Caesalpinia ferrea C. Mart. (Fabaceae) Phytochemistry, Ethnobotany, and Bioactivities: A Review

Caesalpinia ferrea C. Mart., popularly known as “Jucá” or “Pau-ferro”, belongs to the Fabaceae family, and is classified as a native and endemic species in Brazil. Numerous studies that portray its ethnobotany, chemical composition, and biological activities exist in the literature. The present study aimed to systematically review publications addressing the botanical aspects, uses in popular medicine, phytochemical composition, and bioactivities of C. ferrea. The searches focused on publications from 2015 to March 2020 using the Scopus, Periódicos Capes, PubMed, Google Scholar, and ScienceDirect databases. The leaves, fruits, seeds, and bark from C. ferrea are used in popular medicine to treat disorders affecting several systems, including the circulatory, immune, cardiovascular, digestive, respiratory, genitourinary, musculoskeletal, and conjunctive systems. The most commonly found chemical classes in phytochemical studies are flavonoids, polyphenols, terpenoids, tannins, saponins, steroids, and other phenolic compounds. The biological properties of the extracts and isolated compounds of C. ferrea most cited in the literature were antibacterial, antifungal, antioxidant, antiproliferative, anti-inflammatory, and healing potential. However, further studies are still needed to clarify a link between its traditional uses, the active compounds, and the reported pharmacological activities, as well as detailed research to determine the toxicological profile of C. ferrea.

Brown when ripe [19] According to a study performed to evaluate the viability of C. ferrea seeds using the tetrazolium test, viable seeds had the following characteristics: bright light pink color, tissues with a normal and firm appearance, an intense red embryonic axis that did not reach the central cylinder, less than 50% of cotyledons were discolored or had necrotic regions, which did not interfere with the embryonic axis attachment area [22].
C. ferrea is a water demanding species for its growth, since when subjected to hydric stress conditions a relevant reduction in its height and leaf number was observed, indicating that water supply restrictions impaired the development of its morphological and physiological characteristics [23].

Ethnobotany
The ethnobotanical studies were selected according to the data provided for the plant part that was used, including preparation methods or the uses and therapeutic indications of C. ferrea, or its synonym C. ferrea. Table 2 summarizes the 19 articles addressing the medicinal uses of C. ferrea. Table 2. Traditional uses of C. ferrea for curing diseases.

Part Used Method of Preparation or Use Therapeutic Indication Citation
Stem bark and fruit Maceration and cooking Back pain, vision problems, anti-inflammatory and healing [40] Fruit Tea (decoction), tea (maceration), maceration in a bath Sore throat, hoarseness, leg pain, toothache, uterine inflammation, wounds, anemia, gastritis [41] Fruit, bark, roots and seed Tea and tincture Asthma, bronchitis, flu, fever, sore throat, sinusitis, diarrhea, rheumatism, blood clearance, kidneys and soothing [42] Fruits Tea Urinary infection [43] Fruits Bottles Infection [44] Stem bark, bast, fruits and seeds Tea, "lambedor", in natura and in powder Infectious diseases, parasitic, circulatory, immune, cardiovascular, digestive, respiratory, genitourinary, musculoskeletal, conjunctive, injuries and poisoning [45] Seeds Tea and immersed in water Skin cuts, cough, flu and depression [3] Bark, fruit, and seeds Decoction, infusion, maceration and syrup Syphilis, cancer, depurative, diabetes, asthma, gastritis, bronchitis, sinusitis, stomach ache, rheumatism, sexual impotence, healing, bone fracture, headache, fever and throat infection [46] Whole plant and fruits Infusion and maceration Spine, blow, inflammation and kidneys [47] Leafs Tea All kinds of infection and inflammation [5] Ethnobotanical researches are important to understand the use of this plant by traditional communities and the general population for medicinal purposes and to maintain the folk culture. The results of ethnobotanical studies contribute with the association between traditional and modern knowledge, being an important tool to the investigation of the biological properties of medicinal plants.
Given the analysis of the articles, the leaves were indicated as a vermifuge and for the treatment of infections and general inflammation, both of which used tea as a preparation method [5,24]. The bark from C. ferrea is one of the most commonly used organs in traditional medicine through the process of decoction, tea preparations, syrups and bottles for the treatment of various conditions which includes: flus, coughs, kidney and liver inflammation, anxiolytic, rheumatisms, diabetes, hemorrhages, inflammations, infections, and general pains [26,28,32,33,38,39].
After the bark, the fruits are the most commonly used plant parts in the form of teas, bottled and macerated, for the treatment of diarrhea, liver, and kidney problems, pain (throat, legs, spine, and tooth), uterine inflammation, anemia, gastritis and urinary infection, as well as cicatrizing [29,35,41,43,44,47]. The seed tea is used to treat flus and coughs, and when immersed in water it is used as a cicatrizing agent [3].

Phytochemical Aspects
Extracts from C. ferrea leaves, seeds, pods, and basts have been widely studied for having several secondary metabolites such as flavonoids, polyphenols, terpenoids, tannins, saponins, steroids, and other phenolic compounds that present a variety of bioactivities. In this review, 23 articles that investigated the phytochemicals in C. ferrea extracts were found (Table 3). Figure 1 represents the main phytocompounds from C. ferrea.
The leaves were subjected to two treatments, one with water at 100 • C and the other with water at 25 • C. After a HPLC phytochemical analysis of these extracts, gallic acid, caffeic acid, epicatechin, quercetin and luteolin were identified in both extracts, with ellagic acid and catechin also being identified in the hot extract (100 • C) [48]. Meanwhile, GC-MS analyzes of the cyclohexanic extract revealed the presence of n-dodecanal, octacosane, docosane, pentadecane, and heptacosane [8].

Fruits or Pods
The phytochemical analyzes of the aqueous and hydroalcoholic fruit extracts identified the presence of ellagic acid and gallic acid with the HPLC technique [13,55,61]. Meanwhile, qualitative chemical analyzes of the hydroalcoholic fruit extract showed the presence of seven chemical classes: saponins, organic acids, reducing sugars, phenols, tannins, sesquiterpene lactones, and anthraquinones [56].

Seeds and Roots
The seed hydroalcoholic extract presented ellagic acid as its main phytochemical constituent and Thin-Layer Chromatography (TLC) qualitative chemical analyzes showed the presence of fatty acids, coumarins, as well as total and hydrolyzable tannins [59,62]. The root aqueous extract made with water at different temperatures (100 and 25 • C) presented the following constituents in common: gallic and ellagic acid, epicatechin, quercetin and luteolin, while the hot extract (100 • C) also presented catechin in its composition [48].

Compostos De Valor Quimiotaxônomico
The species of the subfamily Caesalpiniaceae present hydrophilic polysaccharides such as galactomannans with a the mannose/galactose ratio ranging from 2.5:1 to 4.3:1 [63]. In C. ferrea, the presence of these polysaccharides was detected by different authors, and these biomolecules are chemotaxonomic markers used to the analysis and identification of these species [64,65]. Other chemical compounds useful as chemotaxonomic markers of Caesalpiniaceae are flavonoids, terpenoids, and isoflavonoids [12,14,48,66].

Bioactivities
A total of 57 articles investigating the bioactivity of the extracts and compounds isolated from C. ferrea were found. Table 4 represents the summary of the extracts' bioactivities and Table 5 corresponds to those of the isolated compounds.

Antimicrobial Activity
The antibacterial activity of the C. ferrea pod hydromethanolic extract was evaluated against oral bacteria that are commonly associated with bad breath, where a Minimum Inhibitory Concentration (MIC) of 50 µg/mL and a Minimum Bactericidal Concentration (MBC) >50 µg/mL were obtained for Parvimonas micra, whereas the Porphyromonas gingivalis microorganism obtained a MIC of 120 µg/mL and a MBC of 130 µg/mL [14]. Moreover, the pod hydroalcoholic extract presented an antibacterial activity against Helicobacter pylori with a MIC and MBC of 512 µg/mL [12].
The bark hydroalcoholic extract presented an antimicrobial potential with species from the Staphylococcus spp., obtaining inhibition halo sizes of 61.1%, 27.78%, and 5.56% for the crude extract at the 70% and 50% concentrations, respectively [70]. The aforementioned extract also presented an antimicrobial activity against S. aureus ATCC 10390, P. aeruginosa ATCC 9721, and E. coli ATCC 25,922 strains with MIC values of 0.39, 0.79, and 0.19 mg·mL −1 , respectively [67].
The C. ferrea fruit hydroalcoholic extract presented antimicrobial potential against the following strains: S. aureus, E. coli, Klebsiella pneumoniae, and P. aeruginosa with inhibition halo averages of 18, 12, 10 and 11 mm, respectively [68]. The C. ferrea pod ethanolic extract also presented antimicrobial activity against Gram-positive and Gram-negative strains with MIC values ranging from 50 to 125 µg/mL [73]. The glycolic leaf extract on the other hand exhibited an average inhibition halo of 0.97 cm over S. aureus ATCC 6538 [57].
The C. ferrea fruit aqueous extract presented antibiofilm activity for biofilms formed by bacteria from the Proteobacteria and Bacteroidetes phylum, inhibiting their growth by 82% at a concentration of 4 mg·mL −1 [74].

Anti-Halitosis Activity
Volatile sulfuric compounds are produced by bacteria present in the oral cavity, with these compounds being responsible for unpleasant breath odors. Tests using a salivary sediment model have shown the C. ferrea pod hydromethanolic extract inhibited the formation of these odors, reducing the concentration of volatile sulfuric compounds associated with halitosis [14].
Extracts from the C. ferrea stem bark using three different solvents (water, ethanol, and acetone) exhibited antifungal activity over dermatophyte fungi species, presenting the same MIC value of 62.5 µg/mL for Trichophyton rubrum ATCC 28,189 and 31.3 µg/mL for Trichophyton mentagrophytes ATCC 11481, with the author classifying MIC values ≤ 75.0 µg/mL as having an effective antifungal activity. The stem bark aqueous extract also showed antifungal activity over clinical isolates (T. rubrum and T. mentagrophytes) with a MIC 50 value of 31.3 µg/mL and MIC 90 value of 62.5 µg/mL for both species, where MIC 50 and MIC 90 refer to the concentration (µg/mL) of the extract that inhibited growth of all isolates by 50% and 90%, respectively [78].
Tests using the C. ferrea leaf ethanolic extract as an alternative control for Alternaria brown spots, caused by the fungus Alternaria alternata in 'Dancy' mandarin fruits, showed the 500 µg/mL concentration presented a 52.0% disease severity reduction [93]. The aqueous and ethanolic extracts also showed 96.49% and 99.12% disease severity reduction in 'Ponkan' tangerine seedling leaves, respectively, at the 1 mg/mL concentration [94].
The C. ferrea leaf alcoholic extract demonstrated an antifungal potential over Colletotrichum sp. in Sideroxylon obtusifolium ("quixaba") seeds, since all seeds treated with the extract did not present symptomatic seedlings percentages or pathogen transmission rates [77]. The aqueous extract also demonstrated an antifungal activity over Colletotrichum sp. in S. obtusifolium seeds, since pathogen incidence decreased by up to 96% at the 0.075 mg·mL −1 concentration [76]. C. ferrea extracts also showed antifungal activity over Lasiodiplodia theobromae, inhibiting mycelial growth by 85.6 and 78.9% at 30% and 20% concentrations, respectively [79].

Anti-Inflammatory Activity
The C. ferrea leaf aqueous extract decreased leukocyte accumulation (76 ± 2%) and myeloperoxidase levels (85 ± 7%) in the articular fluid of rats at 100, 200, and 300 mg/kg doses when compared to the zymosan control group, a substance used to stimulate intra-articular inflammation. In addition, the extract significantly reduced inflammatory cytokine levels such as beta interleukins (IL-1β) and tumor necrosis factor alpha (TNF-α) in the articular tissue of rats treated with 200 and 300 mg/kg doses [7]. The fruit aqueous and hydroalcoholic extracts (20-80%) also showed an anti-inflammatory activity at all tested doses (50, 100, and 200 mg/kg), decreasing the migration of inflammatory cells and myeloperoxidase activity levels [13].

Antioxidant Activity
Generally, two parameters are used to assess the integrity of the body's antioxidant defense: the first is the quantity of glutathione, which is responsible for promoting detoxification and free radical elimination, the second is malondialdehyde (MDA) content, which is characterized as a lipid peroxidation marker. The fruit and leafs aqueous and hydroalcoholic extracts of Pau-ferro showed antioxidant potential at all evaluated doses (50, 100, and 200 mg/kg), increasing total glutathione levels and decreasing MDA levels [7,13,54].
The leaf hydroalcoholic extract also showed high antioxidant activity in the DPPH and ABTS free radical elimination assays with Half Maximal Inhibitory Concentration (IC 50 ) values of 28.96 and 145.10 µg/mL, respectively [12]. Four pod extracts (chloroformic, n-hexane, hydroalcoholic, and ethyl acetate) were evaluated for their antioxidant activity; however, only two extracts presented free radical elimination activity, these being the hydroalcoholic extract, with IC 50 values of 74.36 µg/mL for DPPH and ABTS IC 50 of 9.76 µg/mL, and the ethyl acetate extract, with IC 50 values of 116.10 and 29.13 µg / mL for DPPH and ABTS, respectively [56].

Antileishmanial Activity
The fruit methanolic extract and leaf hexanic extract showed antileishmanial activity, with IC 50 values of 15.04 and 53.09 µg·mL −1 against Leishmania (L.) amazonensis promastigotes. Meanwhile, the leaf and fruit methanol extracts showed an IC 50 activity of 129.42 and 173.11 µg·mL −1 against Leishmania (V.) guyanensis promastigotes. The fruit methanol extract showed low in vitro toxicity on infected macrophages, and was thus selected for antileishmanial activity tests with intracellular infected macrophages, the results of which showed the 500 µg.mL −1 concentration inhibited 62% and 54% of L. (V.) guyanensis and L. (L.) amazonensis amastigotes survival, respectively [80].

Antiproliferative and Apoptotic Effects
C. ferrea fruit ethanol extracts were evaluated for their antiproliferative effects on human colorectal cancer cells (HT-29), with a potential for inhibiting cancer cell proliferation being observed for extracts with 40, 60, and 80% ethanol, where the following results can be highlighted: 15-25% proliferation inhibition between 25 and 100 µg/mL doses of the 40% ethanolic extract, while the 60% ethanolic extract showed a 50% rate of proliferation inhibition at the 25 µg/mL dose, and the 80% ethanolic extract showed 43.7% inhibition at the 12.5 µg/mL dose, where all of results were observed in the first 24 h of the experiment. During this same period, the extracts did not present embryonic renal cell line (HEK-293) toxicity, these being tumor-free [54].
As for apoptotic effects, the fruit extract with 40% ethanol at a 25 µg/mL dose presented a high percentage of cells undergoing apoptosis (38.7%) in the HT-29 tumor line, while the number of cells undergoing apoptosis in HEK-293 non-tumor cell line did not differ statistically from the control [54].

Anti-Wrinkle and Anti-Melanogenic Activity
The C. ferrea pod and bark ethanolic extract showed high elastase inhibitory activity, with 35.99% inhibition at 250 µg/mL for the bark extract and 19.6% for the pod extract. In terms of collagenase activity, the extracts did not show significant inhibitory potentials, whereas for hyaluronidase, the two extracts obtained better inhibitory potentials than the control [53].
The anti-melanogenic effect of the two extracts were analyzed in B16F10 cells (murine melanoma), where the cells were pre-treated with 3-isobutyl-1-methylxanthine (IBMX) and showed an increase in tyrosinase activity before receiving treatment with the extracts at the 25 µg/mL concentration for 48 h. After treatment with the extracts, significant reductions of 99.0 and 96.4% in tyrosinase activity were observed when treated with the bark and pod extracts, respectively [53]. Tests analyzing the photoprotective activity of the bark ethanolic extract demonstrated a sun protection factor (SPF) of 3.29 at the 0.100 mg/mL concentration [6].

Anti-Hyperglycemic Activity
A galactomannan extracted from C. ferrea seeds demonstrated an anti-hyperglycemic activity when orally administered to streptozotocin-induced diabetic rats at a 10 mg/kg dose. During the first days of treatment, a reduction in blood glucose and blood triacylglycerol levels was observed, in addition to a boost in adipose tissue insulin sensitivity, contributing to the functional recovery of the tissue [65].
Oral administration of the C. ferrea leaf ethanolic extract also showed anti-hyperglycemic activity in streptozotocin-induced diabetic rats, reducing liver function levels, elevated serum glucose and a-amylase, while, in contrast, increasing serum insulin levels, total proteins and body weight [9].

Hypolipidemic Effects
The C. ferrea leaf hydroethanolic extract was evaluated for its in vitro hypolipidemic effect on the activity of HMG CoA-reductase, an enzyme responsible for cholesterol biosynthesis. The extract showed an enzymatic inhibitory activity of 86%, a result similar to that of the medication Lipantil used as the positive control. In in vivo tests with Wistar rats, the group treated with the extract showed significant reductions in total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and total lipids of 53.08, 25.03, 48.84 and 23.28%, respectively, while HDL-C showed a significant increase of 158.71% compared to the untreated group, that is, the hypercholesterolemic group. Histopathological analyzes showed that rats treated with the extract had normal-looking livers and a very mild presence of congestion and degenerative changes [50].

Toxicity
Pregnant rats treated with C. ferrea bark and seed extracts showed changes in some biochemical parameters, among which increases in creatinine levels in the maternal serum stood out when compared to the control. Additionally, the group of rats exposed to the seed extract presented amniotic fluid rich in glucose and aspartate aminotransferase and low levels of calcium, which as a result, the fetuses had shorter head and body section lengths when compared to the control, as well as exhibiting visceral and skeletal anomalies [59].
No behavioral changes were observed through toxicological tests using adult zebrafish (Danio rerio) as a model organism when these were exposed to the C. ferrea fruit ethanolic extract, however, histopathological analyzes of different tissues showed changes in their gills, intestines, and livers. In contrast, assays using 25, 50, and 125 mg/L concentrations of the extract showed embryonic lethality rates of 30, 33.3, and 10%, respectively, while higher concentrations (250 and 500 mg/L) triggered edema in the heart, yolk sac and scoliosis [1]. Meanwhile, the bark hydroalcoholic extract showed an LC 50 of 822.6334 µg/mL in the toxicity evaluation assay over Artemia salina L., this being considered a low toxicity [81]. The evaluation of the C. ferrea leaf ethanolic extract toxicity demonstrated a non-toxic profile, since the rats subjected to the extract did not exhibit significant behavioral changes, neurological responses or mortality rates in any of the doses until the end of the assays [9]. Similar results were found in the acute toxicity evaluation of the fruit ethanol extract and the pod hydroalcoholic extract in Wistar rats, with a lethal dose (LD) greater than 2000 mg/kg for the pod extract [12,61].

Genotoxicity
The genotoxic activity of the C. ferrea seed ethanol extract on Astyanax sp. erythrocytes was measured through the comet assay, where the tail length increased the level of DNA breaks in red cells by 2.5× when exposed to 5, 10, and 20 mg/L doses compared to the negative control; thus, demonstrating a genotoxic potential over Astyanax sp. erythrocytes, in addition, a clastogenic response following exposure to the 20 mg/L dose, as evidenced by a decrease in tail length [82].

Cytotoxicity
The cytotoxic potential of the C. ferrea leaf hydroethanolic extract over human cancer cell lines (liver HepG2, breast MCF-7, colon HCT-116, larynx Hep2 and prostate PC3) was analyzed using the sulforhodamine B (SRB) assay. The results showed the extract presented cytotoxic activity over the five tumor cell lines analyzed with an IC 50 of 19.3 µg/mL for the HepG-2 liver cell line, this being considered the most efficient cytotoxic activity. As for the other lines, larynx Hep2, breast MCF-7, and colon HCT-116, IC 50 values of 20, 21.8, and 24.47 µg/mL, respectively, were obtained, while a negative cytotoxic activity was observed with the PC3 prostate cell line [49].
The 2"-O-galloylvitexin compound was isolated from the C. ferrea leaf hydroethanolic extract and was analyzed for its cytotoxicity potential over the aforementioned strains using the same methodology, presenting similar results with more effective cytotoxic activity on the HepG-2 liver cell line with an IC 50 of 18.5 µg/mL, followed by the HCT-116 colon, Hep2 larynx, and MCF-7 breast cell lines with IC 50 values of 22.6, 24.2, and 28.4 µg/mL, respectively [49].
The cytotoxicity of the C. ferrea bark and pod ethanolic extracts were evaluated against B16F10 cells (murine melanoma) and normal human fibroblasts (NHF). The pod extract obtained an IC 50 of 50.1 µg/mL for the B16F10 cells after the 48-h treatment period, while the bark extract showed a 47% viability percentage of B16F10 cells. Neither extract presented significant cytotoxicity in over NHF [53].
The cytotoxicity potential of galactomannan extracted from C. ferrea seeds was evaluated, in vitro, in human neutrophils through the lactate dehydrogenase (LDH) assay, where it is possible to detect cell death, such as necrosis. The results showed that galactomannan did not increase LDH activity at any of the analyzed concentrations (10-200 µg/mL) when compared to the negative control data [65]. Assays with sulfated galactomannans at concentrations of 25, 50, and 100 g/mL also did not show cytotoxicity in Vero cells [100].
The C. ferrea pod aqueous extract exhibited cytotoxicity over meristematic cells from Allium cepa roots, inhibiting cell division at concentrations of 1 g/500 mL and 1 g/1000 mL following 24 and 48 h of exposure. Moreover, the extract showed a cytoprotective effect at both concentrations in tests used to evaluate their cytoprotective potential in cells treated with paracetamol at a concentration of 0.008 mg/mL. In addition, the extract did not contribute to the antiproliferative activity caused by a mutagenic compound in meristematic cells from A. cepa roots [83].

Cicatrizing Activity
Powder and ointment formulations developed from C. ferrea pods were evaluated for their cicatrizing potential in clean rabbit (Oryctolagus cuniculus) wounds, following three times a day administration. The results showed that animals treated with the 24% ointment showed a better lesion area percentage inhibition, while inefficiency at reducing the final cicatrizing period was observed with the other treatments [84].
C. ferrea bark extracts that are rich in polysaccharides at concentrations of 0.025, 0.05, 0.75, and 0.1% decreased the wound area and increased wound contraction in Wistar rats, in addition to reducing the infiltration of inflammatory mediators, such as TNF-α and IL-1β, contributing to the acceleration of the wound healing process, as evidenced by the presence of attenuated clinical signs (edema, hyperemia, exudate). Likewise, ulcers treated with the extract showed the formation of organized connective tissue and collagen deposition, as well as a layer of epithelial tissue protecting the granulation tissue [58].
Positive results were found for the wound cicatrizing process in Wistar rats using the C. ferrea pod powder, with a significant reduction in the lesion area occurring and the wounds drying with no exudate from the third day of treatment, exhibiting a regular, thick crust with the presence of mononuclear red blood cells and fibrin, in the form of a blood clot at the edges of the wound [85].
Cutaneous wound treatment in Wistar rats with the C. ferrea fruit ethanolic extract stimulated the formation of dark brown to black crusts over the wounds of treated animals at concentrations of 50 and 12.5%, where crust detachment was also observed during topical treatment days with the extract. In the group treated with the extract at a concentration of 12.5%, all animals exhibited a constituted epidermis, this being more efficient at skin wound treatment in rats than the 50% concentration [61].
Diabetic and non-diabetic Wistar rats with lesions induced by thermal contact were treated with the C. ferrea bark hydroalcoholic extract incorporated with bacterial nanocellulose membranes, where the non-diabetic rat group exhibited epithelialization after 14 days of treatment, while the remaining animals presented epithelialization after 21 days of treatment [67].

Repellent Action
The repellent action of the C. ferrea fruit bark powder against fly species from the Calliphoridae family was analyzed using traps containing deteriorating bovine liver as an attractant for the flies. The treatments that had the powder at the 20 and 50% tested concentrations presented a higher repellency percentage of 97.5 and 100%, respectively [88].

Insecticidal Activity
The insecticidal activity of the C. ferrea leaf hydroalcoholic extract was evaluated using Aphis craccivora (black aphid) nymphs, which demonstrated the 5% concentration showed insecticidal activity with 51.71% efficiency [90]. The insecticidal activity of the leaf and pod aqueous and methanolic extracts against Dactylopius opuntiae ("Cochonilha-do-carmin") were also verified, with a 72.46-99.33% of adult female mortality being observed [91]. Results using the same extract and D. opuntiae demonstrated LC 50 values ranging from 20-150 mg/mL for the nymphs and 43-50 mg/mL for the adults, while other tests using termites as a study model (Nasutitermes corniger) presented LC 50 values ranging from 0.255-1.279 mg·mL −1 for the workers and 0.146-8.003 mg·mL −1 for the soldiers [89,92].

Fertilizer
The C. ferrea leaf litter was used to evaluate its fertilizing potential against Sorghum bicolor L. (Sorgo) cultures, where following a period of 75 days the C. ferrea litter increased potassium, calcium, and magnesium soil content; however, it did not increase the dry matter production of the S. bicolor L. aerial part [95].

Allelopathic Potential
The C. ferrea seed hydroalcoholic extract presented a 30% rate of abnormal melon seedlings (Cucumis melo L.) at the highest concentration (1%), where the seedlings had imperfect roots, including the absence of absorbent hair, a necrotic, dark, and hard apex, in addition to negative gravitropism. The leaf hydroalcoholic extract on the other hand contributes to the growth of the melon seedling aerial parts at the highest tested concentration (1%), while it negatively interfered with root growth compared to the control [96].
Decomposing C. ferrea leaves exhibited an allelopathic potential over Vigna unguiculata L. seedlings, affecting the length of the aerial part and root system, as well as the total seedling dry mass [97]. The hot leaf, bark, and root extracts exhibited allelopathic potential over Calotropis procera, preventing its germination, while Cenchrus echinatus germination was inhibited by the hot leaf extract [48].

Biosorbent
Tests with a biosorbent produced from C. ferrea fruits used to remove methylene blue from aqueous media showed rapid kinetics coupled to good adsorption, demonstrating that the fruits can become an excellent lower cost alternative used for the removal of pollutants in wastewater [98]. Activated coals prepared from pod waste showed a removal percentage of up to 97.67% of the pharmaceutical captopril from aqueous media [99].

Other Bioactivities
The C. ferrea stem bark tea presented an erosive potential on human third molars, with a pH value of 0.28 ± 0.05, this being considered close to the pH value that promotes tooth enamel demineralization, with 37.03% of enamel demineralization [87].
The pod hydroalcoholic extract showed an antimetastatic potential, since it decreased the migration of ACP02 cells (gastric adenocarcinoma) following 24 h of treatment, presenting a dose-response effect that increased from 50 µg/mL concentrations [56]. The C. ferrea seed aqueous extract did not have the potential to inhibit hemorrhages induced by Bothrops jararaca venom in Swiss mice [62].
Polysaccharide extracts from C. ferrea leaves, pods and barks showed an edematogenic effect in Wistar rats at 0.01-1 mg/kg doses, with these effects being inferior to those developed by the drugs used as control (carrageenan and dextran) [86].

Materials and Methods
The plant's name was checked on the www.theplantlist.org/ (The List Plant) website to check for synonyms. For data collection, a comprehensive article search was performed using the Scopus, Periódicos Capes, PubMed, Google Scholar, and ScienceDirect databases, using the following descriptors: Caesalpinia ferrea and its synonym Libidibia ferrea. Studies published between 2015 and March 2020 were reviewed. Full-text articles were selected if the title, abstract, or keywords included the aforementioned descriptors.
Articles duplicated between the search engines, as well as review articles, were removed in the first step. The remaining articles were then selected based on their title, abstract, and keywords. Lastly, full articles were analyzed according to the following criteria (1): botanical aspects; (2): phytochemistry; (3): ethnobotanical uses; (4): bioactivities; (5): bioactivities of compounds isolated from C. ferrea. The chemical structures of the isolated secondary metabolites of this plant were drawn using the software ChemDraw Ultra 7.0.

Critical Analysis
Phytochemical investigations are fundamental for understand the chemical basis of the compounds from medicinal plants; however, many of these studies still use colorimetric techniques that have limitations. By this fact, is necessary the usage of metabolomic techniques to trace the phytochemical profiles. The phytocompounds of C. ferrea have a wide range of therapeutic properties, however only few compounds were isolated and evaluated by in vivo and in vitro assays, as evidenced in this review. The studies that evaluated pharmacological activities did not show results about the mechanisms of action of the crude extracts and the isolated compounds. By this fact, investigations to evaluate the toxicological in vivo effects are necessary to understand the pharmacokinetic and pharmacodynamic mechanisms of these products. Pharmacological studies have focused on the antibacterial, antioxidant, anti-inflammatory, antihyperglycemic and healing effects, demonstrating the ethnomedicinal uses of this plant. However, many traditional uses are not supported to experimental results, as the effects against malaria, anemia, and the calming properties of this plant.

Conclusions
In this work, we reported the ethnobotanical, phytochemical, and pharmacological aspects of C. ferrea. This medicinal plant is used in traditional practices to treat certain diseases and has interesting biological properties. Different pharmacological assays had demonstrated antibacterial, antioxidant, anti-inflammatory, anti-diabetic, and healing activities. However, these pharmacological investigations have focused mainly on the organic fractions of the crude extracts, with few attentions to the aqueous extracts, since that are the mainly used formulations. Another point is the necessity of more comprehensive clinical trials. Regarding the phytochemical analysis of this species, different compounds as flavonoids, polyphenols, terpenoids, tannins, saponins, steroids, and other phenolic compounds were reported. However, the reports about the pharmacological properties cited in this review have not demonstrated the mechanisms molecular of C. ferrea extracts. Therefore, it is necessary to develop new research to establish a link between traditional uses and pharmacological activities, mainly studies to determine the toxicological profile of C. ferrea.