatty alcohol (364), and a fatty amide (365) (Table 5 and Figure 1). A. brasiliana has the largest spectrum of lipid compounds (335, 337–348, 353–363, 365).

Regarding the evaluation of biological activity, only the antimicrobial and antimelanosis activities have been evaluated as described below. Compounds (8E)‐10‐hydroxy‐8‐octadecenoic acid (337), (10E)‐9‐hydroxy‐10‐octadecenoic (338), (8E,12Z)‐10‐hydroxy 8,12‐octadecadienoic acid (339), (9Z,11E)‐13‐hydroxy‐9,11‐octadecadienoic acid (340), (9Z,11E,15Z)‐13‐hydroxy‐9,11,15‐octadecatrienoic acid (341), (9Z,12Z,14E)‐16‐hydroxy‐9,12,14‐octadecatrienoic acid (342), (9Z,13E)‐12‐hydroxy‐9,13‐octadecadienoic acid (343), (9Z,13E,15Z)‐12‐hydroxy‐9,13,15‐octadecatrienoic acid (344), (10E,12E)‐9‐hydroxy‐10,12‐octadecadienoic acid (345), (10E,12Z)‐9‐hydroxy‐10,12‐octadecadienoic acid (346), (9Z)‐9‐octadecenedioic acid (354), (7E)‐9‐oxo‐7‐octadecenoic acid (356), (8E)‐10‐oxo‐8‐octadecenoic acid (357), (9E,11E)‐13‐oxo‐9,11‐octadecadienoic acid (358), (9Z,11E)‐13‐oxo‐9,11‐octadecadienoic acid (359), (10E,12E)‐9‐oxo‐10,12‐octadecadienoic acid (360), and (10E,12Z)‐9‐oxo‐10,12‐octadecadienoic (361) were evaluated against three bacteria, but only nine of them showed activity as detailed in Table S1 [ref. 32].

Of the 35 compounds identified, only 17 have been evaluated for biological activity, highlighting a significant research opportunity.

Other Compounds

A total of 146 other compounds were reported, which consisted of 26 phytosterols (386–412), 22 aliphatic hydrocarbons (419–440), 20 phytoecdysteroids (368–385), 7 carboxylic acids (447–443), 6 alkanes (441–446), 4 saponins (414–417), 4 feruloyl tyramine derivatives (454–457), 4 tocopherols (464–467), 3 hydrocarbons (460–462), 2 phytoecdysones (366–367), 2 vitamins (468–469), 2 heterocyclic compounds (458–459), 1 phytosteroid (413), 1 aliphatic alcohol (418), 1 organic acid (463), and 43 compounds that were not classified (470–512) (Table 6 and Figure 1). With 30 compounds, Gomphrena elegans Mart. had the highest number of secondary metabolites of another type (421–427, 429–434, 436–437, 439–440, 461–462, 475–476, 479–480, 488, 493, 495–498, 508, 511), highlighting that 77.27% of aliphatic hydrocarbons were reported in G. elegans Mart. Additionally, it can be seen from Table 6 that feruloyl tyramine‐type compounds were only reported in A. philoxeroides.

In 1998, Sarker was the first to report the phytoecdysteroid 2‐dehydro‐3‐epi‐20‐hydroxyecdysone (370) in seeds of Froelichia floridana (Nutt.) Moq. [ref. 192]. Another important aspect was that Roriz, in 2014, reported tocopherols (464, 466, 467) for the first time in G. globosa [ref. 97].

The biological activity of these compounds has been studied little. Compounds Δ⁷‐stigmasterol (411) and 3‐O‐β‐d‐glucopyranosyl Δ⁷‐stigmasterol (416), and the following mixtures 411 and campesterol (386); spinasterol (396) and 411; 3‐O‐β‐d‐glucopyranosyl stigmasterol (415) and 416; sitosterol glycoside (394) and 3‐O‐β‐d‐glucopyranosyl spinasterol (414), were evaluated against bacteria, yeast, and fungi, showing activity to varying degrees, as detailed in Table S1 [ref. 142]. Likewise, the mixture of compounds sitosteryl (395) and stigmasteryl 3‐β‐O‐glucoside 6′‐O‐palmitate (412) was evaluated for antimicrobial activity against 15 microorganisms but showed activity against 6 (Table S1) [ref. 151]. Compound stigmast‐6‐en‐3‐O‐β‐(d‐glicopyranoside) (417) was evaluated against five microorganisms but only had activity against two of them (Table S1) [ref. 157]. On the other hand, the mixture of compounds 395 and 412 was evaluated against T. cruzi and L. amazonensis and showed activity (Table S1) [ref. 151]. Compound (449) was tested against six bacteria and showed activity against all of them, although the activity was lower than that of the extracts tested (Table S1) [ref. 82].

Additionally, compounds β‐ecdysone (367), 22‐oxo‐20‐hydroxyecdysone (377), pterosterone (381), taxisterone (384), and 2β,3β,14α,17β‐tetrahydroxy‐5β‐androst‐7‐en‐6‐one (385) were evaluated as melanogenesis inhibitors, but none showed activity. Notably, terpenoid compounds were also assessed as melanogenesis inhibitors and demonstrated significant activity (see Table 9) [ref. 161]. Compounds (455), (456), and (457) were evaluated against HeLa cells, and two of them showed significant effects, as evidenced in Table S2 [ref. 36].

Pharmacological Activities

To date, 162 articles have evaluated biological activity, both in vitro (108 articles) and in vivo (73 articles), of 30 species within the Gomphrenoideae subfamily. This research shows that only 6.10% of the members of this subfamily have been studied in terms of biological activity. Furthermore, of the 15 genera, only 6 have been studied. This indicates that the remaining genera, Froelichia, Froelichiella, Hebanthodes, Pedersenia, Pseudoplantago, Quaternella, Tidestromia, and Xerosiphon, remain unexplored in terms of biological activity.

On the other hand, it should be noted that the pharmacological investigations of different extracts and isolated compounds from members of this subfamily confirm various biological activities. These include antioxidant, antimicrobial, anticancer, anti‐inflammatory, antidiabetic, antihyperglycemic, antiarthritic, antihypertensive, analgesic, immunomodulatory, neuroprotective, cardioprotective, gastroprotective, hepatoprotective, diuretic, and wound‐healing properties.

It is important to emphasize that when consolidating and analyzing the biological activity data of the isolated compounds, fractions, extracts, and extract‐based nanoparticles, a notable variability becomes evident. In some cases, isolated compounds exhibit greater activity compared to extracts and fractions, whereas in others, the opposite occurs. This variability can be attributed to synergistic and antagonistic interactions between the compounds, as well as the specific concentrations of each compound present in the extract, which can influence the overall activity.

In this sense, the importance of conducting studies focused on examining extracts, fractions, isolated compounds, and compound mixtures is evident, as this could lead to the discovery of phytotherapeutics that are beneficial for the pharmaceutical industry and the community. Additionally, it is crucial to conduct studies that evaluate the potential of free extracts and drug delivery systems, such as nanoparticles, because the latter have shown that they can enhance the biological activity of the extract in many cases.

Another important observation, which is discussed in the following sections, is that extracts from the same species exhibited different results for the same biological activity. This variability can be attributed to the fact that the study plants were sourced from different geographical locations and times, resulting in distinct phytochemical profiles and consequently varying biological activities. These findings underscore the importance of conducting studies that consider different varieties of the same species, plants collected at different times and locations, and various environmental and stress conditions, as well as the use of in vitro systems and greenhouses to assess the stability of the phytochemical profile and biological activity. Such studies can help determine the optimal conditions for producing bioactive substances of interest.

The significance of the studies that lead to the discovery of new phytotherapeutic compounds lies in their lower cost, greater availability, reduced adverse effects, biodegradability, and environmental safety compared to synthetic drugs [ref. 14, ref. 16, ref. 129, ref. 192].

An overview of the modern pharmacological studies conducted on different extracts and isolated compounds is described in the following subsections, Tables 7, 8, 9, 10, and Schemes 4, 5, 6, 7. In general, the reported studies used standardized and/or similar techniques and concentrations, allowing comparisons between the reported results, thus generating a more comprehensive analysis.

Antimicrobial Activity

Infections caused by fungi and bacteria are responsible for the development of serious diseases and over fifty thousand deaths per year [ref. 96]. Additionally, many microorganisms have developed resistance to existing drugs, posing a risk to public health and presenting a challenge for the pharmaceutical and healthcare industries, with economic implications [ref. 11, ref. 14, ref. 89, ref. 129, ref. 223].

In addition to the development of drug resistance by microorganisms, developing and underdeveloped countries lack access to medications to treat infections, leading to increased mortality rates. Therefore, the search for new broad‐spectrum antimicrobials with low toxicity derived from natural sources is necessary [ref. 14, ref. 89, ref. 223].

To date, 46 articles have evaluated the antimicrobial activity of members of 5 genera of this subfamily. Twenty‐seven articles report the presence or absence of antibacterial activity, evaluating a total of 98 bacterial strains; 14 articles discuss antifungal potential, evaluating 19 yeast strains and 8 fungal strains; 6 articles report on antiparasitic activity against T. cruzi and L. amazonensis; and 2 articles discuss antiviral potential of A. philoxeroides, evaluating its activity against 13 viruses. These studies examined the potential of approximately 46 extracts, 16 fractions, 6 mixtures of compounds, and 73 isolated compounds (6, 7, 9, 10, 17, 20, 24, 25, 33, 34, 39, 40, 43, 50, 51, 54, 58, 60, 70, 71, 72, 80, 88, 92, 93, 94, 95, 100, 101, 106, 107, 108, 109, 156, 159, 226, 238, 274, 275, 298, 299, 300, 301, 304, 305, 309, 310, 311, 313, 324, 325, 327, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 354, 356, 357, 358, 359, 360, 361, 411, 416, 417, 449). These studies cover only 3.54% of the Gomphrenoideae members (A. bettzickiana, A. brasiliana, A. caracasana HBK, A. dentata, A. littoralis P. Beauv., A. philoxeroides, A. pungens, A. repens, A. sessilis (Linn.), A. tenella Colla, B. portulacoides, G. agrestis, G. boliviana, G. celosioides, G. globosa, G. martiana, H. eriantha, I. herbstii, P. glomerata, and P. paniculata). Schemes 4 and 5 summarize the main methodologies, and Table S1 presents the results obtained.

Kumar and his research group are currently the only ones who have studied the antibacterial activity of Alternanthera dentata, demonstrating that AgNPs of AqE of leaves are active against the four microorganisms evaluated [ref. 225]. Research by Zavala and collaborators showed that the ME of A. repens was not active against bacteria and yeasts [ref. 216].

Bhattacherjee and his research group are currently the only ones who have studied the antibacterial activity of A. philoxeroides. They demonstrated that fraction X of leaf ME exhibits remarkable activity, as it was able to inhibit Escherichia coli and Micrococcus luteus with relatively small MICs (11.23 ± 0.11 and 16.23 ± 0.23 µg/mL, respectively) and large ZI, when compared with the results obtained for the AuNPs of AqE from A. bettzickiana, the subfractions of FEaMc and extracts of A. brasiliana, ME of A. sessilis, EE and PEE from G. boliviana, extracts from G. celosioides, AcE from G. globosa, compounds (20, 24, 25, 34, 43, 72, 88, 410, 411), and mixtures of compounds (411 and 386), (396 and 411), (415 and 416), (394 and 414) [ref. 26, ref. 27, ref. 32, ref. 75, ref. 82, ref. 89, ref. 142, ref. 141, ref. 173, ref. 226].

A. sessilis was studied by four research groups, three of which used nanoparticles. Niraimathi et al. and Kabeerdass et al. demonstrated that the AgNPs of AqE of leaves are active against bacteria, especially gram‐negative strains [ref. 60, ref. 227]. Venkatraman and collaborators showed that the ZnONPs of leaves possess antibacterial activity and suggested that the mechanism of action involves membrane destruction, leading to metabolic dysfunction and protein excretion by the bacteria [ref. 228]. Ullah and collaborators reported similar results, demonstrating that the ME of the whole plant presented activity against 10 of the 12 microorganisms evaluated [ref. 226].

G. celosioides was studied by five research groups. Moura’s results for E. coli differed from those obtained by some authors; he reported that the EE of aerial parts and compounds 156 and 417 did not show activity against this strain. However, Dosumu and Omokhua‐Uyi reported that this strain was sensitive to AcE, EaE, and compound 449 [ref. 82, ref. 89, ref. 151]. Another interesting discovery was made by Dosumu, who concludes that the higher activity observed in EaE was due to synergistic relationships between molecules [ref. 82]. However, this information cannot be extrapolated, because extracts sometimes present less activity due to antagonistic relationships between molecules, as observed in the study by Sporna‐Kucab in G. globosa [ref. 173]. Additionally, Dosumu also reported that ME has antifungal activity similar to that of tioconazole [ref. 82]. This finding is particularly relevant because there are currently very few antifungal agents available on the market, highlighting the need for new broad‐spectrum antifungals. In this context, Abalaka et al. also obtained interesting results, demonstrating that AuNPs of leaf extract exhibited activity similar to CAM and streptomycin [ref. 229].

Rahamouz Haghighi and Sharafi in 2024 published the first article of the antibacterial activity of H. eriantha, demonstrating that it was active against the five microorganisms evaluated, having the same effect as gentamicin on S. aureus [ref. 230].

Dipangar and Murugan obtained results similar to Bhattacherjee with AgNPs of AqE from leaves of I. herbstii, which inhibited three gram‐negative bacteria and two gram‐positive with MICs between 6.25 and 50 µg/mL [ref. 231].

A. brasiliana was studied by six different researchers, two of whom studied both antibacterial and antifungal activity. In summary, Johann, Andreaza, and Coutinho reported that the HeE and EE of the whole plant, the HaE of aerial parts, and the EE of leaves did not show relevant activity against the tested microorganisms [ref. 23, ref. 26, ref. 232]. Araújo obtained similar results when evaluating AqE of leaves, showing that the extract did not show activity against four microorganisms, had clinically irrelevant activity against four microorganisms, and showed activity only against Mycobacterium smegmatis (MIC: 15.6 µg/mL) and C. albicans (MIC: 31.2 µg/mL) [ref. 27]. These results are consistent with those obtained by Marchete in 2021, who indicated that the HaE of the leaves has weak activity against P. aeruginosa, S. aureus ATCC 25923, oxacillin‐resistant S. aureus, and E. coli ATCC 25922 [ref. 193]. In contrast, Trapp reported that the FEaMc (1:1) and three sub‐fractions showed activity against B. subtilis and M. luteus, and that compounds 340, 341, 342, 344, 346, 354, 358, 359, and 361 showed activity against B. subtilis, M. luteus, E. coli, and P. aeruginosa [ref. 32]. The difference in results could be attributed to the extraction methods used.

Dominguez et al. in 2022 published the only article that discusses the effect of glycolic extract of the roots of P. paniculata on mixed‐species biofilms of C. albicans and S. mutans, S. aureus, or P. aeruginosa. Their main results reported biofilm inhibition to varying degrees [ref. 233].

Another important discovery was made by the research groups of Nagalingman and Andreazza, who concluded that the effect of the extract on microorganisms can be potentiated when used with drug delivery systems such as nanoparticles or in combination with other methods such as photosensitization [ref. 21, ref. 23].

To date, the trypanocidal and leishmanicidal effects have been evaluated in A. littoralis Beauv. ex Moq., B. portulacoides, G. agrestis, and P. glomerata, all of which showed antiparasitic activity [ref. 2, ref. 8, ref. 117, ref. 151, ref. 177, ref. 234]. The greatest activity was observed in compound 324 isolated from A. littoralis, with IC₅₀ values of 0.23 and 0.16 mM for T. cruzi and L. amazonensis, respectively. Additionally, it should be noted that compounds 226 and FH from the HaE of P. glomerata showed high activity against T. cruzi, with IC₅₀ values of 44.78 and 47.86 µg/mL, respectively [ref. 8, ref. 177].

Antiviral activity has only been evaluated in vitro and in vivo for A. philoxeroides, and the results were promising, as that compound 238 showed in vitro activity against HSV‐1, HSV‐2, human cytomegalovirus, measles virus, and mumps virus. In a genital herpes model in mice (in vivo) caused by HSV‐2, compound 238 was effective, indicating that this compound could be a candidate for an anti‐herpes agent. Additionally, compounds 59, 40, and 60 significantly blocked the secretion of HBsAg in HepG2.2.15 cells [ref. 40, ref. 41].

Antioxidant Activity

Antioxidant compounds play a crucial role in protecting the human body against free radicals, including reactive oxygen species (ROS), which can lead to various pathological conditions. These conditions include Alzheimer’s disease, anemia, arthritis, asthma, atherosclerosis, cancer, cataracts, liver cirrhosis, diabetes, neurological disorders, Parkinson’s disease, cardiovascular diseases, hypertension, hypotension, ischemia, inflammation, Down syndrome, neurodegeneration, and the aging process. Therefore, antioxidant compounds are important in the treatment and prevention of these diseases [ref. 14, ref. 77, ref. 151, ref. 224].

In recent years, there has been a growing interest in the antioxidant potential of plants. This interest persists despite the availability of synthetic drugs on the market, as concerns about their safety and toxicity continue to be significant.

To date, 32 articles have discussed the antioxidant potential of the Gomphrenoideae subfamily members, with 2 studies conducted using in vivo models. These studies described the antioxidant potential of 3.54% of the subfamily members (A. bettzickiana, A. brasiliana, Alternanthera flavescens, A. littoralis P. Beauv., A. paronychioides, A. philoxeroides, A. pungens, A. sessilis (Linn.), A. tenella Colla, G. celosioides, G. globosa, Gomphrena haageana K, I. angustifolia, I. herbstii, P. glomerata, P. paniculata, P. townsendii), evaluating 47 extracts, 22 fractions, and 14 compounds (24, 25, 34, 43, 50, 67, 70, 88, 106, 129, 274–275, 324, 325). Additionally, two extracts contained in nanoparticles, a green leaf juice, a commercial preparation, and a flower infusion were assessed. Scheme 6 summarizes the main methodologies, and Table S2 summarizes the results obtained.

A. brasiliana was evaluated by five different research groups. Pereira et al. evaluated the antioxidant potential of EE, BuF, DF, and FEA using the DPPH assay, but only FEA exhibited radical scavenging activity, which was dose‐dependent [ref. 235]. Marchete et al. showed that the HaE of leaves has antioxidant activity, evidenced by an increase in the scavenging capacity of DPPH, FRAP, and ABTS free radicals [ref. 193]. Paliwal et al. obtained similar results to Marchete et al., showing that HaE of leaves had higher activity than ClE and ME of leaves [ref. 236].

The antioxidant potential of A. philoxeroides was evaluated by five different research groups. In general, fraction X of the ME of leaves showed better activity against DPPH and ABTS radicals compared to the HdE of the tender stem, shoots, and leaves, as well as the EE of the whole plant. The IC₅₀ values were 33.94 ± 3.45 µg/mL for DPPH and 60.76 ± 4.31 µg/mL for ABTS [ref. 132, ref. 135, ref. 136, ref. 141, ref. 237].

Two research groups demonstrated that the antioxidant potential of A. pungens was low [ref. 16, ref. 238].

The antioxidant potential of A. sessilis was evaluated by eight different authors. The best results for DPPH activity were obtained with the FEA of the ME of leaves (EC₅₀: 10.81 ± 0.29 µg/mL), followed by the CF of the ME of callus (EC₅₀: 34.12 ± 0.67 µg/mL), ME of aerial parts (IC₅₀: 35.39 µg/mL), BuF of the ME of leaves (EC₅₀: 35.71 ± 1.24 µg/mL), AF of the ME leaves (EC₅₀: 35.96 ± 1.28 µg/mL), FEA of the ME of callus (EC₅₀: 43.87 ± 0.39 µg/mL), and BuF of the ME of callus (EC₅₀: 57.11 ± 0.13 µg/mL). The other extracts evaluated showed IC_5O, EC₅₀, or SC₅₀ values greater than 80 µg/mL [ref. 49, ref. 55, ref. 57, ref. 60, ref. 195, ref. 196, ref. 238]. Additionally, Mohd Hazli and Muniandy evaluated the EE of the stem of A. sessilis, obtaining IC₅₀ values of >1000 µg/mL and 782 ± 29.9 µg/mL, respectively [ref. 55, ref. 57]. Despite the similarity in the results, discrepancies were observed that could be due to differences in the growth conditions of each plant.

The ethanolic extract of G. celosioides has been studied in vitro and in vivo. According to the in vitro study, the EE of leaves eliminates the DPPH radicals more efficiently than Trolox. Additionally, in the in vivo rat model, it is capable of reducing TBARS levels and increasing the total antioxidant ability in serum [ref. 77, ref. 194, ref. 239].

The antioxidant potential of G. globosa has been studied by four research groups. The extracts, commercial preparations, and floral infusions demonstrated antioxidant activity in various assays, including DPPH, FRAP, TBARS, and radical scavenging activities involving O₂ ⁻ and NO. However, they exhibited high values in EC₅₀ and IC₅₀, in most cases exceeding 500 µg/mL [ref. 73, ref. 98, ref. 150, ref. 153].

Dipankar and Murugan, in their study, evaluated the antioxidant potential of EE of I. herbstii and AgNPs synthesized using the AqE of the leaves, concluding that the NPs potentially enhance the antioxidant activity of the extract [ref. 231].

Regarding H. eriantha (Poir.) Pedersen, it has been reported to have low antioxidant potential [ref. 215]. However, in that publication, the plant is cited as P. paniculata, which is a synonym of H. eriantha according to GBIF (https://www.gbif.org/es/species/101306355).

In 2018, Corrêa et al. conducted an analysis on various extracts and compounds derived from the whole plant of P. townsendii Pedersen. The study encompassed hexanoic and ethanolic extracts, as well as the hexane, dichloromethane, and hydroalcoholic phases. Additionally, the research included an examination of compounds 67 and 106, both individually and in combination. The results demonstrated that the mixture of compounds 67 and 106 exhibited the highest DPPH radical scavenging activity, with an EC₅₀ value of 3.7 µg/mL. Individually, compound 67 showed significant activity with an EC₅₀ of 4.9 µg/mL, whereas compound 106 alone had an EC₅₀ of 83.2 ± 2 µg/mL. Remarkably, when compound 106 was combined with compound 67, there was a 95.55% reduction in the EC₅₀ value, indicating an enhanced activity likely stemming from a synergistic interaction between the two compounds. Notably, the HeE and the hexane phase both displayed the lowest DPPH activity, with EC₅₀ values exceeding 200 µg/mL [ref. 127].

Anticancer Activity

Cancer is one of the main causes of morbidity and mortality worldwide, characterized by irregular cell growth triggered by genetic or environment stimuli. Currently, chemotherapy remains a primary treatment option; however, it often leads to adverse effects, including the development of cancer cell lines resistant to multiple medications, leading to chemotherapy failure. Therefore, one strategy to combat cancer is the search for bioactive compounds with antiproliferative and antitumoral activities [ref. 131, ref. 240].

Currently, 33 articles discuss the in vivo and in vitro anticancer potential of 28 extracts, 16 fractions, 5 NPs, and 22 isolated compounds (35, 36, 243, 244, 245, 246, 247, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 269, 270, 455, 456, 457), 3 mixtures of active molecules, and a paste of leaves and plant powder obtained from 3.13% of the members of Gomphrenoideae (A. bettzickiana, A. brasiliana, A. flavescens, A. philoxeroides, A. sessilis, A. tenella, G. celosioides, G. elegans mart., G. globosa, G. macrocephala, G. martiana, H. erianthos (Synm. Hydrangea paniculata, Synm. P. paniculata), I. diffusa, I. herbstii). Ten articles discuss their activity in vivo models, and 26 discuss their activity in vitro models. Scheme 7 summarizes the main methodologies, and Table 10 and Table S3 summarize the results obtained.

In vitro activity was evaluated across a range of cancer cell lines. These included four leukemia cell lines (HL60, MT‐1, MT‐2, MK‐1); four colon cancer cell lines (Caco‐2, HT‐29, HCT‐8, HCT116); three pancreatic cancer cell lines (Panc‐1, MIA PaCa‐2, Capan‐1); two prostate cancer cell lines (PC3, Human LNCaP); two breast cancer cell lines (MCF‐7 cell, MDA‐MB‐435); two cervical cancer lines (HeLa, KB); two cholangiocarcinoma cells (KKU‐100, KKU‐213); two skin cancer cell lines (B16F10, B‐16); one line of lung cancer (A549); one Ehrlich ascites carcinoma cell line (EAC cell); one liver cancer cell line (Hep‐G2); one human neuroblastoma cell line (SK‐N‐SH); a cell line glioblastoma (SF‐295); and one oral cavity carcinoma cell line (HSC‐2 cells).

The ME of aerial parts of A. brasiliana and A. flavescens Kunth. were evaluated against Caco‐2 and HT‐29 cell lines. In both cell lines, the extract of A. brasiliana was more effective, with the lowest IC₅₀ values: 252.9 ± 5.7 µg/mL for Caco‐2 and 160.3 ± 8.5 µg/mL for HT‐29 [ref. 31]. Regarding HCT‐8, it was evaluated only in G. elegans, and it was found that HeE from leaves caused the highest percentage of lethality (101.16%), followed by FnH (%L: 100), AqE, and FnB from leaves with 99.68% lethality, and ClE with %L of 79.08%. The other 12 extracts and 8 fractions showed a lethality percentage lower than 30% [ref. 156, ref. 241]. The HCT11‐6 cell line was evaluated only with the ME of roots of H. paniculata, which generated a decline in cell viability [ref. 230]. These findings suggest that these four plants exhibit cytotoxic activity against colon cancer cell lines.

The ME of the aerial parts of A. brasiliana and A. flavescens, and the pfaffosidic fraction of H. paniculata (Syn. H. eriantha (Poir.) Pedersen), were evaluated against the Hep‐G2 cell line. It was shown that both the extracts and the fraction exhibited activity against this cell line, with the pfaffosidic fraction presenting the highest activity, reducing more than 50% of the cells at a concentration of 100 µg/mL [ref. 31, ref. 121].

Five compounds isolated from A. philoxeroides, AuNPs from the AqE of A. sessilis leaves, the EE from the whole A. sessilis plant, AgNPs of the AqE of I. herbstii leaves, and the ME of the whole G. globosa plant were evaluated against HeLa cells. The results indicated that compounds 455, 456, 457, and 35 isolated from A. philoxeroides exhibited the highest activity against this cell line, followed by AgNPs of I. herbstii. On the other hand, the EE of A. sessilis showed low activity, and G. globosa showed no activity [ref. 37, ref. 62, ref. 231, ref. 242].

The ME of the whole G. globosa plant was evaluated against leukemia cell lines MT‐1, MT‐2, and MK‐1, and the isolated compounds from A. philoxeroides (261–264) were tested against HL60 cell line. The results showed that G. globosa exhibited no cytotoxic activity, whereas all the compounds from A. philoxeroides were active against the HL60 cell line. Compound 264 presented the highest activity with an IC₅₀ value of 45.93 µg/mL, whereas compound 263 had the lowest activity, with an IC₅₀ of 271.45 µg/mL [ref. 37, ref. 243].

Only one study has evaluated the potential of this subfamily against pancreatic cancer cell lines, obtaining remarkable results. Overall, the ME, PEF, and CF of A. sessilis leaves at a concentration of 100 µg/mL reduced survival percentages to less than 2% in Panc‐1 cells. Among these, CF presented the highest activity, and the authors also reported that it obtained IC₅₀ values of 13.08 ± 10.40 µg/mL for MIA PaCa‐2 and 34.92 ± 2.20 µg/mL for Capan‐1 [ref. 244].

The isolated compounds from I. diffuse (269 and 270) were tested against the PC3 and human LNCaP prostate cancer cell lines, and the AgNPs from AqE of the leaves of A. sessilis were tested against the PC3 line. It was found that compounds 269 and 270 showed activity against LNCaP cells. In contrast, the AgNPs of A. sessilis showed remarkable activity inhibiting 94.11% of PC3 cells at 25 µg/mL [ref. 165, ref. 245].

Currently, seven studies have been conducted to find compounds with cytotoxic activity against breast cancer cell lines. In summary, it was found that MCF‐7 cells are sensitive to the AgNPs (IC₅₀: 3.043 µL/mL and 99% of inhibition at 25 µg/mL) and ZnONPs (IC₅₀: 210 µg/mL) of A. sessilis, but not to the AuNPs of this same plant. In this cell line, the AgNPs of A. tenella also showed activity with an IC₅₀ of 42.5 µg/mL. Additionally, the BE of P. paniculata showed cytotoxic activity [ref. 70, ref. 124, ref. 184, ref. 228, ref. 246]. Regarding the MDA‐MB‐435 cell line, different extracts and fractions of G. elegans Mart. were evaluated. It was shown that AqE and FnB at a concentration of 100 µg/mL generated a lethality percentage of 97.39, whereas HeE and FnH reached lethality percentages of 96.35. However, the other 13 extracts and 8 fractions at this same concentration obtained lethality percentages lower than 50% [ref. 155, ref. 241].

Two studies have evaluated the cytotoxic potential against skin cancer cell lines. In this context, the compounds 255, 256, 257, 258, 259, and 260, isolated from P. paniculata, were tested against the B‐16 cell line. Compound 260 presented the highest activity with an IC₅₀ of 30 µg/mL, and the compound with the lowest activity was 259, with an IC₅₀ of 120 µg/mL [ref. 125, ref. 164]. In contrast, the ME of the whole plant of G. globosa was inactive against B16F10 [ref. 247].

A total of 6 of the 10 in vivo studies aimed to find a bioactive substance for treating Ehrlich carcinoma. Remarkably, the EaE of the leaves of A. brasiliana, the AqE of the aerial parts of A. tenella Colla, the BuF from P. paniculata root, and 20 and 60 mg/kg of the mixture of flavonoids (6, 7, 10, 17) isolated from G. martiana increased the survival of mice with EAC. However, only the extract of A. brasiliana and A. tenella reduced viable cells. Additionally, the mixture of flavonoids inhibited tumor formation by 32%, and the root powder of P. paniculata and the EaE of A. brasiliana reduced the volume of EAC [ref. 66, ref. 100, ref. 185, ref. 207]. It should also be noted that Pinello et al. [ref. 210] evaluated the anticancer potential of the ME of P. paniculata root, focusing on macrophage activity. They found that the ME increased peritoneal macrophages and phagocytosis, suggesting that the anticancer activity of P. paniculata may result from the stimulation of macrophages, natural killer cells, and cytotoxic T lymphocytes [ref. 210]. In conclusion, the extracts of A. brasiliana and A. tenella have antitumor activity, the mixture of compounds has moderate cytotoxic activity, and the root powder and BuF of P. paniculata have an antineoplastic effect.

Da Silva et al. [ref. 208, ref. 211] demonstrated that P. paniculata root powder has anti‐hepatocarcinogenic properties, reducing liver lesions and adenoma in mice. The chemopreventive effect is attributed to the inhibition of cell proliferation and an increase in apoptotic processes [ref. 208, ref. 211]. However, A. sessilis exhibited no activity against squamous cell adenocarcinoma of the stomach in mice [ref. 206].

Analgesic and Antinociceptive Activity

Pain, a sensory perception, often represents the primary symptom in the diagnosis of various diseases. Considered a global public health issue, the search for treatments to alleviate or control pain is crucial. Among these treatments, the use of medicinal herbs and their compounds stands out [ref. 190, ref. 191, ref. 248, ref. 249].

It should be noted that many medications commonly used to treat pain have unwanted side effects, including respiratory depression, drowsiness, decreased gastrointestinal motility, nausea, gastric ulcers, hepatotoxicity, and various disorders of the autonomic nervous and endocrine systems. Furthermore, many of them do not reduce pain in all treated individuals [ref. 191, ref. 248, ref. 249]. This highlights the need to search for new bioactive compounds with analgesic activity that lacks side effects.

Currently, 11 articles discuss the analgesic potential of eleven extracts and 2 isolated compounds from 7 members of the Gomphrenoideae subfamily. The results are described in Table 10. In the acetic acid‐induced abdominal contractions assay, extracts from A. brasiliana, A. philoxeroides, A. sessilis, G. celosioides, and P. glomerata all showed a reduction in the number of contractions. Notably, the AqE of A. brasiliana and the ME of A. sessilis exhibited better activity than dipyrone and aspirin, respectively [ref. 30, ref. 39, ref. 87, ref. 118, ref. 133, ref. 204, ref. 205]. In the carrageenan‐induced paw edema assay, the EE of A. maritima (Mart.) A.St.‐Hil. (Synm. A. littoralis Beauv. ex Moq.), A. tenella, B. portulacoides, G. celosioides, and compounds 43 and 72 showed inhibition of mechanical hyperalgesia induced by carrageenan. Compound 43 achieved 100% inhibition of hyperalgesia [ref. 34, ref. 67, ref. 71, ref. 78].

In the hot plate test, the EE of the whole plant of A. sessilis and the AqE of G. celosioides increased the reaction time, indicating an analgesic effect on the central nervous system. However, the HaE of the roots and rhizomes of P. glomerata showed no effect, indicating the absence of analgesic activity [ref. 87, ref. 118, ref. 133].

In the carrageenan‐induced cold allodynia test, the EE of the whole plant of A. tenella Colla and the EE of the aerial parts of G. celosioides inhibited the response to cold, with the EE of the A. tenella showing the highest activity. However, compound 43 did not show any effect in this test. These same extracts and compound 43 were evaluated in the zymosan‐induced articular inflammation assay, where all reduced mechanical hyperalgesia and inhibited edema [ref. 67, ref. 78].

Anti‐Inflammatory Activity

Inflammatory diseases, such as asthma, rheumatoid arthritis, psoriasis, autoimmune diseases, and severe autoinflammatory diseases, develop due to the overproduction of pro‐inflammatory mediators. For this reason, their inhibition has therapeutic value in the development of anti‐inflammatory agents [ref. 73, ref. 250].

Over time, GCs have been used to treat various inflammatory disorders characterized by their effectiveness, but their chronic use causes undesirable adverse effects, such as skin atrophy, inhibition of wound healing, osteoporosis, obesity, hyperglycemia, and glaucoma [ref. 71, ref. 250].

It should be noted that the anti‐inflammatory compounds caffeic acid, ferulic acid, vanillic acid, and catechin have been isolated from G. celosioides [ref. 78].

To date, 21 studies have been carried out to evaluate the anti‐inflammatory activity of extracts, fractions, infusions, isolated compounds, and commercial preparations of 2.30% of the members of the Gomphrenoideae subfamily, with 7 studies conducted using in vitro models and fifteen using in vivo models. Tables 7 and 10 provide detailed information on these studies.

Regarding in vitro activity, extracts of A. sessilis, G. celosioides, G. globosa, and Gomphrena haageana Klotzsch have been shown to reduce NO levels [ref. 56, ref. 73, ref. 98, ref. 194]. Additionally, the extract of G. celosioides and A. sessilis reduces COX‐2 expression levels [ref. 56, ref. 194]. The EE of A. sessilis also reduces the viability of RAW 264.7 cells, proinflammatory cytokines, and PGE2, as well as prevents the activation of the NF‐κB pathway. However, none of the extracts of G. celosioides affect RAW 264.7 cell viability [ref. 194].

The in vivo anti‐inflammatory activity was evaluated in most of the studies through edema or pleuritis induced by carrageenan. The results showed that the extracts of A. maritima [ref. 34], A. tenella Colla [ref. 213], B. portulacoides [ref. 71], G. celosioides [ref. 77, ref. 87], P. glomerata [ref. 118, ref. 119], and P. townsendii [ref. 127], as well as compound 72 isolated from A. maritima [ref. 34], and compounds 67 and 106 isolated from P. townsendii [ref. 127], exhibited inhibition of edema formation. The best activity was observed in compounds 67 and 106, which at a concentration of 1 mg/kg, were able to inhibit edema by 75.4% ± 4.0% and 73.00% ± 4.0%, respectively [ref. 127]. This was followed by the activity of the HaE of P. glomerata, which showed an ID₅₀ of 20.4 mg/kg for the intraperitoneal dose and an ID₅₀ of 60.5 mg/kg for the oral dose [ref. 119]. The least efficient extract was that of G. celosioides, which, at a concentration of 400 mg/kg, only achieved a 39.62% inhibition of edema [ref. 87].

Regarding the anti‐inflammatory activity in the carrageenan‐induced pleuritis model, it was observed that the extracts of A. tenella Colla [ref. 67], B. portulacoides [ref. 71], P. townsendii [ref. 127], compound 72 isolated from A. maritima [ref. 34], and compounds 67 and 106 isolated from P. townsendii [ref. 127] reduced leukocyte migration to the pleura. Compound 72 showed the greatest inhibition at a concentration of 10 mg/kg (%I: 77) [ref. 34]. Compounds 67 and 106 also showed high activity, with an inhibition of 50.7% ± 1.03% and 59.4% ± 1.25%, respectively, at a concentration of 1 mg/kg [ref. 127]. In this test, it was also observed that compound 72 and the extract of B. portulacoides reduced protein extravasation [ref. 34, ref. 71]. The EE of A. maritima [ref. 34] and A. tenella Colla [ref. 67], as well as compound 43 [ref. 67], reduced the number of leukocytes, with the extract of A. maritima showing the best activity (%I: 68) [ref. 34, ref. 67]. Additionally, the AqE of A. brasiliana reduced the number of lymphocytes, polymorphonuclear cells, and exudate [ref. 30]. These results suggest that both the extracts and the isolated compounds have anti‐inflammatory activity.

It should be noted that the EE of leaves from A. brasiliana also reduced the formalin‐induced edematogenic process [ref. 26]. The EE of the whole plant of A. tenella Colla and compound 43 inhibited the formation of zymosan‐induced edema [ref. 67]. The EE of B. portulacoides inhibited Bothrops jararacussu venom, BthTX‐I, and BthTX‐II‐induced edema formation but did not affect leukocyte migration [ref. 214]. HaE from roots of P. glomerata reduced edema induced by bradykinin, substance P, histamine, serotonin, and LPS [ref. 119], and the ME of P. paniculata roots reduced colonic and intestinal inflammation, the latter being related to the modulation of the expression and production of MAPKs and mucin [ref. 120, ref. 215].

Antidiabetic Activity and Antihyperglycemic Activity

Diabetes is a disease that is spreading rapidly throughout the world, and every year the number of people suffering from this disease increases. In 2016, the WHO reported that 400 million people were affected by diabetic disorder, and in 2017, the IDF reported that 425 million people had diabetes mellitus. It is estimated that by 2045, the number of people with diabetes will rise to 629 million. Additionally, diabetes can lead to the development of other diseases, including cardiovascular, kidney, and eye diseases, as well as stroke and lower limb amputation [ref. 15, ref. 204].

Currently, diabetes can be treated with insulin or hypoglycemic agents, but both can cause side effects such as hypoglycemia, weight gain, gastrointestinal upset, nausea, diarrhea, liver dysfunction, jaundice, and heart failure [ref. 15].

It should be noted that around 400 plant species and their metabolites are used to treat diabetes mellitus worldwide. The antioxidant potential of medicinal plants is a key factor in reducing the incidence of diabetic complications [ref. 15].

Currently, eight studies have evaluated the antidiabetic and/or antihyperglycemic potential of five extracts, fourteen fractions, five compounds, and a green juice, representing 0.83% of the members of the Gomphrenoideae subfamily (Tables 8 and 10).

In the in vitro studies, the inhibition of α‐glucosidase was evaluated for fraction X of A. philoxeroides, the green leaf juice of A. sessilis, and eight fractions of the latter plant. The results demonstrated that all the evaluated substances had α‐glucosidase inhibitory activity. The most potent activity was observed in fraction X of A. philoxeroides (IC₅₀: 52.41 ± 5.22 µg/mL), whereas the weakest activity was found in the FH of the ME of A. sessilis leaves (EC₅₀: 6.31 ± 1.70 mg/mL) [ref. 141, ref. 195, ref. 196]. It was also described that A. paronychioides has a preventive action on diabetic glucotoxicity [ref. 35], and among the five compounds isolated from G. celosioides (162, 166, 187, 190, 271), compound 190 showed a significant improvement in glucose uptake and the highest inhibitory effect on PTP1B, indicating its potential for use in the prevention and treatment of Type 2 diabetes [ref. 84].

As for the in vivo studies, they were generally analyzed using the OGTT. Notably, the ME of the entire A. philoxeroides plant [ref. 39], the ME of aerial parts of A. sessilis [ref. 204], and the FEA of the EE from the aerial parts of A. sessilis [ref. 212] reduced glucose levels in a manner comparable to GLB. It should also be noted that neither the green juice nor HF and FA of A. sessilis reduced glucose levels [ref. 195, ref. 212].

Hepatoprotective Activity

The liver is responsible for regulating several important metabolic functions, and injury to this organ can disrupt these functions [ref. 251]. Liver damage typically involves oxidative stress and is characterized by a progressive evolution from steatosis to chronic hepatitis, fibrosis, and cirrhosis [ref. 252].

Currently, liver diseases are treated with corticosteroids, vaccines, and antivirals. However, these treatments often cause side effects, particularly with chronic or subchronic use. This highlights the necessity of finding new phytotherapeutic drugs that are both safe and more effective [ref. 252].

To date, only four in vivo studies on the hepatoprotective activity of members of this subfamily have been conducted (Table 10). The HaE from the leaves of A. brasiliana L. [ref. 236], the ME from the entire A. sessilis plant [ref. 51], the AqE from the stems and leaves of G. celosioides [ref. 90], and AqE from G. globosa L. [ref. 218]. All studies showed an improvement in the antioxidant profile and a reduction in liver damage [ref. 51, ref. 90].

Other Activities

Other activities have been studied in members of the Gomphrenoideae subfamily, as shown in Tables 9 and 10. An analysis of some of these activities will be presented below.

Neurological Activity

To date, 14 investigations have been carried out to evaluate the potential of fourteen extracts, 10 fractions, 6 compounds, and an infusion of aerial parts of 7 members of this subfamily. Among the isolated compounds of A. philoxeroides (5, 35, 36, 41, 79), compound 35 exhibited the highest inhibitory activity against MAO‐A (IC₅₀: 0.00046 ± 0.04 µM), higher than that of Clorgyline. Compound 36 showed the highest inhibitory activity against MAO‐B (IC₅₀: 0.00022 ± 0.12 µM) and inhibited the formation of toxic Aβ plaques (%I: 81.96 ± 2.14), exhibiting greater activity than curcumin in the latter. It should be noted that all these compounds demonstrated greater inhibition of MAO‐A and MAO‐B than the EE of this plant. These results are significant because monoamine oxidases are enzymes related to cognitive dysfunction and depression. Therefore, it can be suggested that these flavonoids have antidepressant activity. Furthermore, these five flavonoids play an important role in the search for anti‐Alzheimer’s compounds, since preventing Aβ aggregation is one of the objectives for the development of therapeutic strategies. In general, these flavone derivatives exhibit an antidementia effect [ref. 38, ref. 135]. Additionally, the EE of the entire A. philoxeroides plant was evaluated in an in vivo model, showing that it improves recognition, spatial working, and reference memory in ovariectomized mice, indicating its potential to prevent senile dementia [ref. 135].

The inhibition of AChE and BChE was also evaluated in the EE of A. philoxeroides, but this extract did not exert a significant effect on these neurotransmitters [ref. 135]. A similar result was previously obtained by Silva and collaborators, who evaluated two extracts (AqE and EB) and a commercial preparation of inflorescences of G. globosa L. and found that none of these substances were capable of inhibiting AChE [ref. 98].

Kim (2019) conducted an in vivo and in vitro study to determine whether the EE of the aerial parts of Iresine celosia L. (Syn. of I. diffusa Humb. & Bonpl. ex Willd.) had an anti‐neuroinflammatory effect. In the in vitro study, the extract reduced cytokine levels and inflammatory mediators in the microglia, partly due to the inhibition of the MAPKs/NF‐κB signaling pathway. In the in vivo study, the researchers concluded that the EE improves behavioral dysfunctions caused by neuroinflammation in mice. These results suggest that the extract is a potential therapeutic agent for treating neuroinflammation associated with neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s [ref. 104].

The aqueous and methanol extracts of I. herbstii were shown to affect the CNS by interacting with dopamine and serotonin receptors, suggesting their potential for treating diseases such as Parkinson’s and schizophrenia [ref. 108, ref. 201]. Regarding A. brasiliana, researchers found that the infusion of its aerial parts increases exploratory activity but has no effect on anxiety [ref. 30]. Meanwhile, the ME exhibited anxiolytic, sedative, and anticonvulsant effects [ref. 24]. In 2014, Mondal reported that the EE of A. sessilis has central stimulant activity [ref. 133]. It is also worth noting that P. glomerata was studied by three different research groups, which found that the EE of its roots and rhizomes did not have robust effects on depression and anxiety [ref. 219]. The HaE of the root exhibited stimulating effects, improved the acquisition and retention of behaviors, and partially reversed age‐related memory deficits [ref. 116]. Finally, the HF of ME of root was found to reduce stress and depressive behaviors and protect against anxiety development, possibly by maintaining antioxidant defenses and reducing oxidative damage [ref. 114, ref. 219].

Gastrointestinal Activity

Eight articles are currently discussed the gastrointestinal activity of 14 extracts and 8 fractions of 5 members of the Gomphrenoideae subfamily. It has been reported that the aqueous, methanolic, and hexanolic extracts of A. repens (Syn. A. sessilis (L.) R.Br. ex DC. and A. pungens Kunth), as well as six fractions of the ME, exhibit spasmolytic activity according to in vitro studies [ref. 216]. The AqE, EE, and ME of this plant also demonstrate antidiarrheal activity in vivo models [ref. 46, ref. 47, ref. 216]. Similarly, Saquib and Janbaz reported that the EE of A. sessilis has spasmolytic activity based on in vitro study results [ref. 64]. Additionally, it was reported that ME from the leaves of G. celosioides has an antiulcerogenic effect (both preventive and curative), which is likely related to its antioxidant activity [ref. 88, ref. 217]. The HaE of Guilleminea densa (Humb. & Bonpl. ex Schult.) Moq. leaves have been shown to have a gastroprotective effect. It can inhibit gastric lesions induced by indomethacin, ethanol, cold immobilization, or stress. Additionally, it increases gastric mucus, demonstrating an enhancing effect on the protective mucosal barrier. Finally, it inhibits the presence of ulcers, erosive gastritis, acute inflammation infiltration, and focal hemorrhage [ref. 102]. Freitas reported in 2004 that the AqE from roots and rhizomes of P. glomerata exerts a protective effect on the gastric mucosa [ref. 159].

Wound‐Healing Activity

To date, there are only six articles discussing the wound‐healing potential of members of the Gomphrenoideae subfamily. Four of these studies focused on the healing potential of the ME of A. brasiliana leaves by the Barua research group. Among the most relevant results obtained by this group is that the ME has a positive effect on wound contraction, fibroblast deposition, and angiogenesis. It also has pro‐healing activity in burn wounds, reducing the wound area more efficiently than Himax. Additionally, it increases endogenous antioxidant activity and angiogenesis. Similarly, it was shown that ME maintains its healing potential in wounds of old or immunocompromised mice [ref. 202, ref. 220, ref. 221, ref. 222]. Additionally, the healing potential of the EE of A. sessilis stems was studied in an in vitro model, revealing that the EE can enhance the progression of wound closure in normal and diabetic fibroblast cells, as well as in keratinocytes. This suggests that it has the potential to be used in late healing stages of diabetic patients [ref. 57].

Toxicology of Gomphrenoideae

Members of the Gomphrenoideae subfamily are widely used in traditional medicine to treat different ailments. To date, only 37 articles have reported the toxicity of 2.35% of the members of this subfamily (Table 11). It has been reported that the nHE and HE of A. bettzickiana possess mutagenic activity and toxicity against the BHK‐21 cell line [ref. 17]. Additionally, the AuNPs of AqE of leaves of this same plant have shown toxicity against zebrafish embryos at concentrations higher than 25 µM [ref. 21]. Regarding A. brasiliana, it was found that the ME and EaE of leaves do not present toxicity in mice at the maximum dose evaluated (5 and 2 g/kg, respectively) [ref. 24, ref. 185, ref. 202, ref. 220, ref. 221, ref. 222]. The HaE of the aerial parts did not present toxicity against murine macrophages at the evaluated concentration (20 µg/mL) [ref. 193], but the EE of leaves showed low toxicity against flies [ref. 26], and the AqE of leaves showed an LC₅₀ of 500 µg/mL for Artemia salina [ref. 27]. The ME of A. philoxeroides did not show toxicity [ref. 39], whereas the AqE and EE extracts of the aerial parts of A. repens showed toxicity against mice (LD₅₀: 3.4782 and 4.0639, respectively) [ref. 46]. On the contrary, the ME of the aerial parts and the EE of the stem of A. sessilis did not show toxicity up to the doses evaluated in an in vivo and in vitro model, respectively [ref. 57, ref. 204].

The EE of B. portulacoides and the AqE of G. celosioides did not show toxicity in rats up to the dose evaluated [ref. 71, ref. 87], but the HeE and ME of G. celosioides showed weak cytotoxicity against brine shrimp or nauplii, and the AcE and AqE extracts of this same plant showed low toxicity against Vero cells of monkey kidneys [ref. 82, ref. 89]. On the other hand, the HE of G. haageana and G. globosa flowers did not show toxicity against PLP2 cells [ref. 73]. Additionally, the HaE of G. globosa flowers did not show toxicity against BJ cells but did against HaCat cells [ref. 153]. Regarding P. glomerata and P. paniculata, no toxic effects were observed up to the doses evaluated in rats (3 g/kg) and mice (1 g/kg), respectively [ref. 112, ref. 116, ref. 183, ref. 207, ref. 209]. It was also reported that the commercial extract of the root of P. glomerata has no cytotoxic effect on the J774 cell line, nor mutagenic effects [ref. 234].

It can be concluded that the extracts, fractions, and commercial preparations of the studied members of this subfamily do not present toxicity, or it is very low. Furthermore, toxicological safety evaluations are essential for the application or use of plants and the development of new drugs. Therefore, it is necessary to evaluate the toxicity of the other members of this subfamily.

Relationship Among Traditional Uses, Biological Activity, and Chemical Profile

Different parts or even the whole plant of the members of Gomphrenoideae have been used in traditional medicine to treat bacterial, fungal, and viral infections, parasitic diseases, diabetes, cancer, hypertension, inflammatory diseases, gastrointestinal diseases, and liver damage. They have also been used as antioxidants, analgesics, and diuretics, as well as to treat other pathologies. Therefore, during the last decades, they have been studied at the laboratory level, mainly to verify their antimicrobial, antioxidant, anticancer, antidiabetic, hepatoprotective, gastroprotective, diuretic, and insecticidal properties. An attempt to compare traditional use with results from the laboratory is described as follows:

Alternanthera bettzickiana: Out of the 17 traditional uses, only 4 have been evaluated at the laboratory level, confirming its antimicrobial, antioxidant, and cytotoxic (against the A549 cell line) activities. Additionally, two in vitro studies showed antiarthritic potential. The results obtained to date under laboratory conditions confirm only 23.53% of the traditional uses; therefore, it is necessary to confirm the other traditional uses.

Alternanthera brasiliana: To date, only 10 of the 25 traditional uses of this plant have been evaluated, confirming its anticancer potential against the A549, CaCo‐2, HT‐29, and Hep‐G2 cell lines, as well as its positive effect in mice bearing EAC. In addition, its use in the treatment of infections was confirmed, because it has been reported to have activity against some bacteria and yeasts. Its anti‐inflammatory, analgesic, anticonvulsant, anxiolytic, and immunomodulatory activities were also confirmed, as well as its great potential in wound healing.

Alternanthera flavescens: None of its traditional uses have been evaluated under laboratory conditions, but its antioxidant and anticancer activities have been evaluated.

Alternanthera littoralis P. Beauv. (Alternanthera maritima (Mart.) St. Hil.): Currently, its two traditional uses have been evaluated under laboratory conditions, confirming that this plant has antifungal activity against yeasts and anti‐inflammatory activity. Although its traditional uses do not include antioxidant, antiparasitic, and immunomodulatory activities, these properties were evidenced through pharmacological studies.

Alternanthera paronychioides: Of the seven uses in traditional medicine, only antidiabetic activity has been evaluated under laboratory conditions through in vitro tests, suggesting that this plant has antidiabetic properties as well as antioxidant activity.

Alternanthera philoxeroides: Of the 21 traditional uses, 4 have been evaluated under laboratory conditions, confirming that this plant has antiviral activity (e.g., anti‐herpes, anti‐measles), potential antidiabetic activity (inhibits α‐glycosidase), analgesic, and antidepressant effects. Additionally, this plant has been reported to have antibiotic, antioxidant, cytotoxic (against HeLa cells), anticoagulant, and cardioprotective activities, as well as an antidementia and memory‐enhancing effect in mice.

Alternanthera porrigens Kuntze: None of its traditional uses have been confirmed under laboratory conditions.

Alternanthera pungens Kunth: None of its traditional uses have been confirmed under laboratory conditions. However, some articles report that this plant has antitumor activity, but it does not have antifungal activity, nor is it a significant antioxidant.

Alternanthera repens (Alternanthera caracasana): Of the nine traditional uses, only its antidiarrheal activity has been evaluated and confirmed under laboratory conditions. It should be noted that this plant has also been reported to have no activity against C. albicans.

Alternanthera sessilis: To date, only 11 of the 63 traditional uses have been evaluated under laboratory conditions, confirming that it has antiasthmatic, antidiarrheal, antidiabetic, hypotensive, hepatoprotective, analgesic, wound healing, anti‐inflammatory, antioxidant, and antimicrobial (against bacteria) activity. It has also been shown to be cytotoxic against HeLa, Panc‐1, MIA, PaCa‐2, Capan‐1, PC3, L929, and MCF‐7 cells and to have antiallergic and CNS‐stimulating properties.

Alternanthera tenella: Of the 18 uses in traditional medicine, only the anti‐inflammatory, analgesic, and antimicrobial activities have been confirmed by pharmacological studies. Additionally, it has been reported to also have antioxidant, anticancer, and immunomodulatory properties.

Blutaparon portulacoides: Of the two traditional uses, studies confirm its potential to treat vulvovaginitis under laboratory conditions. Additionally, it has also been reported to have antibiotic, antiparasitic, anti‐inflammatory, and analgesic properties, as well as diuretic and cardioprotective effects.

Gomphrena agrestis: There are no reports of traditional uses but has been evaluated for antimicrobial, antifungal, and antiparasitic activity.

Gomphrena arborescens L.f.: Under laboratory conditions, none of the traditional uses have been confirmed.

Gomphrena boliviana: Four traditional uses have been reported, of which only antimicrobial activity has been confirmed under laboratory conditions.

Gomphrena celosioides: Of the 22 traditional uses, 9 have been evaluated through pharmacological studies, confirming that G. celosioides has the potential to be used in the prevention and treatment of Type 2 diabetes, as well as in the treatment of gastric lesions, to counteract renovascular hypertension, and to treat infections (antibiotic and antifungal activities). It also has hepatoprotective, analgesic, anti‐inflammatory, and immunomodulatory properties. Additionally, it has been reported to have cardioprotective and anticarcinogenic activity.

Gomphrena elegans: Its use in traditional medicine has not been reported, but pharmacological studies have shown that it has cytotoxicity against the HCT‐8, SF‐295, and MDA‐MB‐435 cell lines, as well as potential as an insecticide against Aedes aegypti.

Gomphrena globosa: To date, only 2 of its 20 traditional uses have been evaluated under laboratory conditions, which report that this plant has antibacterial, antifungal, and antioxidant activities, although these are considered weak. Assays have shown no cytotoxic activity against the MT‐1, MT‐2, B16F10, HeLa, and MK‐1 cell lines, nor any sun protection effect or AChE inhibition. However, it has anti‐inflammatory and anti‐collagenase properties.

Gomphrena haageana K.: No traditional uses have been reported, but it has been found to have antioxidant and anti‐inflammatory properties.

Gomphrena macrocephala: Its two common uses have not been evaluated by pharmacological studies, but two compounds isolated from this plant have been reported to show cytotoxic activity against HSC‐2 cells.

Gomphrena martiana: Of the eight traditional uses, only its activity in the treatment of infections has been confirmed by antimicrobial studies, indicating that it has antibacterial and antifungal activity. Additionally, its activity against the KB cell line has been evaluated, showing moderate cytotoxicity against it. It has also been shown to have a beneficial effect on mice bearing S‐180 cells or EAC.

Gomphrena virgata Mart.: Its five traditional uses have not yet been confirmed by pharmacological studies, but it has been reported that this plant can inhibit the proliferation of lymphocytes.

Guilleminea densa: Only one of the three traditional uses was evaluated by a pharmacological study, which showed that the plant has a gastroprotective effect, inhibiting gastric lesions and preventing the reduction of mucus induced by toxic agents, confirming its use in the treatment of gastric ulcers.

Iresine difusa: Of the 12 traditional uses, only the anticancer potential has been evaluated under laboratory conditions. It was reported to have cytotoxic activity against the human LNCaP cell line, but not against PC3. Additionally, in vitro and in vivo studies have shown that this plant can be used to treat diseases related to neuroinflammation.

Iresine herbstii: Of the 13 traditional uses, only 2 have been investigated pharmacologically. It was found to have anticancer potential, showing cytotoxic activity against the HeLa cell line. But no significant wound‐healing activity. Although its traditional uses do not mention antibiotic, antioxidant, or neurological activity, in vitro studies suggest that this plant has high antibacterial and antioxidant activities as well as has a beneficial effect on the CNS.

Pfaffia glomerata: Of the 22 known traditional uses, only 7 have been evaluated in the laboratory, confirming its anti‐inflammatory, analgesic, and stimulant properties. It also reduces stress and depressive behaviors and protects against the development of anxiety but has shown variable antioxidant activity. Other studies indicate that this plant has antiparasitic activity against Leishmania braziliensis and L. amazonensis, and its fractions have shown activity against T. cruzi. Additionally, this plant has demonstrated inhibition of melanogenesis.

Pfaffia paniculata: Of the 13 traditional uses, only its anticancer activity (in vitro and in vivo) and anti‐inflammatory properties have been confirmed through pharmacological studies. It was also observed that it did not show antitumor activity in EAC‐bearing mice.

Pfaffia townsendii: Of the four traditional uses reported, only the anti‐inflammatory activity has been confirmed through an in vivo study. Although its traditional uses do not include antioxidant activity, an in vitro study showed that it has antioxidant potential.

Tidestromia oblongifolia: Its traditional use as an analgesic has not been confirmed by pharmacological studies, highlighting that, to date, no study has been carried out to evaluate its biological potential.

From the above, it can be concluded that only 21.18% of the traditional uses reported for the members of this subfamily have been evaluated under laboratory conditions, whereas 78.2% remain untested. These data are relevant because they suggest a promising field of study, as most studies have shown that the plants of this subfamily indeed have biological activity consistent with their traditional uses. The traditional uses of these plants justify multidisciplinary research, which may include determination of biological activity, identification of chemical profiles, correlation between phytochemical profiles and biological activity, comparative studies of extracts, fractions, isolated compounds, and drug delivery, as well as comparative studies between varieties, plants collected from different locations under varying environmental conditions, and in vitro systems.

Gomphrenoideae Subfamily: Perspectives and Research Directions

Despite significant progress in understanding the biotechnological and chemical potential of the Gomphrenoideae subfamily, many research opportunities remain. These opportunities can be categorized into the following key areas of focus.

Evaluation of the Chemical Profile and Activity of Species That Remain Unstudied

Over 80% of species have not yet been studied in terms of their chemical profiles and biological activities, presenting a valuable opportunity to discover new chemical structures and significant biological activities that could be of interest to the pharmaceutical industry.

In Vitro Cultures: A Sustainable and Efficient Strategy in Biotechnological Studies

In the sections on pharmacological activity and phytochemical, it is evident that the same species can exhibit multiple chemical profiles, which, in turn, modulate their biological activity. This variation occurs because the phytochemical profile of plants is influenced by various biotic and abiotic factors, including climatic conditions, UV radiation exposure, soil characteristics, nutrient availability, and interactions with other organisms, such as microorganisms.

In this context, a viable alternative is the use of in vitro plant tissue cultures, which allow for the production of genetically identical plants or callus under controlled growth conditions. The use of in vitro cultures not only standardizes growth conditions but also optimizes the production process and helps prevent ecosystem degradation.

Co‐Cultures of Plants and Endophytic Microorganisms

Endophytic microorganisms play a crucial role in the phytochemistry of plants in natura. In this context, three key theories should be considered: (1) Endophytic microorganisms are responsible for producing certain chemical compounds; (2) microorganisms function as elicitors in the plant and stimulate the production of secondary metabolites; and (3) the interaction between the plant and the microorganism is necessary for the synthesis of specific compounds, which cannot be synthesized in their absence. This could be because endophytes act as stimulants, provide essential precursors for synthesis, or vice versa.

In this context, the use of in vitro plant tissue cultures in co‐culture with one or more endophytic microorganisms represents a valuable approach, which also allow for a better understanding of plant‐microorganism interactions.

Endophytic Microorganisms as a Source of Secondary Metabolites

Endophytic microorganisms are sometimes responsible for producing certain plant secondary metabolites, making them a sustainable alternative that minimizes environmental impact, shortens production times, and allows for process optimization.

Additionally, microorganisms are recognized as a promising source of bioactive molecules due to their metabolic plasticity, which enables them to mimic the metabolism of their host.

Conclusion

The members of the Gomphrenoideae subfamily (Amaranthaceae) have been used in traditional medicine around the world since ancient times. Although some members of this subfamily have been studied at the pharmacological and phytochemical levels, many others remain unstudied, presenting opportunities for research. Additionally, the literature review reveals a direct relationship between the traditional uses of these plants and the biological activity exhibited by the extracts, fractions, and compounds studied. There is also a correlation between the chemical profile and the types of compounds present and the observed biological activity. Demonstrating the importance of understanding the pharmacological activity of plants to harness this knowledge for the development of new drugs.

Research focused on discovering bioactive compounds can contribute to the development of drugs with fewer side effects and greater effectiveness than current options. Currently, drugs for treating pain, inflammation, cancer, diabetes, microbial infections, and oxidative stress‐related conditions are known for their side effects and limited effectiveness. This highlights the need to discover new drugs.

In general, it can be concluded that some phytochemicals found in the subfamily Gomphrenoideae can be used in drug development. Studying the members that have not yet been researched could lead to the discovery of new chemical compounds and the potential development of new drug.

Currently, 512 compounds have been isolated, including 173 phenolic compounds, 95 terpenoids, 87 lipid compounds, 62 alkaloids, and 95 other types of compounds, with phenolic compounds being the most abundant. These different extracts, fractions, and isolated compounds have been associated with various biological activities, such as antioxidant, analgesic, antibacterial, antifungal, antiparasitic, anticancer, antitumor, anti‐inflammatory, antidiabetic, antiarthritis, cardioprotective, healing, diuretic, gastroprotective, hepatoprotective, radioprotective, and hypertension and blood pressure management. The most extensively studied biological activities to date are anticancer, antimicrobial, and antioxidant activities. In conclusion, these plants represent a promising source of bioactive molecules with low or no toxicity.

Author Contributions

Dayanna Isabel Araque Gelves: bibliographic survey, writing and revision of text, design of graphical abstract, design of chemical structures and tables. Giulia Cristina Andreoli de Souza: bibliographic survey, writing and revision of text, design of graphical abstract, design of chemical structures and tables. Alvaro Jose Hernandez Tasco: bibliographic survey, writing and revision of text, design of graphical abstract, design of chemical structures and tables. Marcos Jose Salvador: bibliographic survey, writing and revision of text, design of graphical abstract, design of chemical structures and tables.

Conflicts of Interest

The authors declare no conflicts of interest.

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