Simon M. N. Efange

AfroDb: a select highly potent and diverse natural product library from African medicinal plants.

Computer-aided drug design (CADD) often involves virtual screening (VS) of large compound datasets and the availability of such is vital for drug discovery protocols. We assess the bioactivity and “drug-likeness” of a relatively small but structurally diverse dataset (containing >1,000 compounds) from African medicinal plants, which have been tested and proven a wide range of biological activities. The geographical regions of collection of the medicinal plants cover the entire continent of Africa, based on data from literature sources and information from traditional healers. For each isolated compound, the three dimensional (3D) structure has been used to calculate physico-chemical properties used in the prediction of oral bioavailability on the basis of Lipinski’s “Rule of Five”. A comparative analysis has been carried out with the “drug-like”, “lead-like”, and “fragment-like” subsets, as well as with the Dictionary of Natural Products. A diversity analysis has been carried out in comparison with the ChemBridge diverse database. Furthermore, descriptors related to absorption, distribution, metabolism, excretion and toxicity (ADMET) have been used to predict the pharmacokinetic profile of the compounds within the dataset. Our results prove that drug discovery, beginning with natural products from the African flora, could be highly promising. The 3D structures are available and could be useful for virtual screening and natural product lead generation programs.

CamMedNP: Building the Cameroonian 3D structural natural products database for virtual screening

BackgroundComputer-aided drug design (CADD) often involves virtual screening (VS) of large compound datasets and the availability of such is vital for drug discovery protocols. We present CamMedNP - a new database beginning with more than 2,500 compounds of natural origin, along with some of their derivatives which were obtained through hemisynthesis. These are pure compounds which have been previously isolated and characterized using modern spectroscopic methods and published by several research teams spread across Cameroon.DescriptionIn the present study, 224 distinct medicinal plant species belonging to 55 plant families from the Cameroonian flora have been considered. About 80 % of these have been previously published and/or referenced in internationally recognized journals. For each compound, the optimized 3D structure, drug-like properties, plant source, collection site and currently known biological activities are given, as well as literature references. We have evaluated the “drug-likeness” of this database using Lipinski’s “Rule of Five”. A diversity analysis has been carried out in comparison with the ChemBridge diverse database.ConclusionCamMedNP could be highly useful for database screening and natural product lead generation programs.

Cameroonian medicinal plants: a bioactivity versus ethnobotanical survey and chemotaxonomic classification

BackgroundIn Cameroon herbs are traditionally used to meet health care needs and plans are on the way to integrate traditional medicine in the health care system, even though the plans have not been put into action yet. The country however has a rich biodiversity, with ~8,620 plant species, some of which are commonly used in the treatment of several microbial infections and a range of diseases (malaria, trypanosomiasis, leishmaniasis, diabetes and tuberculosis).MethodsOur survey consisted in collecting published data from the literature sources, mainly from PhD theses in Cameroonian university libraries and also using the author queries in major natural product and medicinal chemistry journals. The collected data includes plant sources, uses of plant material in traditional medicine, plant families, region of collection of plant material, isolated metabolites and type (e.g. flavonoid, terpenoid, etc.), measured biological activities of isolated compounds, and any comments on significance of isolated metabolites on the chemotaxonomic classification of the plant species. This data was compiled on a excel sheet and analysed.ResultsIn this study, a literature survey led to the collection of data on 2,700 secondary metabolites, which have been previously isolated or derived from Cameroonian medicinal plants. This represents distinct phytochemicals derived from 312 plant species belonging to 67 plant families. The plant species are investigated in terms of chemical composition with respect to the various plant families. A correlation between the known biological activities of isolated compounds and the ethnobotanical uses of the plants is also attempted. Insight into future direction for natural product search within the Cameroonian forest and Savanna is provided.ConclusionsIt can be verified that a phytochemical search of active secondary metabolites, which is inspired by knowledge from the ethnobotanical uses of medicinal plants could be very vital in a drug discovery program from plant-derived bioactive compounds.

In silico drug metabolism and pharmacokinetic profiles of natural products from medicinal plants in the Congo basin.

PurposeDrug metabolism and pharmacokinetics (DMPK) assessment has come to occupy a place of interest during the early stages of drug discovery today. The use of computer modelling to predict the DMPK and toxicity properties of a natural product library derived from medicinal plants from Central Africa (named ConMedNP). Material from some of the plant sources are currently employed in African Traditional Medicine.MethodsComputer-based methods are slowly gaining ground in this area and are often used as preliminary criteria for the elimination of compounds likely to present uninteresting pharmacokinetic profiles and unacceptable levels of toxicity from the list of potential drug candidates, hence cutting down the cost of discovery of a drug.In the present study, we present an in silico assessment of the DMPK and toxicity profile of a natural product library containing ~3,200 compounds, derived from 379 species of medicinal plants from 10 countries in the Congo Basin forests and savannas, which have been published in the literature. In this analysis, we have used 46 computed physico-chemical properties or molecular descriptors to predict the absorption, distribution, metabolism and elimination and toxicity (ADMET) of the compounds.ResultsThis survey demonstrated that about 45% of the compounds within the ConMedNP compound library are compliant, having properties which fall within the range of ADME properties of 95% of currently known drugs, while about 69% of the compounds have ≤ 2 violations. Moreover, about 73% of the compounds within the corresponding “drug-like” subset showed compliance.ConclusionsIn addition to the verified levels of “drug-likeness”, diversity and the wide range of measured biological activities, the compounds from medicinal plants in Central Africa show interesting DMPK profiles and hence could represent an important starting point for hit/lead discovery.

ConMedNP: a natural product library from Central African medicinal plants for drug discovery

We assess the medicinal value and “drug-likeness” of ∼3200 compounds of natural origin, along with some of their derivatives which were obtained through hemisynthesis. In the present study, 376 distinct medicinal plant species belonging to 79 plant families from the Central African flora have been considered, based on data retrieved from literature sources. For each compound, the optimised 3D structure has been used to calculate physicochemical properties which determine oral availability on the basis of Lipinskis “Rule of Five”. A comparative analysis has been carried out with the “drug-like”, “lead-like”, and “fragment-like” subsets, containing respectively 1726, 738 and 155 compounds, as well as with our smaller previously published CamMedNP library and the Dictionary of Natural products. A diversity analysis has been carried out in comparison with the DIVERSet™ Database (containing 48 651 compounds) from ChemBridge. Our results prove that drug discovery, beginning with natural products from the Central African flora, could be promising. The 3D structures are available and could be useful for virtual screening and natural product lead generation programs.

Okundoperoxide, a bicyclic cyclofarnesylsesquiterpene endoperoxide from Scleria striatinux with antiplasmodial activity

Okundoperoxide (1) was isolated by bioassay-guided fractionation of extracts from Scleria striatinux (syn. S. striatonux). The compound contains a cyclic endoperoxide structural moiety and possesses moderate antimalarial activity.

Bioassay-guided discovery of antibacterial agents: in vitro screening of Peperomia vulcanica, Peperomia fernandopoioana and Scleria striatinux

BackgroundThe global burden of bacterial infections is high and has been further aggravated by increasing resistance to antibiotics. In the search for novel antibacterials, three medicinal plants: Peperomia vulcanica, Peperomia fernandopoioana (Piperaceae) and Scleria striatinux (Cyperaceae), were investigated for antibacterial activity and toxicity.MethodsCrude extracts of these plants were tested by the disc diffusion method against six bacterial test organisms followed by bio-assay guided fractionation, isolation and testing of pure compounds. The minimum inhibitory (MIC) and minimum bactericidal (MBC) concentrations were measured by the microdilution method. The acute toxicity of the active extracts and cytotoxicity of the active compound were performed in mice and mammalian cells, respectively.ResultsThe diameter of the zones of inhibition (DZI) of the extracts ranged from 7–13 mm on Escherichia coli and Staphylococcus aureus of which the methylene chloride:methanol [1:1] extract of Scleria striatinux recorded the highest activity (DZI = 13 mm). Twenty-nine pure compounds were screened and one, Okundoperoxide, isolated from S. striatinux, recorded a DZI ranging from 10–19 mm on S. aureus. The MICs and MBCs indicated that the Peperomias had broad-spectrum bacteriostatic activity. Toxicity tests showed that Okundoperoxide may have a low risk of toxicity with an LC50 of 46.88 μg/mL.ConclusionsThe antibacterial activity of these plants supports their use in traditional medicine. The pure compound, Okundoperoxide, may yield new antibacterial lead compounds following medicinal chemistry exploration.

Isolation and identification of an antiparasitic triterpenoid estersaponin from the stem bark of Pittosporum mannii (Pittosporaceae)

Objective To screen for antiparasitic properties of Pittosporum mannii Hook (Pittosporaceae) through in vitro bioassay tests and to identify the bioactive compound(s).

1-Aryl-1,2,3,4-tetrahydroisoquinolines as potential antimalarials: synthesis, in vitro antiplasmodial activity and in silico pharmacokinetics evaluation†

In the present study, twenty-one 1-aryl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline (THIQ) analogues were synthesized by base-catalyzed Pictet–Spengler reaction, and tested in vitro against P. falciparum using the [3H]hypoxanthine incorporation assay. Two compounds were found to be inactive while seventeen compounds displayed moderate antiplasmodial activity and two compounds were found to be highly active (IC50 < 0.2 μg ml−1). The two highly active compounds, 1-(4-chlorophenyl)-6-hydroxyl-1,2,3,4-tetrahydroisoquinoline and 6-hydroxyspiro[1,2,3,4-tetrahydroisoquinoline-1:1′-cyclohexane], also displayed low cytotoxicity, against rat skeletal myoblast cells, with CC50 values of 257.6 and 174.2 μM respectively. These results justify further investigation of simple 1-aryl-1,2,3,4-tetrahydroisoquinolines as potential anti-malarial agents.

4-aroylpiperidines and 4-(α-hydroxyphenyl)piperidines as selective sigma-1 receptor ligands: synthesis, preliminary pharmacological evaluation and computational studies

BackgroundSigma (σ) receptors are membrane-bound proteins characterised by an unusual promiscuous ability to bind a wide variety of drugs and their high affinity for typical neuroleptic drugs, such as haloperidol, and their potential as alternative targets for antipsychotic agents. Sigma receptors display diverse biological activities and represent potential fruitful targets for therapeutic development in combating many human diseases. Therefore, they present an interesting avenue for further exploration. It was our goal to evaluate the potential of ring opened spipethiane (1) analogues as functional ligands (agonists) for σ receptors by chemical modification.ResultsChemical modification of the core structure of the lead compound, (1), by replacement of the sulphur atom with a carbonyl group, hydroxyl group and 3-bromobenzylamine with the simultaneous presence of 4-fluorobenzoyl replacing the spirofusion afforded novel potent sigma-1 receptor ligands 7a–f, 8a–f and 9d–e. The sigma-1 receptor affinities of 7e, 8a and 8f were slightly lower than that of 1 and their selectivities for this receptor two to threefold greater than that of 1.ConclusionsIt was found that these compounds have higher selectivities for sigma-1 receptors compared to 1. Quantitatitive structure–activity relationship studies revealed that sigma-1 binding is driven by hydrophobic interactions.Graphical abstractIdentified pharmacophore features for sigma binding.