In Vitro and Molecular Docking Evaluation of the Anticholinesterase and Antidiabetic Effects of Compounds from Terminalia macroptera Guill. & Perr. (Combretaceae).

Alzheimer's disease (AD) and diabetes are non-communicable diseases with global impacts. Inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are suitable therapies for AD, while α-amylase and α-glucosidase inhibitors are employed as antidiabetic agents. Compounds were isolated from the medicinal plant Terminalia macroptera and evaluated for their AChE, BChE, α-amylase, and α-glucosidase inhibitions. From 1H and 13C NMR data, the compounds were identified as 3,3'-di-O-methyl ellagic acid (1), 3,3',4'-tri-O-methyl ellagic acid-4-O-ß-D-xylopyranoside (2), 3,3',4'-tri-O-methyl ellagic acid-4-O-ß-D-glucopyranoside (3), 3,3'-di-O-methyl ellagic acid-4-O-ß-D-glucopyranoside (4), myricetin-3-O-rhamnoside (5), shikimic acid (6), arjungenin (7), terminolic acid (8), 24-deoxysericoside (9), arjunglucoside I (10), and chebuloside II (11). The derivatives of ellagic acid (1-4) showed moderate to good inhibition of cholinesterases, with the most potent being 3,3'-di-O-methyl ellagic acid, with IC50 values of 46.77 ± 0.90 µg/mL and 50.48 ± 1.10 µg/mL against AChE and BChE, respectively. The compounds exhibited potential inhibition of α-amylase and α-glucosidase, especially the phenolic compounds (1-5). Myricetin-3-O-rhamnoside had the highest α-amylase inhibition with an IC50 value of 65.17 ± 0.43 µg/mL compared to acarbose with an IC50 value of 32.25 ± 0.36 µg/mL. Two compounds, 3,3'-di-O-methyl ellagic acid (IC50 = 74.18 ± 0.29 µg/mL) and myricetin-3-O-rhamnoside (IC50 = 69.02 ± 0.65 µg/mL), were more active than the standard acarbose (IC50 = 87.70 ± 0.68 µg/mL) in the α-glucosidase assay. For α-glucosidase and α-amylase, the molecular docking results for 1-11 reveal that these compounds may fit well into the binding sites of the target enzymes, establishing stable complexes with negative binding energies in the range of -4.03 to -10.20 kcalmol-1. Though not all the compounds showed binding affinities with cholinesterases, some had negative binding energies, indicating that the inhibition was thermodynamically favorable.

In vivo validation of anti-malarial activity of crude extracts of Terminalia macroptera, a Malian medicinal plant.

BACKGROUND: Plasmodium falciparum malaria is still one of the most deadly pathology worldwide. Efficient treatment is jeopardized by parasite resistance to artemisinin and its derivatives, and by poor access to treatment in endemic regions. Anti-malarial traditional remedies still offer new tracks for identifying promising antiplasmodial molecules, and a way to ensure that all people have access to care. The present study aims to validate the traditional use of Terminalia macroptera, a Malian plant used in traditional medicine. METHODS: Terminalia macroptera was collected in Mali. Leaves (TML) and roots ethanolic extracts (TMR) were prepared and tested at 2000 mg/kg for in vivo acute toxicity in Albino Swiss mice. Antiplasmodial activity of the extracts was assessed against a chloroquine resistant strain P. falciparum (FcB1) in vitro. In vivo, anti-malarial efficacy was assessed by a 4-day suppressive test at 100 mg/kg in two malaria murine models of uncomplicated malaria (Plasmodium chabaudi chabaudi infection) and cerebral malaria (Plasmodium berghei strain ANKA infection). Constituents of TMR were characterized by ultra-high-performance liquid chromatography coupled to high resolution mass spectrometry. Top ranked compounds were putatively identified using plant databases and in silico fragmentation pattern. RESULTS: Lethal dose of TML and TMR were greater than 2000 mg/kg in Albino Swiss mice. According to the OECD's Globally Harmonized System of Classification, both extracts are non-toxic orally. Antiplasmodial activity of T. macroptera extracts was confirmed in vitro against P. falciparum FcB1 strain with IC50 values of 1.2 and 1.6 µg/mL for TML and TMR, respectively. In vivo, oral administration of TML and TMR induced significant reduction of parasitaemia (37.2 and 46.4% respectively) in P. chabaudi chabaudi infected mice at the 7th day of infection compared to untreated mice. In the cerebral malaria experimental model, mice treated with TMR and TML presented respectively 50 and 66.7% survival rates at day 9 post-infection when all untreated mice died. Eleven major compounds were found in TMR. Among them, several molecules already known could be responsible for the antiplasmodial activity of the roots extract of T. macroptera. CONCLUSIONS: This study confirms both safety and anti-malarial activity of T. macroptera, thus validating its traditional use.

Antipsychotic-like effect of ethyl acetate fraction of Terminalia macroptera leaf in mice.

Psychosis is a chronic neuropsychiatric disorder that affects millions of individuals worldwide and impairs the quality of life and productivity of the patients. Terminalia macroptera Guill & Perr. (Combrataceae) is a plant that is used in the management of anxiety related disorders. The present study investigates the antipsychotic effects of ethyl acetate fraction of T. macroptera (EFTM) leaf in ketamine-induced psychosis in mice. Acute toxicity of EFTM was determine using Lorke's method. Ketamine (25 mg/kg) was injected once daily for 7 consecutive days in Swiss albino mice to induce psychosis. The effect of the extracts (100, 200 and 400 mg/kg) was evaluated against psychotic-like behaviors induced by ketamine including locomotor activity and stereotypy in the open field test, immobility duration in the forced swim test, and memory impairment using the Y- maze test. The acute antipsychotic effect of EFTM was evaluated on apomorphine climbing test, while woodblock test was performed to assess its extrapyramidal side effects. The LD50 was found to be 3807 mg/kg p.o. which is considered safe. EFTM (100, 200 and 400 mg/kg) exhibited significant antipsychotic effect by reducing ketamine-induced hyperactivity, immobility, and memory deficit in mice, EFTM also suppressed stereotypic climbing behavior due to apomorphine. Accordingly, the antipsychotic activity of EFTM was not associated with extrapyramidal side effects as evidenced by lack of catalepsy. The study revealed that EFTM ameliorated psychotic-like symptoms and is devoid of extrapyramidal side effects in mice, underscoring its antipsychotic-like effect.

Ethnopharmacology, Chemistry and Biological Properties of Four Malian Medicinal Plants.

The ethnopharmacology, chemistry and pharmacology of four Malian medicinal plants, Biophytum umbraculum, Burkea africana, Lannea velutina and Terminalia macroptera are reviewed. These plants are used by traditional healers against numerous ailments: malaria, gastrointestinal diseases, wounds, sexually transmitted diseases, insect bites and snake bites, etc. The scientific evidence for these uses is, however, limited. From the chemical and pharmacological evidence presented here, it seems possible that the use in traditional medicine of these plants may have a rational basis, although more clinical studies are needed.

Immunomodulating pectins from root bark, stem bark, and leaves of the Malian medicinal tree Terminalia macroptera, structure activity relations.

The root bark, stem bark, and leaves of Terminalia macroptera were sequentially extracted with ethanol, 50% ethanol-water, and 50°C water using an accelerated solvent extractor (ASE). Six bioactive purified pectic polysaccharide fractions were obtained from the 50°C crude water extracts after anion exchange chromatography and gel filtration. The root bark, stem bark, and leaves of T. macroptera were all good sources for fractions containing bioactive polysaccharides. The high molecular weight fraction 50WTRBH-I-I, being the most active fraction in the complement fixation test, has a highly ramified rhamnogalacturonan type I (RG-I) region with arabinogalactan type II (AG-II) side chains. The most abundant fractions from each plant part, 50WTRBH-II-I, 50WTSBH-II-I, and 50WTLH-II-I, were chosen for pectinase degradation. The degradation with pectinase revealed that the main features of these fractions are that of pectic polysaccharides, with hairy regions (RG-I regions) and homogalacturonan regions. The activity of the fractions obtained after pectinase degradation and separation by gel filtration showed that the highest molecular weight fractions, 50WTRBH-II-Ia, 50WTSBH-II-Ia, and 50WTLH-II-Ia, had higher complement fixation activity than their respective native fractions. These results suggest that the complement fixation activities of these pectins are expressed mainly by their ramified regions.

Complement activity of polysaccharides from three different plant parts of Terminalia macroptera extracted as healers do.

ETHNOPHARMACOLOGICAL RELEVANCE: Water decoctions of the root bark, stem bark and leaves of Terminalia macroptera are used by traditional healers in Mali to cure a wide range of illnesses, such as wounds, hepatitis, malaria, fever, cough and diarrhea as well as tuberculosis. Plant polysaccharides isolated from crude water extracts have previously shown effects related to the immune system. The aims of this study are comparing the properties of the polysaccharides among different plant parts, as well as relationship between chemical characteristics and complement fixation activities when the plant material has been extracted as the traditional healers do, with boiling water directly. MATERIALS AND METHODS: Root bark, stem bark and leaves of Terminalia macroptera were extracted by boiling water, and five purified polysaccharide fractions were obtained by anion exchange chromatography and gel filtration. Chemical compositions were determined by GC of the TMS derivatives of the methyl-glycosides and the linkage determined after permethylation and GC-MS of the derived partly methylated alditol acetates. The bioactivity was determined by the complement fixation assay of the crude extracts and purified fractions. RESULTS: The acidic fraction TRBD-I-I isolated from the root bark was the most active of the fractions isolated. Structural studies showed that all purified fractions are of pectic nature, containing rhamnogalacturonan type I backbone. Arabinogalactan type II side chains were present in all fractions except TRBD-I-II. The observed differences in complement fixation activities among the five purified polysaccharide fractions are probably due to differences in monosaccharide compositions, linkage types and molecular sizes. CONCLUSION: The crude extracts from root bark and stem bark have similar total activities, both higher than those from leaves. The root bark, leaves and stem bark are all good sources for fractions containing bioactive polysaccharides. But due to sustainability, it is prefer to use leaves rather than the other two plant parts, and then the dosage by weight must be higher when using leaves.

Enzyme inhibition, antioxidant and immunomodulatory activities, and brine shrimp toxicity of extracts from the root bark, stem bark and leaves of Terminalia macroptera.

ETHNOPHARMACOLOGICAL RELEVANCE: The root bark, stem bark and leaves of Terminalia macroptera have been traditionally used against a variety of ailments such as wounds, hepatitis, malaria, fever, cough, and diarrhea as well as tuberculosis and skin diseases in African folk medicine. Boiling water extracts of Terminalia macroptera, administered orally, are the most common preparations of this plant used by the traditional healers in Mali. This study aimed to investigate the inhibition of the activities of α-glucosidase, 15-lipoxygenase and xanthine oxidase, DPPH scavenging activity, complement fixation activity and brine shrimp toxicity of different extracts obtained by boiling water extraction (BWE) and by ASE (accelerated solvent extraction) with ethanol, ethanol-water and water as extractants from different plant parts of Terminalia macroptera. MATERIALS AND METHODS: 27 different crude extracts were obtained by BWE and ASE from root bark, stem bark and leaves of Terminalia macroptera. The total phenolic and carbohydrate contents, enzyme inhibition activities (α-glucosidase, 15-lipoxygenase and xanthine oxidase), DPPH scavenging activity, complement fixation activity and brine shrimp toxicity of these extracts were evaluated. Principal component analysis (PCA) was applied for total biological activities evaluation. RESULTS: Several of the extracts from root bark, stem bark and leaves of Terminalia macroptera obtained by BWE and ASE showed potent enzyme inhibition activities, radical-scavenging properties and complement fixation activities. None of the extracts are toxic against brine shrimp larvae in the test concentration. Based on the results from PCA, the ASE ethanol extracts of root bark and stem bark and the low molecular weight fraction of the 50% ethanol-water extract of leaves showed the highest total biological activities. The boiling water extracts were less active, but the bark extracts showed activity as α-glucosidase inhibitors and radical scavengers, the leaf extract being less active. CONCLUSION: The observed enzyme inhibition activities, radical scavenging properties and complement fixation activities may explain some of the traditional uses of this medicinal tree, such as in wound healing and against diabetes.