A Review on ethnobotanical uses, biological activities and phytochemical aspects of Acacia senegal (L.) Willd. and Acacia seyal Delile. (Fabaceae)

The genus Acacia is a group of tropical plants species used in folk medicine due to virtue of its many therapeutic properties. In this document, we review the Ethnopharmacology, biological and phytochemical activities of the two major plant species used. Although, several researchers has been done, Acacia senegal (L.) Willd. and Acacia seyal Delile. are among the species of the genus for which phytochemical study is limited, few bioactive compounds and properties described. Based on these current traditional uses, it is necessary to carry out more biochemical and pharmaceutical assays in order to identify the precise ingredient that supports the recommendation in traditional medicine. The characterization of the active compound that plays a role for treating human diseases (infection, cancer, etc.) represents a key step in phytochemical research of new compounds. Moreover, this information about the active compound will help the clinician/pharmacist to define a rational and combined use with the synthetic molecules for which resistance mechanisms are currently reported in clinical cases.


Introduction
Traditional medical practices vary from country to country and region to region, and are influenced by several factors including culture, history, attitudes and personal philosophy [1]. The renewed interest over the centuries and the transmission of experience from generation to generation are proof of the safety and effectiveness of this medicine. The lack of health care centers in remote areas, often linked to the high cost of conventional medicines, means that 80% of people in African countries use traditional medicine for their primary health needs [2]. Nowadays, developing countries such as Burkina Faso are adopting policies to promote traditional recipes through collaboration between health practitioners and traditional healers. Today, infectious diseases are the leading cause of death in the world and antibiotic resistance has become a global concern [3]. The emergence and spreading of pathogens that present resistance to many if not for all clinically used antibiotics has led WHO to classify them as a human health priority [4][5][6]. Therefore, researchers are increasingly turning to medicinal plants in search of new approaches to develop new effective drugs against microbial infections. The screening of potential antimicrobial activity of active molecules from medicinal plants is of concern [7]. Some recent reviews point on the possible use of natural products to combat multidrug resistant bacteria (for an example see. Interestingly, Acacia senegal (L.) Willd. and Acacia seyal (Del.), of the Fabaceae-Mimosoideae family, are well known in traditional medicine and often used in combination with other plants to combat microbial infections [12][13][14]. The available knowledge on these plants was searched using the keywords Acacia senegal (L.) Willd. and Acacia seyal Del. in the databases 'Google scholar', 'NCBI', 'Springer Link', Free Scientific Publications' and' Web of Science'. Their properties are of a major interest in the research and development of new active molecules targeting multidrug resistant pathogens or the identification of adjuvant that can restore the antibiotic activity in resistant bacteria. This review summarizes the current knowledge regarding these two plants and presents some perspectives for a future study and application about their antimicrobial properties to combat antibiotic resistance.

Taxonomy of Fabaceae
Leguminosae Fabaceae previously identified and described by Adanson and de Jussieu are subdivided into three sub-families including Caesalpinioideae, Mimosoideae and Papilionoideae [15][16][17]. With about 765 genera and more than 19500 species, Fabaceae, constitute the third most important plant family [18,19]. The species in this family are well distributed in all tropical and warm temperate regions of the world. Recent data indicated that the Legume Phylogeny Working Group has subdivided the Fabaceae into six sub-families instead of three, namely Cercidoideae (12 genera, 335 species), Detarioideae (84 genera, 335 species), Detarioideae (84 genera, 335 species) and Cercidoideae (84 genera, 760 species), Duparquetioideae (1 genus, 1 species), Dialioideae (17 genera, 85 species), Caesalpinioideae (148 genera, 4400 species; includes genera of the Mimosoideae) and Papilionoideae with 503 genera, and 14,000 species [20,21]. Acacia genus belongs to the subfamily of Mimosoideae and is the second most important genus in the Fabaceae family, with about 1350 species currently recognized. The highest concentrations of Acacia sp. are found in Australia (955 species), with high numbers also in America (about 185 species), Africa (144 species) and Asia (89 species) [22,23]. This family represents an important source of molecules that are involved in the treatment of various diseases.  The Fabaceae family is an important source of biologically active molecules. However, few species have been examined specifically for these substances; in fact, the secondary metabolites of only a small proportion of Acacia species have been examined in detail [81]. Acacia senegal and Acacia seyal are among the few that have been studied.

Acacia senegal
The data contained in Table 3 summarize the biological activities and molecules or groups of molecules that have been informed by the different authors about Acacia senegal (L) Willd. and their supposed involvement in biological activities. The dichloromethane extract from the root wood of A. senegal showed good activity against two bacterial species, E. coli and S. aureus while the ethanolic extract, dichloromethane and ethyl acetate showed significant antifungal activity against C. albicans. From the wood of the root, ten molecules were isolated, including eicosanyl 3-Oferuloyl-quinate, isolated from nature for the first time. The molecules of 3αhydroxyeuph-25-ene and α-amyrin were isolated for the first time from this species [82]. The α-amyrin and its derivatives have presented various biological activities e.g. anti-HIV and anti-acyl coenzyme A: cholesterol acyltransferase (ACAT) activities [83]. Other authors have reported the antifungal activity of β-sitosterol isolated from the methanolic fraction of M. azedarach leaves against Ascochyta rabiei [84]. A recent study demonstrated by bio-autographic analysis that extracts of A. senegal leaves (Acetone, chloroform, ethanol and petroleum ether) possesses antioxidant derivatives (DPPH) and an antibacterial activity against Pseudomonas aeruginosa. Analysis revealed antibacterial activity of four fractions of acetone extract, four fractions of chloroform extract, two fractions of ethanolic extracts and four fractions of petroleum-ether extracts. The phytochemical compounds present in the extracts are glycosides, alkaloids and flavonoids. In addition, ethanolic extract was the richest in secondary metabolites and the antibacterial and oxidative activity observed is believed to be related to the presence of its compound groups [85]. However, to date, no molecules have been isolated and identified from the various fractions and certified to be responsible for the activity. Furthermore, methanol and ethanol extracts from the trunk bark of A. senegal showed antibacterial activity against K. pneumoniae, Proteus vulgaris, Salmonella typhi, Salmonella dysenteriae and E. coli. According to the authors, the tannins and saponins contained in the extracts are responsible for the observed activity. In addition, toxicity studies of ethanolic extract from stem bark revealed any significant toxicity against Artemia salina [86]. According to some authors, the hexanic fraction of A. senegal stem bark is active against respiratory pathogenic bacteria including Klebsiella pneumonia and Streptococcus pneumoniae [87]. Page: 41 www.raftpubs.com activity against Bacillus cereus and Salmonella enteritidis [92]. Ethanolic extract from the leaves of A. senegal has decreased the activity of the sucrose enzyme and appears to facilitate the control of carbohydrate hydrolysis and therefore reduces postprandial increases in blood glucose levels in diabetics [93]. Ethyl acetate extract from the bark of the stem of A. senegal significantly reduced blood glucose, serum TC, serum TTG, serum LDL, serum urea and creatinine levels, and increased serum HDL levels in alloxane-induced diabetic albino rats [94]. Neutral sugar gums (rhamnose, arabinose and galactose), acids (glucuronic acid and 4methoxyglucuronic acid), calcium, magnesium, potassium and sodium have been identified [26]. 70 % ethanol Neurotoxicity [96]) Hepatotoxicity However, the study did not pay any attention to the relationship between activity and the chemical compounds produced by the gum. Methanolic extract from the bark of the stem showed 100% mortality against adult Fasciola gigantica worms in vitro at concentrations of 1000, 500 and 250 ppm after 6, 12 and 24 hours respectively [95]. A recent study evaluated the efficiency of Acacia senegal extracts against in improving DEHP-induced liver and brain toxicity. Sprague Dawley rats in which acute hepatotoxicity and neurotoxicity was induced by Di-2-Ethylhexyl phthalate (DEHP), received as oral treatment ethanolic extract at 70% of A. senegal pods for 28 days under several conditions. The results showed that the extract of A. senegal has an ameliorative effect by restoring the activities of antioxidant enzymes to normal by reducing the level of LPO in both tissues. Also, the extract improved the levels of cerebral amino acids, monoamines and their metabolites [96].

Acacia seyal
Table 4 also summarizes the molecules or groups of molecules identified from Acacia seyal (Del.). Ethanolic extracts (leaves, root bark and trunk) and dichloromethane from Acacia seyal showed interesting activity against Klebsiella pneumoniae [99]. Previous work on other species of the same genus (Acacia nilotica (L.) Willd ex Del., Acacia sieberiana DC.) has shown good antibacterial activity against Escherichia coli and Klebsiella pneumoniae [99]. Many authors have reported of acacia genus, many biologically active compounds e.g. ethyl gallate, octasanol, β-amyrin, α-betulin and flavonoids [100,101]. Concerning A. seyal, we have few information on the phytochemical composition of the different parts. However, the authors attribute the activity found by the species to the presence of similar compounds. The methanolic extract from the bark showed good antibacterial activity. Four compounds were isolated (epicatechin, catechin, digallic catechin and β-sitosterol) and tested for their activities. The author indicated that the activity of the isolated compounds was less interesting compared to totum [102]. This shows a synergy of activity between the compounds. In addition, different teams have reported the activity of βsitosterol on inhibiting the growth of S. aureus and E. coli [103,104]. Methanolic extract from the leaves of A. seyal reduced the incidence of green mold (Penicillium digitatum) by 56.1% on fruits inoculated per injury. The extract of A. seyal revealed a high content of gallic acid, salicylic acid, p-coumaric acid, caffeic acid, 3,4 dihydroxy benzoic acid, ferulic acid [105]. Isolated p-coumaric acid from Nauclea pobeguinii (Pobeg.) Merr. did not activate against bacteria tested (E. coli, E. aerogenes, K. pneumoniae, P. aeruginosa, P. stuartii) at a concentration of 256 µg/mL [106]. In other hand, researchers have reported that caffeic and p-coumaric acid cause membrane damage of 44% and 59%, respectively, in Gram-positive bacteria, Oenococcus oeni [107]. Also, p-cumaric and ferulic acids have shown synergistic activity with amikacin against E. coli, E. aerogenes and S. aureus [108]. Ethyl gallate has shown antibacterial activity and synergistically when combined with tetracycline and fusidic acid against specific resistant and methicillin-sensitive strains of Staphylococcus aureus [109]. Ethanolic extracts (leaves, bark) and dichloromethane extract from the bark of Acacia seyal showed an activity higher than 85% with respect to the enzyme acetylcholinesterase. Alkaloids are known to have many pharmacological properties, including inhibition of acetylcholinesterase enzyme activity and the author associate the activity with alkaloids [99]. A recent study showed that methanolic extract from the bark of A. seyal showed 100% mortality against Biomphalaria Pfeifferi at different doses used [110]. The root extract of A. seyal has demonstrated antimicrobial activity against fungal and bacterial pathogens [111]. The cytotoxic study of the hydroethanolic extract of the stem bark of A. seyal to reduce the protein content of Bcl-xL and Bcl-2 which in turn promotes the intrinsic induction of apoptosis. In addition, the phytochemical analysis of this extract shows that it is rich in pro-apoptotic components such as flavonoids [112]. The structure of the gum of A. senegal (L.) and A. seyal has recently been revised by methylation analysis and nuclear magnetic resonance (NMR) spectroscopy. It has been found that A. seyal gum is more strongly branched than A. senegal and is composed of galactopyranosyl bound to 1,3. Galacturonic acid was recently identified for the first time in A. seyal [113] (Figure 1-5).

Conclusion
This literature review provides an opportunity to learn about the therapeutic potentialities of Acacia senegal (L.) Willd. and Acacia seyal (Delile.). Although phytochemical knowledge of both species is limited, it appears to be a rich source of various active compounds with a wide range of pharmacological and therapeutic properties. For traditional use, it has become more common for several plants to be used in combination to treat a disease. This shows that the synergy of activity is well known to traditional healers. Among the diseases traditionally managed by A. senegal and A. seyal, infectious diseases occupy a prominent place. The pharmacological activity is objectively based on empirical experience and with the recent development of tools/methods based on Omics technologies (e.g. genomic, proteomic, transcriptomic, membranomic, etc.), it is important to measure the effects of these natural compounds on the physiology and metabolism of selected targeted cells (cancer cells, parasites, bacteria). Interestingly, this panel of research will be used to characterize the antimicrobial potential of Acacia species found in Burkina Faso. With the rise of resistant infections, natural extracts could be assayed in combination with usual antibiotics on multiresistant bacterial strains (MDR) to formulate future combined therapeutic strategies. To this aim, different approaches could be envisaged in this way. For instance, today a main resistance mechanism is associated with the lack of internal concentration of active antibiotics close to its target [120]. It will be interesting to test the capability of Acacia extracts to permeabilize the bacterial membrane and improve the activity of antibiotics in resistant bacterial strains as previously reported for some other natural products [106,121,122]. Alternatively, it will be interesting to use the purified extracts in order to impair the activity of efflux pumps present in multidrug resistant bacteria that expel the antibiotic before it blocks the target [123,124]. This mode of action has been reported for different natural compounds Page: 48 www.raftpubs.com that block or inhibits the antibiotic flux across the pump channel [125][126][127]. These different perspectives are especially attractive taking into account the methods recently reported that allow measuring the drug transport across bacterial membrane [120]. Another approach can be to research some compound having new activity against bacterial physiology [128,129]. To conclude, the Acacia represents an attractive source for future development of antimicrobial compounds that could be identified and characterized using the new tools available in biochemical, physicochemical and biological domains.
RDM, HMK and AH had collected all data reported. RDM wrote the paper. AH and ADR supervised the study. All authors read and approved the final manuscript.

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