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Our prior studies have illustrated that the uracil ruthenium(II) diimino complex, [Ru(H3ucp)Cl(PPh3)] (1) (H4ucp = 2,6-bis-((6-amino-1,3-dimethyluracilimino)methylene)pyridine) displayed high hypoglycemic effects in diet-induced diabetic rats. To rationalize the anti-diabetic effects of 1, three new derivatives have been prepared, cis-[Ru(bpy)2(urdp)]Cl2 (2) (urdp = 2,6-bis-((uracilimino)methylene)pyridine), trans-[RuCl2(PPh3)(urdp)] (3), and cis-[Ru(bpy)2(H4ucp)](PF6)2 (4). Various physicochemical techniques were utilized to characterize the structures of the novel ruthenium compounds. Prior to biomolecular interactions or in vitro studies, the stabilities of 1-4 were monitored in anhydrous DMSO, aqueous phosphate buffer containing 2% DMSO, and dichloromethane (DCM) via UV-Vis spectrophotometry. Time-dependent stability studies showed ligand exchange between DMSO nucleophiles and chloride co-ligands of 1 and 3, which was suppressed in the presence of an excess amount of chloride ions. In addition, the metal complexes 1 and 3 are stable in both DCM and an aqueous phosphate buffer containing 2% DMSO. In the case of compounds 2 and 4 with no chloride co-ligands within their coordination spheres, high stability in aqueous phosphate buffer containing 2% DMSO was observed. Fluorescence emission titrations of the individual ruthenium compounds with bovine serum albumin (BSA) showed that the metal compounds interact non-discriminately within the protein's hydrophobic cavities as moderate to strong binders. The metal complexes were capable of disintegrating mature amylin amyloid fibrils. In vivo glucose metabolism studies in liver (Chang) cell lines confirmed enhanced glucose metabolism as evidenced by the increased glucose utilization and glycogen synthesis in liver cell lines in the presence of complexes 2-4.

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ETHNOPHARMACOLOGICAL RELEVANCE: The analyses of patterns of over-representation of southern African traditional medicinal plants at the genus and family level provide information about the differences in plant use among southern African countries and disease categories. 'Over-representation' refers to the phenomenon whereby the proportion of plants belonging to a taxonomic group is higher in ethnobotanical pharmacopoeia than in the total flora. AIM OF THE STUDY: This study aimed to use the Imprecise Dirichlet Model (IDM) to analyse data from ten southern African countries to establish how over-represented medicinal plant families compare with over-represented genera, how over-represented medicinal taxa differ among countries in this region of Africa, and how over-represented taxa differ among six major disease categories. MATERIALS AND METHODS: Floral data for the total species composition of each country were obtained from online databases. Medicinal plant species lists were generated from published surveys, inventories, and books. IDM calculations were executed using the inverse of the cumulative beta probability density function in Microsoft Excel™. Python programming language source code was used to calculate Pearson correlation (r) values and Jaccard coefficients (J). RESULTS: Nine of forty-two over-represented medicinal plant families in southern Africa (group 1) do not have over-represented genera. Seven of the forty genera with the highest margins of over-representation belong to under-represented families. Nineteen of the forty-two over-represented families have margins of over-representation smaller than the cumulative margins of their over-represented genera. Groups of countries with similar overall flora (J ≥ 0.333) are Botswana and Namibia (group 2), Malawi, Mozambique, Zambia and Zimbabwe (group 3). The families and genera with the highest margins of over-representation are Loganiaceae and Albizia in group 1, Combretaceae and Vachellia in group 2, Dioscoreaceae and Senna in group 3, and Sapotaceae and Solanum in group 4 (South Africa). The families and genera with the highest margins of over-representation across disease categories are Ebenaceae and Albizia, Canellaceae and Dicoma, Combretaceae and Pterocelastrus, Ebenaceae and Bersama, Francoaceae and Erythrina, and Aristolochiaceae and Strychnos for plants used in the treatment of STIs, febrile and mosquito-vector diseases, microbial infections, pain, skin conditions, and female sexual/reproductive problems, respectively. CONCLUSIONS: Genus-level calculations are more efficient in generating taxonomic lists that can be used for ethnopharmacological investigations due to the exclusion of under-represented genera. Limiting the size of geographical areas from which medicinal plant lists are sampled and targeting plants used to treat specific types of disease prevents the underestimation of niche over-represented taxa.

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Rhoicissus tridentata is one of the most frequently used plants in preparing Isihlambezo, a herbal drink consumed by many South African women to induce labour and tone the uterus in pregnancy. This study aimed to identify the uteroactive compounds in this plant. Chromatographic purification of the methanol and water extracts from the roots yielded eight compounds, i.e. morin 3-O-α-L-rhamnopyranoside, trans-resveratrol 3-O-ß-glucopyranoside, a mixture of asiatic and arjunolic acids, quercetin 3-O-rhamnopyranoside, catechin, ß-sitosterol, and linoleic acid. All compounds were evaluated for their uterotonic effects using uterine smooth muscle isolated from stilboestrol-primed Sprague-Dawley rats. The mixture of asiatic and arjunolic acids showed the highest activity with EC50 of 0.02129 µg/mL for amplitude. These results validate the use of R. tridentata in ethnomedicine to facilitate labour in childbirth. Morin 3-O-α-L-rhamnopyranoside and trans-resveratrol 3-O-ß-glucopyranoside caused a relaxation of the uterine muscle, which suggests that some compounds in R. tridentata possess opposing activities.

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Previous research shows that the root and bark extracts of Euclea natalensis have antiplasmodial activity, but the leaves have not been examined yet. This study investigated the phytochemical, antiplasmodial, and cytotoxic properties of the plant leaves. The activity against 3D7 Plasmodium falciparum was determined using the parasite lactate dehydrogenase assay, and the cytotoxicity against Vero and HeLa cells was evaluated using the MTT and resazurin assays, respectively. The bioactive compounds were isolated by chromatography, and their structures were established with spectroscopic and spectrometric techniques. The extract showed antiplasmodial activity (IC50 =25.6 µg/mL) and was not cytotoxic against Vero cells (IC50 =403.7 µg/mL). Purification of the extract afforded six flavonoid glycosides, four triterpenoids, and a coumarin. The glycosides showed antiplasmodial and cytotoxic activities, against HeLa cells, at 50 µg/mL, but the activity was reduced at 10 µg/mL. Naphthoquinones, which are among the predominant phytochemicals in the root and root bark of E. natalensis, were not detected in the leaves.

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Vachellia xanthophloea is used in Zulu traditional medicine as an antimalarial remedy. A moderate antiplasmodial activity was previously reported for extracts of the plant against D10 Plasmodium falciparum. This study aimed to identify the phytochemicals responsible for the antiplasmodial activity of the leaf extract. The compounds were isolated by chromatography and their structures were determined using spectroscopic and spectrometric methods. The antiplasmodial activity was evaluated using a parasite lactate dehydrogenase assay and cytotoxicity was determined using a resazurin assay. The ethyl acetate fraction inhibited P. falciparum with IC50 = 10.6 µg/mL and showed minimal cytotoxicity (98% cell viability at 33 µg/mL). The chromatographic purification of this fraction afforded sixteen compounds, including two new flavonoids. A 1:1 mixture of phytol and lupeol was also isolated from the hexane fraction. All the compounds were reported from V. xanthophloea for the first time. Among the isolated metabolites, methyl gallate displayed the best activity against P. falciparum (IC50 = 1.2 µg/mL), with a 68% viability of HeLa cells at 10 µg/mL. Therefore, methyl gallate was responsible for the antiplasmodial activity of the V. xanthophloea leaf extract and its presence in the leaf extract might account for the folkloric use of the plant as an antimalarial remedy.

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Previous results indicated that the methanol extract of Gardenia thunbergia has antiplasmodial activity but no compounds have ever been isolated from the plant. Therefore, this study aimed to investigate the phytochemical and antiplasmodial properties of the plant. The methanol leaf extract of G. thunbergia inhibited Plasmodium falciparum at 50 µg/mL (> 80% inhibition) and was not cytotoxic against HeLa cells. Chromatographic purification of the extract afforded a new saponin and eight other known compounds. The saponin and two flavonoid glycosides displayed non-selective antiplasmodial activity at 50 µg/mL but the activities were diminished at 10 µg/mL. The presence of the isolated compounds in the leaf extract of G. thunbergia could account for the folkloric use of the plant in treating malaria.

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Ethnobotanical surveys indicate that the Masai and Kikuyu in Kenya, the Venda in South Africa, and the Gumuz people of Ethiopia use Pappea capensis for the treatment of malaria. The present study aimed to investigate the phytochemical and antiplasmodial properties of the plant leaves. The bioactive compounds were isolated using chromatographic techniques. The structures were established using NMR, HRMS, and UV spectroscopy. Antiplasmodial activity of P. capensis leaf extract and isolated compounds against chloroquine-sensitive 3D7 P. falciparum was evaluated using the parasite lactate dehydrogenase assay. Cytotoxicity against HeLa (human cervix adenocarcinoma) cells was determined using the resazurin assay. The extract inhibited the viability of Plasmodium falciparum by more than 80% at 50 µg/mL, but it was also cytotoxic against HeLa cells at the same concentration. Chromatographic purification of the extract led to the isolation of four flavonoid glycosides and epicatechin. The compounds displayed a similar activity pattern with the extract against P. falciparum and HeLa cells. The results from this study suggest that the widespread use of P. capensis in traditional medicine for the treatment of malaria might have some merits. However, more selectivity studies are needed to determine whether the leaf extract is cytotoxic against noncancerous cells.

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ETHNOPHARMACOLOGICAL RELEVANCE: Epilepsy is one of the major chronic diseases that does not have a cure to date. Adverse drug reactions have been reported from the use of available anti-epileptic drugs (AEDs) which are also effective in only two-thirds of the patients. Accordingly, the identification of scaffolds with promising anti-seizure activity remains an important first step towards the development of new anti-epileptic therapies, with improved efficacy and reduced adverse effects. Herbal medicines are widely used in developing countries, including in the treatment of epilepsy but with little scientific evidence to validate this use. In the search for new epilepsy treatment options, the zebrafish has emerged as a chemoconvulsant-based model for epilepsy, mainly because of the many advantages that zebrafish larvae offer making them highly suitable for high-throughput drug screening. AIM OF THE STUDY: In this study, 20 medicinal plants traditionally used in South Africa to treat epilepsy were screened for anti-epileptic activity using a zebrafish larvae model. MATERIALS AND METHODS: Toxicity triaging was conducted on 120 crude extracts, 44 fractions and three isolated compounds to determine the maximum tolerated concentration (MTC) of each extract, fraction or compound. MTC values were used to guide the concentration range selection in bioactivity studies. The effectiveness of crude extracts, fractions and isolated compounds from Rauvolfia caffra Sond. in suppression of pentylenetetrazole (PTZ) induced seizure-like behaviour in a 6-dpf zebrafish larvae model was measured using the PTZ assay. RESULTS: Following a preliminary toxicity triage and bioactivity screen of crude extracts from 20 African plants used traditionally for the treatment and management of epilepsy, the methanolic extract of Rauvolfia caffra Sond. was identified as the most promising at suppressing PTZ induced seizure-like behaviour in a zebrafish larvae model. Subsequent bioactivity-guided fractionation and spectroscopic structural elucidation resulted in the isolation and identification of two tryptoline derivatives; a previously unreported alkaloid to which we assigned the trivial name rauverine H (1) and the known alkaloid pleiocarpamine (2). Pleiocarpamine was found to reduce PTZ-induced seizures in a dose-dependent manner. CONCLUSIONS: Accordingly, pleiocarpamine represents a promising scaffold for the development of new anti-seizure therapeutic compounds. Furthermore, the results of this study provide preliminary evidence to support the traditional use of Rauvolfia caffra Sond. in the treatment and management of epilepsy. These findings warrant further studies on the anti-epileptic potential of Rauvolfia caffra Sond. using other models.

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Ozoroa obovata (Oliv.) R. & A. Fern. var. obovata found in KwaZulu-Natal in South Africa was investigated for phytochemical constituents, and for antiplasmodial and cytotoxic effects. The plant leaves were collected from the University of KwaZulu-Natal (UKZN) arboretum on the Pietermaritzburg Campus, in March 2019. The inhibitory activity against 3D7 Plasmodium falciparum was determined using the parasite lactate dehydrogenase (pLDH) assay and cytotoxicity against HeLa cells was evaluated using the resazurin assay. The bioactive compounds were isolated by chromatographic purification and their structures were established with spectroscopic and spectrometric techniques. The plant leaf extract displayed significant antiplasmodial activity at 50 µg/mL and was also cytotoxic against HeLa cells. Chromatographic purification of the extract led to the isolation of two biflavonoids, four flavonoid glycosides, a steroid glycoside, and a megastigmene derivative. The compounds displayed antiplasmodial and antiproliferative activities at 50 µg/mL but the activity was substantially reduced at 10 µg/mL. The activities and compounds are being reported in O. obovata for the first time.

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Chirality in drug design has been attracting wide interests and attention over the years based on its innate potentials of enhancing the selectivity and prowess of therapeutic molecules. This approach was fundamental to the recent design of two inhibitors, where (R,R)-HEC72702 exhibited higher potency inhibition against hepatitis B virus capsid (HBVC) than (R,S)-HEC72702. Nevertheless, the detailed molecular mechanism has remained unresolved. Here, we apply multiple computational approaches to explore, validate, and differentiate the binding modes of (R,R) and (R,S)-HEC72702 and to explain the systematic roles mediated by chirality on the distinctive inhibition of HBVC dimer (HBVCd). Our findings revealed that chirality change from R,S to R,R engenders variations in the position of the propanoic acid group of HEC72702 toward the α5' and C-TER' region of HBVCd chain B which could explain the higher inhibitory affinity of (R,R)-HEC72702. Estimated binding free energies revealed a good correlation with bioactivity data. Moreover, analysis of energy decomposition revealed the prominent effects of van der Waals interactions in the binding process of both compounds to HBVCd. Furthermore, hierarchical clustering of residue-based energetic contributions suggested two hot-spot residues W125´ and F156´ play crucial roles in the systematic motions of the propanoic acid group toward chain B.

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Abelmoschus esculentus (Okra) is used in the traditional treatment of cancer, hyperlipidaemia and hyperglycaemia. We, therefore, investigated its composition and potential cytotoxic or antioxidant properties that might underlie its phytotherapeutic applications. Its methanolic fruit extract yielded compounds 1, 2 and 3, identified through NMR, UV and MS analyses as olean-12-en-3-O-ß-d-glucopyranoside, isoquercitrin (quercetin glucoside) and 5,7,3',4'-tetrahydroxy-flavonol-3-O-[ß-d-glucopyranosyl-(1→6)]-ß-d-glucopyranoside (quercetin diglucoside), respectively. Following 48 h exposure, oleanene glucoside was mildly toxic to the HeLa and the MRC5-SV2 cancer cells, isoquercitrin was not toxic except at 100 µg/ml in HeLa, and quercetin diglucoside elicited no toxicity. In a 2',7'-dichlorofluorescein diacetate (DCFDA) assay of intracellular levels of reactive oxygen species (ROS), hydrogen peroxide increased ROS levels, an effect not affected by oleanene glucoside but protected against by isoquercitrin and quercetin diglucoside, with IC50 values, respectively, of 2.7±0.5 µg/ml and 1.9±0.2 µg/ml (3 h post-treatment) and 2.0±0.8 µg/ml and 1.5±0.4 µg/ml (24 h post-treatment.) This is the first report of this oleanene skeleton triterpenoid in the plant. The work provides some insight into why the plant is included in remedies for cancers, cardiovascular complications and diabetes, and reveals it as a potential source of novel therapeutics.

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BACKGROUND: The leaf of Anacardium occidentale L. has been a component of many herbal recipes in South-Western Nigeria. The work reported herein, therefore, explored the phytochemical composition of this plant and the potential anti-cancer activity of an isolated chemical constituent. METHODS: Phytochemical methods (including chromatographic analysis) combined with spectroscopic and spectrometric analyses (IR, HRMS and NMR (1D and 2D)) were used to identify chemical constituents. Cytotoxic effects were determined using the MTT viability assay and bright-field imaging. Induction of oxidative stress was determined using the fluorescence-based 2',7'-dichlorofluorescein diacetate (DCFDA) assay. RESULTS: For the first time in the plant, Compound 1 was isolated from the leaf extract and identified as pentagalloylglucose. Compound 1 was significantly cytotoxic against the cancer cell lines HeLa (human cervical adenocarcinoma cell line) and MRC5-SV2 (human foetal lung cancer cell line), with IC50 of 71.45 and 52.24 µg/ml, respectively. The selectivity index (SI) for Compound 1 was 1.61 (IC50 against the normal human foetal lung fibroblast cell line MRC-5 was 84.33µg/ml), demonstrating better cancer cell-selectivity compared to doxorubicin with a SI of 1.28. The cytotoxic activity of Compound 1 in HeLa cells was also rapid, as shown by its concentration- and time-dependent 3 h and 6 h cytotoxicity profiles, an effect not observed with doxorubicin. Generation of reactive oxygen species at high concentrations of pentagalloylglucose to induce oxidative stress in cancer cells was identified as a mechanistic event that led to or resulted from its cytotoxicity. CONCLUSIONS: We suggest that pentagalloylglucose is selectively cytotoxic to cancer cells, and at high concentrations could exhibit pro-oxidant effects in those cells, as opposed to its general anti-oxidant effects in cells. Also, the presence of Compound 1 (pentagalloylglucose) in the plant and its cancer cell-selective cytotoxicity provide some rationale for the ethno-medicinal use of the plant's leaf extract for treating diseases associated with excessive cell proliferation. Further studies are required to dissect the molecular mechanisms and players differentially regulating the biphasic anti-oxidant and pro-oxidant effects of pentagalloylglucose in normal and cancer cells.

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4-(2-Fluorophenyl)-7-methoxycoumarin (6) was synthesized by Pechmann reaction under mild conditions via a three-step reaction. The solution-state 1H NMR spectra of 6 showed a strong intramolecular interaction between F and H5 (J FH = 2.6 Hz) and 13C NMR suggested that this C-F···H-C coupling is a through-space interaction. The 2D 19F-{1H} HOESY and 1H-{19F} 1D experiments were done to confirm this F···H interaction. The single crystal X-ray structure and the DFT-optimized structure showed that the fluorinated phenyl ring favors the orientation with the fluorine atom closer to H5 than H3. The X-ray structure also showed the existence of the intermolecular C-F···H-C interaction.

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BACKGROUND: Malaria remains a significant public health challenge in regions of the world where it is endemic. An unprecedented decline in malaria incidences was recorded during the last decade due to the availability of effective control interventions, such as the deployment of artemisinin-based combination therapy and insecticide-treated nets. However, according to the World Health Organization, malaria is staging a comeback, in part due to the development of drug resistance. Therefore, there is an urgent need to discover new anti-malarial drugs. This article reviews the literature on natural products with antiplasmodial activity that was reported between 2010 and 2017. METHODS: Relevant literature was sourced by searching the major scientific databases, including Web of Science, ScienceDirect, Scopus, SciFinder, Pubmed, and Google Scholar, using appropriate keyword combinations. RESULTS AND DISCUSSION: A total of 1524 compounds from 397 relevant references, assayed against at least one strain of Plasmodium, were reported in the period under review. Out of these, 39% were described as new natural products, and 29% of the compounds had IC50 ≤ 3.0 µM against at least one strain of Plasmodium. Several of these compounds have the potential to be developed into viable anti-malarial drugs. Also, some of these compounds could play a role in malaria eradication by targeting gametocytes. However, the research into natural products with potential for blocking the transmission of malaria is still in its infancy stage and needs to be vigorously pursued.

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The non-structural 5B (NS5B) polymerase of hepatitis C virus (HCV) is an attractive target for antiviral intervention. Quercetagetin (Que) is a natural flavonoid, which has been exhibited to have anti-HCV property through inhibition of RNA binding to NS5B. The last few decades have witnessed a growing interest in the extraction of natural flavonoids with a plethora of different biological activities. Considering the high therapeutic potential of Que, the aim of this study is to explore wide structure entities with potent activity using Que as a prototype. A virtual screen protocol involving docking and molecular dynamics has been performed to examine the potency of forty-three natural flavonoids which recently extracted from plants for inhibition of NS5B. During two screening stages, two compounds 24 and 41 were identified to have more favorable binding affinity to NS5B as compared to Que. The comparative analysis showed that there is a significant difference in the binding free energy of Que and 41 (ΔΔGbind = -11.17 kcal/mol). It was revealed that van der Waals (vdW) interaction drives the binding process of both 24 and 41 and plays an important role in increasing their activities relative to Que. PHE162 serves as a crucial residue in both the NS5B-24 and NS5B-41 systems, contributing the most vdW energy by π-π interaction, suggesting that aromatic interactions are critical for the binding of 24 and 41 to NS5B. Moreover, hydrogen bond analysis indicates that the hydrogen bonds formed by LYS98, THR137, ASP164 and ARG168, can play important roles in the increased binding affinity of 41 to NS5B relative to Que. The findings of this study will provide useful structure-activity relationship (SAR) guidelines for the design of novel inhibitors with improved/enhanced therapeutic activities in the treatment of hepatitis C.

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Introduction: Reports indicate that oral administration of plant-derived maslinic acid (MA) exhibits hypoglycemic and renoprotective effects in streptozotocin (STZ)-induced diabetic rats. Challenges with triterpenes such as MA include low bioavailabilty which affects treatment efficacy in experimental animals. The goal of this study was to synthesize the MA derivative phenylhydrazine (PH-MA) in an effort to improve the efficacy of MA. Methods: Separate groups of non-diabetic and STZ-induced diabetic rats (n = 6) were anesthetized and the jugular vein cannulated for the infusion of 0.077 M NaCl at 9 mL/h. The bladder was catheterized for collection the urine samples every 30 min. After 30.5 h equilibration period, consecutive 30 min urine collections were made over the subsequent 4 h of 1 h control, 1.5 h treatment, and 1.5 h recovery periods. PH-MA (22 µg/h) and MA (90 µg/h) were added during the treatment periods for analysis of proximal tubular Na+ handling, plasma aldosterone and arginine vasopressin in male Sprague-Dawley rats. Results: Intravenous infusion of PH-MA (22 µg/h) and MA (90 µg/h) significantly (p Ë‚ .05) increased Na+ output, fractional excretion of Na+ (FENa) and lithium (FELi). Interestingly, like MA, PH-MA significantly (p Ë‚ .05) increased glomerular filtration rate (GFR) over the treatment period and decreased plasma aldosterone levels. Our findings indicate that PH-MA inhibited sodium reabsorption in the proximal and distal tubule as shown by increased FENa and low plasma aldosterone levels, respectively. Conclusions: PH-MA is, therefore, a promising multitarget antidiabetic agent that may ameliorate kidney function of diabetic patients at a dose four times lower than the parent compound (MA).

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The concept of chirality has become prominent over the years, particularly with regards to the design of therapeutic molecules. This phenomenon was recently reported for pro-carcinogenic fibroblast growth factor receptor 1 (FGFR1), wherein two inhibitors exhibited disparate inhibitory potencies due to the effects of chirality. Therefore, the ability of the R-enantiomer (R-21c) to possess a potency 10.44 times that of the S-enantiomer (S-21c) leaves us with a curiosity to investigate the underlying mechanisms using computational methods. Hence, presented in this study are insights that clearly explain the systematic effects of chirality on the differential activities of (R)-21c and (S)-21c towards FGFR1. The findings showed that the "R-configured" (R)-21c induced a notable conformational change in the active site P-loop, which enhanced its motion, as complemented by rotation of two dihedral angles: φ1(CNCC) and φ2(CC*OC), providing a favorable orientation. Likewise, optimal positioning of (R)-21c at the binding cavity allowed adequate interspaces that facilitated the formation of strong interactions with target residues. Moreover, the estimated ΔG binding correlated with bioactivity data (IC50) and, when decomposed, we observed that van der Waals (vdW) interactions were the major highlight of the binding process of both 21c enantiomers and also accounted for their differential activities. Active site interactions of (R)-21c with residues Phe489 and Arg629 stabilized its two benzimidazole motifs, while Arg570 and Pro663 formed two strong NH-N hydrogen bonds and one π-alkyl interaction, which altogether accounted for its inhibitory prowess towards FGFR1. In contrast, these interactions were not observed in (S)-21c due to its non-flexible S-configuration, which disallowed its extension into the active site region and prevented interaction with crucial residues. These results are expected to facilitate the discovery and rational design of novel and specific FGFR1 inhibitors.

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Schistosomiasis, a chronic neglected tropical disease caused by the Schistosoma spp. parasite, is associated with disabling patient symptoms. The new focus of the WHO roadmap on 'transmission control, wherever possible' offers drug development opportunities for intermediate-host control to prevent human-to-snail-to-human parasite transmission. Reports on the analysis of the impact of 'chemical-based mollusciciding' have concluded that constant application of molluscicides may contribute significantly towards the elimination of schistosomiasis in endemic areas. In South-Western Nigeria, Tetrapleura tetraptera is a tree whose fruit has been widely used in snail vector control. The presence of molluscicidal N-acetyl triterpene glycosides in the fruit has been reported. In this study, a bioactivity-directed fractionation of the fruit extract was performed to isolate the most potent molluscicidal saponin from the fruit. In an attempt to provide mechanistic insight into the observed activity, in silico screening was performed, profiling the molluscicidal N-acetyl triterpene glycosides reported from the fruit against two potential therapeutic targets in the mollusk used, NADH-ubiquinone oxidoreductase (NAD1) and retinoid X receptor. The docking predicted binary complexes of the saponins, which were subjected to explicit solvent conformational sampling from which patterns of structural stability were obtained. The binding energies alone did not account for the potency of the saponins indicating the influence of other factor like pharmacokinetic parameters. The study concluded that there is a preferential suitability of ND1's MWFE site for the rational design and development of novel molluscicidal agents.

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INTRODUCTION: Nigerian medicinal plants have been demonstrated to be veritable source of lead compounds for drug discovery efforts. One such example is mangiferin. Mangiferin was originally isolated from the Nigerian plant Ceiba pentandra (Mombacaceae), after which its structure was elucidated with the aid of spectroscopy. Mangiferin, a xanthone glycoside, has also been reported in certain other plant families including Gentianaceae and Anacardiaceae. In certain other climes and different parts of the world, folkloric and traditional medicine has extensively employed Mangifera indica (another source of mangiferin) in treating different diseases. For many of such cultural uses carefully designed experimental investigations have been conducted confirming mangiferin's efficacies in those different pathologies which have included but not limited to cytotoxic as well as chemopreventive properties in selected cancer cell lines. METHODS: In this study, computational techniques were employed to profile the interaction of the xanthone glycoside at the atomistic level against nine selected molecular targets with clinical relevance in tumorigenesis. In attempt to investigate the potential of the mangiferin structure as a viable starting point for synthetic exploration of mangiferin-based analogs, extensive structural modifications were performed. RESULTS AND CONCLUSION: By analyzing the resulting structure-energetic pattern, critical points capable of improving mangiferin interaction with the profiled targets were identified. The outcome of this study provides both direction and impetus for synthetic derivitization of the mangiferin molecule into novel optimized inhibitors for anticancer lead development.

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