Maclura tinctoria (L.) D. Don ex Steud. (Moraceae): a review of the advances in ethnobotanical knowledge, phytochemical composition, and pharmacological potential

Maclura tinctoria (Moraceae), commonly known as dinde, is a lactescent tree of significant economic importance with extensive ethnomedicinal and ethnobotanical applications. Among native populations in the Neotropics, dinde is used to address diverse forms of inflammatory arthritis, along with ailments stemming from viral, bacterial, or fungal origins. Its efficacy stands out notably in the treatment of conditions affecting the buccal cavity, respiratory tract, and venereal infections. These medicinal attributes have spurred investigations into their potential for developing nutraceuticals and pharmacological agents. Also, dinde has a commercial appeal intertwined with the remarkable qualities of its wood, which include the resistance to moisture and termites. This review consolidates information encompassing peer-reviewed articles from major scientific databases such as Science Direct, Scopus, Springer, PubMed, and Google Scholar. The review spans fifty-four phytocompounds, characterized by remarkable structural complexity and identified from the year 2000 onward. These compounds are categorized into flavones, isoflavones, flavonols, flavanols, flavanones, chalcones, and xanthones, where a significant portion exhibiting glycosylation or prenylation. Additionally, phenolic acids and condensed tannins contribute to the chemical diversity of this species. This comprehensive review offers updated insights into the potential bioactivity of chemical constituents identified in this plant, elucidating findings derived from different studies employing both in vitro and in vivo assays.

It has been reported that the fruits of M. tinctoria are edible and have high nutritional value (Oyama et al. 2013).
The leaves, sap, bark, and wood, including fruits, are important natural sources of molecules with therapeutic properties, including flavonoids, chalcones, xanthones, phenolics, and tannins, which support their use in traditional medicine for treating colds, oral infections, relief of toothaches, as a purgative and diuretic, venereal diseases, gout, and rheumatism (Lamounier et al. 2012;Camargo et al. 2022).Santos-Buelga et al. reported that the chemical properties of the organic extracts obtained from M. tinctoria are affected by temperature, light, and environmental conditions (Santos-Buelga et al. 2019); however, the microencapsulation technique has been recommended as a viable alternative to preserve the properties of its extracts (Diaz et al. 2021).
This species has been recognized as a natural source of morin 1, a flavonol with antioxidant, anti-inflammatory, antiarthritic, antifertility, antiplasmodial, and anticancer properties (Mbaveng et al. 2014;Jangid et al. 2018).One of the most important attractions of the dinde is its wood, which is durable and resistant to rot and termites.However, due to low germination rates (∼ 30%) and indiscriminate use of its wood, M. tinctoria is considered endangered (Gomes et al. 2010).
The economic, cultural, and medicinal significance of M. tinctoria has driven the ethnobotanical, phytochemical, and biological studies focused on this species.This review aims to present up-to-date information to guide future research on the potential advantages of this plant.

Methodology
Information presented was collected using electronic searchers for articles published in peer-reviewed journals (Science Direct, Scopus, Springer, PubMed, and Google Scholar).The search terms were "Maclura tinctoria" and "phytochemistry" or "ethnobotanical" or "ethnopharmacology" or "biological activities" from 2000.Relevant original articles, scientific research in the area of interest, and crucial reference articles were used as inclusion criteria.Some botanical aspects of the plant were taken from "The World Flora Online (WFO)".Duplicate publications and irrelevant articles were excluded.

Botanical description, habitat, and global distribution
Description.Tree species are 10-20 m tall and 40-60 cm in diameter, dioecious, thorny, lactescent, and semideciduous (Battilani et al. 2006).Leaves: the leaves are ovate, elliptic, or obovate, measuring 6-13 cm in length and 2-6 cm in width.They have a pointed to attenuate apex and a mostly asymmetric base, which can be obtuse to truncate, rounded, or slightly cordate.The margins are serrated or toothed, especially on the distal part.The upper surface of the leaves is either glabrous or slightly scabrous, while the veins on the lower surface are visible.Petioles and stipules: the petioles are 5-11 mm long, connecting the leaves to the stem.The stipules are paired, deciduous, and measure 3-6.2 mm in length.Inflorescences: the flowers of M. tinctoria are arranged in solitary inflorescences (WFO 2022).Fruits: the fruit originates from the subglobose female inflorescence, oblong and formed by compressed nutlets, with a sweet, fleshy pericarp; indehiscent, and greenish-yellow when mature (Battilani et al. 2006).The ovule is anacampylotropous, suspended, bitegmic, and crassinucellate.Mature seed flattened, slightly ovated, cream-colored, with unspecialized membrane coat with thin-walled cells more or less crushed.Seeds: the seed has a parenchymatic endosperm with lipophilic content.The embryo is straight, with two cotyledons of the same size.Ontogenetic studies have revealed that fruits are infructescences (Oyama and Souza 2011).Habitat: Humid and dry tropical forest (Lachance et al. 2001;Cioffi et al. 2003), common in the Pacific and north-central zones with an altitudinal elevation range of 0-1500 m.a.s.l.(Bernal et al. 2019).Distribution.From México to Central America, and South America (even Argentina), including the Antilles (WFO 2022).Some botanical and phytochemical aspects of M. tinctoria are shown in Fig. 1.

Ethnobotanical applications
The tree of M. tinctoria is leafy and serves as a shade tree for cattle (Gomes et al. 2003).Peel, leaves, and stem segments produce a milky liquid that has been used in folk medicine for the treatment of different pathologies (Gomes et al. 2010).The tree produces edible and juicy fruit, with a very nice and sweet flavor, which is consumed either alone or in juices mixed with wine and in pastries (Lamounier et al. 2012).The fruit is attractive to local fauna (Coldebella et al. 2021) and contains a large number of seeds that quickly become nonviable (Gomes et al. 2003).
The wood of M. tinctoria is characterized by being moderately heavy, flexible, and very durable (Lamounier et al. 2012).This species resists adverse conditions related to humidity and climate and is highly resistant to xylophagous organisms (Oyama and Souza 2011;Lamounier et al. 2012).These characteristics make wood an appropriate resource for the manufacture of furniture, external and heavy construction, flooring, turnery, fence posts, and railroad ties.It has been introduced for production, conservation, and restoration purposes in agricultural landscapes and is recommended for shipbuilding (Lamounier et al. 2012).Furthermore, the wood has a beautiful golden sheen due to a yellow dye called fustic (from which morin 1 is extracted), historically used to dye brown, yellow, khaki, and green textiles (Montes-Londoño et al. 2018).Currently, M. tinctoria syncarps (accessory fruits ∼ 2 cm in diameter) are frequently used to produce yellow dye for dyeing fabrics (Gardner et al. 2017).Morin 1 is also used to perform spot tests for certain metal ions (Oyama et al. 2013) and plays a role in preventing fungal attacks (Lachance et al. 2001).
Maclura tinctoria has been used to explore the creation of various combinations and alternatives for the incorporation of fibers (low-density polyethylene) and natural substrates within a polymeric matrix to determine its potential use as reinforcement or filler material and to evaluate its potential as an agent that promotes the biodegradation of the material (Nikolaeva et al. 2015).

Uses in traditional medicine
Native populations of the Neotropics use stem resin, leaves, stem segments, and bark infusion from M. tinctoria for the treatment of several illnesses.The leaves are used as a dressing after tooth extractions to prevent pain and swelling, and it has been reported that the extract acts as a natural biocide against bacteria in the oral cavity (Coldebella et al. 2021).These anti-inflammatory properties have also been approached by Guarani-Kaiowá indigenous people in Brazil and the Amazonian indigenous community in Bolivia, who use infusions of the bark against toothache (Gomes et al. 2003;Bueno et al. 2005;Oyama et al. 2013).The use of this species extends to wound management due to its healing properties.It is also useful for the treatment of hernias (Gomes et al. 2010).In Latin America, M. tinctoria is used to treat urinary tract infections, coughs, gout, pharyngitis, rheumatism, sore throat, and syphilis (Oyama et al. 2013).
Table 1 summarizes the country where the plant material was collected, the specific part of the plant used, and the extraction solvent used.

Flavonoids
Flavonoids are the most abundant, ubiquitous, and structurally diverse secondary metabolites of the plant kingdom (Mathesius 2018;Ateba et al. 2019).Currently, these are some of the most studied compounds due to their versatile biological properties, making them attractive for studying new therapeutic agents in both the pharmaceutical and healthcare industries.In plants, flavonoids exert protective functions against many biotic and abiotic stressors (UV radiation, herbivores, heat, cold, salinity), serve as phytoalexins and exogenous antioxidants, and participate in the regulation of photosynthesis, morphogenesis, and growth factors, among others (Górniak et al. 2018).The ability of flavonoids to neutralize reactive oxygen species (ROS) and reactive nitrogen species (RNS) has led to a much deeper pharmacological investigation, and their potential has been demonstrated in multiple pathologies related to inflammatory processes, including cancer (Ullah et al. 2020), inflammatory bowel diseases (Pei et al. 2020), age-related neurodegenerative diseases such as dementia, Parkinson's and Alzheimer's disease (Ullah et al. 2020), and other medicinal benefits, such as the management of topical infections and wounds (Sychrová et al. 2022), as well as cardioprotective properties (Ciumărnean et al. 2020).among others (Górniak et al. 2018;Maleki et al. 2019;Ciumărnean et al. 2020).These diverse patterns afford complexity and diversity in flavonoid structures and influence solubility, stability, bioavailability, and biological activities (Maleki et al. 2019).For example, glycosylation patterns include both O-glycoside and C-glycoside (Ji et al. 2020).The type of sugar (mainly glucose, rhamnose, and apiose), number, and location of substitution exert unique properties in flavonoid glycosides (increase in water solubility, toxicity decreased, improved specific targeting, rapid absorption,  and easy metabolism: glucuronidation, methylation, and others) in contrast to their corresponding aglycones (Yang et al. 2018;Al-Maharik 2019;Ciumărnean et al. 2020;Ji et al. 2020).Other molecules with enormous biological potential are prenylated flavonoids.These flavonoids combine a subclass of backbone and prenyl side chain(s), which increases lipophilicity and membrane permeability (Ateba et al. 2019).Prenylated compounds of this type, exhibit anticancer, antiinflammatory, neuroprotective nutraceutical, antifungal, antibacterial, antiviral, antioxidant, antidiabetic, estrogenic, and vasorelaxant properties (Kushwaha et al. 2020;Osorio et al. 2021;Wen et al. 2022).
Phytochemistry studies of M. tinctoria have (tentatively) identified flavonols: morin 1, quercetin 2; flavones: apigenin Many of these compounds are currently being investigated.A brief review of research articles on the biological effects of these compounds (in vitro and in vivo) is mentioned in Table 2.

Xanthones
Xanthones are polyphenols synthesized from the shikimate and acetate pathways.Their structures and chromatographic behavior are related to those of flavonoids.Structurally, xanthones are composed of a tricyclic scaffold (Fig. 6), which can be modified by the addition of isoprene, sugar, methoxyl, and hydroxyl groups in the A and B rings (Gutierrez-Orozco and Failla 2013).
The study of the dichloromethane: methanol (1:1) extract of dinde bark has allowed the identification of diprenylated xanthones: macluraxanthone B 43, macluraxanthone C 44, gartanin 45, and 8-desoxygartanin 46 (Groweiss et al. 2000).In general, some compounds of this type, exhibit anti-inflammatory effects (Xue et al. 2020), antiproliferative activity against breast, colon, and lung cancer cells (Gunter et al. 2022), protective potential of intestinal barrier integrity in HT-29 cells (Tocmo et al. 2021), and act as inhibitors of lipopolysaccharide-stimulated nitric oxide production in RAW 264.7 cells (Jo et al. 2017).A review of articles (PubChem) discussing the relationship between diprenylated xanthones identified in dinde and their biological effects indicates that macluraxanthone B 43 and macluraxanthone C 44 exhibit moderate in vitro antiviral activity against HIV (Pham et al. 2020), while gartanin 45 inhibits the growth of prostate cancer lines via autophagy initiation (Kim et al. 2015;Luo et al. 2017), exhibits an antiproliferative effect in T98G cells (Gao et al. 2016), and exerts neuroprotective effects (Dai and Mumper 2010), among other bioactivities.The chemical structures of chalcones identified in M. tinctoria are shown in Fig. 7.

Phenolic acids
Phenolics are compounds possessing one or more aromatic rings with one or more hydroxyl groups.These compounds exert important functions in plants by acting as a defense mechanism against UV radiation or aggression by pathogens, predators, and parasites.Phenolic acids are considered the simplest molecules within the group of phenolic compounds (Działo et al. 2016).These molecules form a diverse group of phytocompounds that can be grouped into derivatives of hydroxybenzoic acid (e.g., gallic acid 47) and derivatives of hydroxycinnamic acid (e.g., ferulic acid 48).
The wide biological properties of these compounds result from patterns and degrees of substitution in their basic structural skeletons (hydroxybenzoic and hydroxycinnamic acids) (Dong et al. 2022).Phytochemical analysis of M. tinctoria has identified approximately eight phenolic compounds, including gallic acid 47, ferulic acid 48, o-coumaric acid 49, p-hydroxybenzoic acid 50, protocatechuic acid 51, syringic acid 52, and syringaldehyde 53 (Fig. 8) (Pires et al. 2021;Camargo et al. 2022).A brief review of articles that explore the pharmacological potential of the phenolic compounds identified in this plant indicates promising activities: neuroprotective activity (Cavichioli et al. 2022;Çelikezen et al. 2022;Sheikhpour et al. 2023), cytotoxic potential (Pinto et al. 2017), antidiabetic activity (Gan et al. 2023), and other interesting activities that make these compounds promising molecules for the development of therapeutic agents (Table 4).

Condensed tannins
Tannins are water-soluble secondary metabolites of variable chemical structures, characterized by their ability to precipitate proteins (Redondo et al. 2014).Their structural skeletons consist mainly of simple, oligomeric, and polymeric compounds.These can be hydrolyzable or condensed (Rauf et al. 2019).Condensed tannins are one of the most ubiquitous groups of all polyphenolics in the plant kingdom.These types of compounds confer astringency, a property that protects plants from pathogens and predators.Condensed tannins are oligomers or polymers of flavan-3-ol linked through an interflavan carbon bond, produced as an end product of the flavonoid biosynthetic pathway (Rauf et al. 2019).These compounds present structural diversity due mainly to variations in hydroxylation pattern, the stereochemistry at the three chiral centers, the degree of substitution (methoxylation, glycosylation, and galloylation), and the location and type of interflavan linkage (Koleckar et al. 2008;Shnawa et al. 2020).In M. tinctoria, A-type Procyanidin dimer 54,

Antioxidant activity
ROS are byproducts of normal cellular metabolism produced by the electron transport chain.However, elevated ROS levels disrupt the homeostasis of the redox system and cause oxidative stress upon reacting with lipids, proteins, or nucleic acids (Nogueira and Hay 2013).Scientific evidence suggests that oxidative stress plays a pivotal role in both human health and disease.In this sense, lipid peroxidation by ROS causes cell membrane damage that is conducive to cell death (Ullah et al. 2020).Reactive oxygen species may lead to oxidation in both amino acid side chains and protein backbones that are associated with protein fragmentation or protein-protein cross-linkages (Zhang et al. 2013).Additionally, ROS may lead to the modification of cellular nucleic acids (Chao et al. 2013).In the search for new alternatives as antioxidant agents, the scavenging capacity of ROS, and the ability to decrease the production of ROS have been evaluated.Generally, sensitive techniques to identify antioxidant activity based on the ability to scavenge radical cations  et al. 2003).The antioxidant activity of methanol extracts of wood and bark obtained from M. tinctoria was evaluated by DPPH assay.It was observed that the wood of dinde had a higher antioxidant activity than the bark, showing average effective concentration (IC 50 ) values of 18.7 ± 0.5 and 20.9 ± 0.6 μg/mL, respectively (Lamounier et al. 2012).

Antifungal activity
As previously mentioned, phytochemical and biological studies from M. tinctoria were conducted to evaluate the antifungal activity of 2′,4′,4,2′′-tetrahydroxy-3′-(3′′methylbut-3′′-enyl)-chalcone 34, isobavachalcone 37, bakuchalcone 35, bavachromanol 36, and 6,8-diprenylorobol 21 against AIDS-related opportunistic fungal pathogens (Candida albicans and Cryptococcus neoformans) using a modification of the protocol recommended by the National Committee on Clinical Laboratory Standards and amphotericin B as a positive control.The inhibitory activity of the sample was assessed as the minimum inhibitory concentration tested in which no growth was observed.Of all the compounds tested, isobavachalcone 37 was active against both yeasts (ElSohly et al. 2001).

Antibacterial activity
The antibacterial activity against the etiologic agents of dental caries of wood and bark extracts of M. tinctoria was tested by the broth microdilution method using Streptococcus sanguinis (ATCC 10556), S. mitis (ATCC 49456), S. mutans (ATCC 25175), Prevotella nigrescens (ATCC 33563), Actinomyces naeslundii (ATCC 19039), and Porphyromonas gingivalis (ATCC 33277).The most relevant results showed that the hydromethanolic extract of the bark has a minimal inhibitory concentration (MIC) of 80 μg/mL against the major etiologic agents.Furthermore, the cyclohexane: ethanol extract of the bark inhibited growth and showed some of the highest antibacterial activity with an MIC of 20 μg/mL for P. nigrescens, and 60 μg/mL for A. naeslundii and P. gingivalis, respectively.These results suggest that the bark of dinde is very promising for the development of protective agents against dental caries (Lamounier et al. 2012).
The antibacterial activity of ethanol extract obtained from M. tinctoria leaf was evaluated on S. mutans (ATCC25175) and P. gingivalis (ATCC33277) using broth dilution tests to determine the MIC and minimum bactericidal concentration (MBC).The bacteriostatic activity of the extract against S. mutans was observed at a concentration of 125 µg/mL, while the bactericidal activity was determined at higher concentrations (250 and 500 µg/mL).The ethanol extract was less active against P. gingivalis, and MIC and MBC values of 500 µg/mL were observed (Matson Robles et al. 2015).
das Chagas Almeida et al. ( 2019) demonstrated the antimicrobial activity of organic or aqueous extracts from dinde using Galleria mellonella larvae infected with Staphylococcus aureus by in vitro standard methods.An organic extract obtained from leaves showed the lowest MIC (0.08 mg/mL).Its fractionation led to fraction 11FO d (MIC of 0.04 mg/ mL).This fraction showed strong activity against veterinary S. aureus isolates and contributed to the increased survival of G. mellonella larvae infected with S. aureus (ATCC 29213).The phytochemical study led to the identification of an enriched fraction in prenylated isoflavones and flavanones luteone 18, wighteone 19, euchrestaflavanone 32, and cudraflavanone A 31 with possible antistaphylococcal properties.
The antibacterial activity of extracts obtained from leaves, bark, sapwood, and heartwood from dinde was evaluated against Aeromonas hydrophila (ATCC 7966), A. hydrophila (MF 372509), A. hydrophila (MF 372510), A. hydrophila (MH 397689), A. veronii (MH 397688), and Escherichia coli (ATCC 25922).The most important results indicated that the heartwood extract presented the lowest MIC and MBC against the six strains analyzed, compared to the evaluated extracts obtained from the other plant organs (leaves, bark, sapwood), where MIC values ranged from 400 to 1600 µg/ mL, and MBC ranged from 800 to 6400 µg/mL (Pires et al. 2021).

Sedative effects
The central depressant activity and long-term effects induced by ethanolic extracts of M. tinctoria (leaves, bark, sapwood, and heartwood) were evaluated in black catfish (Rhamdia quelen) to explore its possible sedative effects.In brief, the fish submitted to the extracts presented a light sedation induction profile (stage S2) characterized by the absence of reaction to external stimuli.The assay revealed that only the leaf extract at a concentration of 300 mg/L took the catfishes to the deep sedation stage (S3b).Exposure of black catfish to 30 mg/L heartwood extracts for 24 h mimicked a sedative profile previously detected, indicating a greater safety profile.Only the animals exposed to 100 mg/L of leaf extract presented a deepening of the sedation stages, with behavior similar to that observed for diazepam (DZP).The fish exposed to bark, sapwood, and heartwood at 30 mg/L presented a behavior similar to the vehicle control after 30 min, while those subjected to bark, sapwood, and heartwood at 100 mg/L only after 10 h of exposure.These results indicated that heartwood extract can be considered a promising sedative for catfish and its use can be evaluated in aquaculture (Pires et al. 2021).

Neuroprotective and antidepressant-like effects
The neuroprotective and antidepressant effects of M. tinctoria aqueous extract were evaluated by Camargo et al. against glutamate-induced toxicity and in a model of antidepressantlike effects in mice, respectively.It was demonstrated that repeated treatment with the aqueous extract at the lowest dose (1 mg/kg) was effective in abolishing the depressivelike phenotype, and this effect was comparable to fluoxetine administration (10 mg/kg).Furthermore, dinde aqueous extract (1 mg/kg) exhibited neuroprotective effects against glutamate-induced toxicity.These effects were attributed to flavonoids and phenolics identified in the extract, including quercetin 2, catechin 25, epicatechin 26 (major flavonoid), gallic acid 47, ferulic acid 48, syringic acid 52, and syringaldehyde 53 (Camargo et al. 2022).

Conclusions
For centuries, the traditional use of medicinal plants has played a significant role in the therapeutic approach to various diseases.This property is associated with the wide range of phytocompounds identified in the different species, which confirms the folkloric uses of the plants.Maclura tinctoria is a tree of economic importance and culture for Latin America because it offers multiple ecosystem services.These services are attributed to the different applications since dinde serves as a shade tree for cattle.Its wood is an appropriate resource for the manufacture of furniture and external constructions.Additionally, the wood produces a yellow dye called fustic amply used to dye brown, yellow, khaki, and green textiles.The fruits are attractive to fauna and comestibles for humans and have applications in pastries.Phytochemical and pharmacologic studies in M. tinctoria have allowed the identification of a wide variety of complex structures isolated from leaves, fruits, bark, and wood.Of all identified compounds, flavonoids of type flavones, isoflavone, flavonols, flavanols, flavanone, flavanonol, and flavonoid precursors such as chalcones and related compounds such as xanthones, and polyphenols were remarkable.In vitro and in vivo studies have explored the antioxidant properties, antimicrobial potential, sedative effects, and neuroprotective effects of dinde extracts.Other findings are the anti-inflammatory, antibacterial, anticancer activities, and protective effects on the liver, kidneys, brain, and heart (including blood vessels) of both isolated phytocompounds and prenylated or glycoside derivatives.This spectrum of bioactivities observed in dinde indicates that this species is a natural source of molecules with the potential for drug agents and nutraceutical development.

Table 1
Results of phytochemical studies of M. tinctoria Country and date of collection Part of the plant/solvent of extraction Group of extracted compounds References

Table 2
Research articles (PubChem) discussing the relationship between some flavonoids identified in M. tinctoria and their biological effects