A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.

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BackgroundCancer has become a global public health problem and the search for new control measures is urgent. Investigation of plant products such as essential oils from Monodora myristica, Xylopia aethiopica and Xylopia parviflora might lead to new anticancer therapy. In this study, we have investigated the antineoplastic activity of essential oils from fruits of these plants growing in Chad and Cameroon.MethodsThe essential oils obtained by hydrodistillation of fruits of Monodora myristica, Xylopia aethiopica and Xylopia parviflora collected in Chad and Cameroon were analyzed by GC-FID and GC-MS and investigated for their antiproliferative activity against the breast cancer cell line (MCF7).ResultsOverall, monoterpenes were mostly found in the six essential oils. Oils from X. aethiopica and X. parviflora from Chad and Cameroon mainly contain β-pinene at 24.6%, 28.2%, 35.7% and 32.9% respectively. Monodora myristica oils from both origins contain mainly α-phellandrene at 52.7% and 67.1% respectively. The plant origin did not significantly influence the chemical composition of oils. The six essential oils exerted cytotoxic activity against cancer (MCF-7) and normal cell lines (ARPE-19), with more pronounced effect on neoplastic cells in the majority of cases. The highest selectivity was obtained with the essential oils of X. parviflora from Chad and Cameroon (5.87 and 5.54) which were more cytotoxic against MCF-7 than against normal cell line (ARPE-19) with IC50 values of 0.155 μL/mL and 0.166 μL/mL respectively.ConclusionsEssential oils from fruits of Monodora myristica, Xylopia aethiopica and Xylopia parviflora have shown acceptable antineoplastic potency, and might be investigated further in this regard.

Alzheimer’s disease is first characterised by memory loss related to the central cholinergic system alteration. Available drugs provide symptomatic treatment with known side effects. The present study is aimed to evaluate the properties of Carissa edulis aqueous extract on a Scopolamine mouse model as an attempt to search for new compounds against Alzheimer’s disease-related memory impairment. Memory impairment was induced by administration of 1 mg/kg (i.p.) of Scopolamine for 7 days, and mice were treated with Carissa edulis aqueous extract. Behavioural studies were performed using T-maze and novel object recognition task for assessing learning and memory and open field test for locomotion. Brain acetylcholinesterase enzyme (AChE) activity was measured to evaluate the central cholinergic system. The level of MDA, glutathione, and catalase activity were measured to evaluate the oxidative stress level. Administration of Scopolamine shows a decrease in learning and memory enhancement during behavioural studies. A significant decrease in the time spent in the preferred arm of T-maze, in the time spent in the exploration of the novel object, and in the discrimination index of the familiar object was also observed. The significant impairment of the central cholinergic system was characterised in mice by an increase of AChE activity to 2.55±0.10 mol/min/g with an increase in oxidative stress. Treatment with the different doses of Carissa edulis (62.8, 157, 314, and 628 mg/kg orally administrated) significantly increased the memory of mice in T-maze and novel object recognition tests and also ameliorated locomotion of mice in the open field. Carissa edulis aqueous extract treatment also decreases the AChE activity and brain oxidative stress. It is concluded that administration of Carissa edulis aqueous extract enhances memory of mice by reducing AChE activity and demonstrating antioxidant properties. This could be developed into a novel therapy against memory impairment related to Alzheimer’s disease.

BackgroundDiscovering new lead compounds against malaria parasites is a crucial step to ensuring a sustainable global pipeline for effective anti-malarial drugs. As far as we know, no previous phytochemical or pharmacological investigations have been carried out on Sorindeia juglandifolia. This paper describes the results of an anti-malarial activity-driven investigation of the fruits of this Cameroonian plant.MethodsAir-dried fruits were extracted by maceration using methanol. The extract was fractionated by flash chromatography followed by column chromatography over silica gel, eluting with gradients of hexane-ethyl acetate mixtures. Resulting fractions and compounds were tested in vitro against the Plasmodium falciparum chloroquine-resistant strain W2, against field isolates of P. falciparum, and against the P. falciparum recombinant cysteine protease falcipain-2. Promising fractions were assessed for acute toxicity after oral administration in mice. One of the promising isolated compounds was assessed in vivo against the rodent malaria parasite Plasmodium berghei.ResultsThe main end-products of the activity-guided fractionation were 2,3,6-trihydroxy benzoic acid (1) and 2,3,6-trihydroxy methyl benzoate (2). Overall, nine fractions tested against P. falciparum W2 and falcipain-2 were active, with IC50 values of 2.3-11.6 μg/ml for W2, and 1.1-21.9 μg/ml for falcipain-2. Purified compounds (1) and (2) also showed inhibitory effects against P. falciparum W2 (IC50s 16.5 μM and 13.0 μM) and falcipain-2 (IC50s 35.4 and 6.1 μM). In studies of P. falciparum isolates from Cameroon, the plant fractions demonstrated IC50 values of 0.14-19.4 μg/ml and compounds (1) and (2) values of 6.3 and 36.1 μM. In vivo assessment of compound (1) showed activity against P. berghei strain B, with mean parasitaemia suppressive dose and curative dose of 44.9 mg/kg and 42.2 mg/kg, respectively. Active fractions were found to be safe in mice after oral administration of 7 g/kg body weight.ConclusionsFractions of Sorindeia juglandifolia and two compounds isolated from these fractions were active against cultured malaria parasites, the P. falciparum protease falcipain-2, and in a rodent malaria model. These results suggest that further investigation of the anti-malarial activities of natural products from S. juglandifolia will be appropriate.

Diabetes mellitus is a metabolic disorder of glucose metabolism which correlates with postprandial hyperglycemia and oxidative stress. Control of blood glucose level is imperative in the management of diabetes. The present study tested the hypothesis that Costus afer, an antihyperglycemic medicinal plant, possesses inhibitory activity against carbohydrate hydrolyzing enzymes. Hexane, ethyl acetate, methanol, and water extracts were prepared from the leaf, stem, and rhizome of C. afer and subjected to phytochemical screening, assayed for α-amylase and α-glucosidase inhibitory activities and antioxidant capacity (determined by total phenolic and total flavonoids contents, ferric reducing antioxidant power (FRAP), and DPPH radical scavenging activity). All extracts inhibited α-amylase and α-glucosidase activities. Ethyl acetate rhizome and methanol leaf extracts exhibited the best inhibitory activity against α-amylase and α-glucosidase (IC50: 0.10 and 5.99 mg/mL), respectively. Kinetic analysis revealed two modes of enzyme inhibition (competitive and mixed). All extracts showed antioxidant capacity, with hexane extracts exhibiting the best activity. DPPH assay revealed that methanol leaf, rhizome, and ethyl acetate stem extracts (IC50 < 5 mg/mL) were the best antioxidants. The presence of bioactive compounds such as flavonoids, alkaloids, phenols, and tannins may account for the antioxidant capacity and carbohydrate hydrolyzing enzyme inhibitory activity of C. afer.

BackgroundThe emergence and spread of malaria parasites resistant to artemisinin-based combination therapy stresses the need for novel drugs against malaria. Investigating plants used in traditional medicine to treat malaria remains a credible option for new anti-malarial drug development. This study was aimed at investigating the antiplasmodial activity and selectivity of extracts and fractions from Terminalia mantaly and Terminalia superba (Combretaceae) that are used in Cameroon to treat malaria.MethodsTwelve methanolic (m) and water (w) extracts obtained by maceration of powdered dried leaves (l), stem bark (sb) and root (r) of Terminalia mantaly (Tm) and Terminalia superba (Ts) and 12 derived fractions of hexane, chloroform, ethyl acetate and 4 final residues of selected extracts were assessed for antiplasmodial potential in vitro against the chloroquine-resistant PfINDO and the chloroquine-sensitive Pf3D7 strains of Plasmodium falciparum using the SYBR green I-based fluorescence assay. The cytotoxicity of potent extracts and fractions was evaluated in vitro using the MTT assay on HEK239T cell line.ResultsThe antiplasmodial IC50 of extracts from both plants ranged from 0.26 to > 25 µg/mL. Apart from the extracts Tmrm and Tsrw that exerted moderate antiplasmodial activities (IC50: 5–20 µg/mL) and Tmrw that was found to be non-active at the tested concentrations (IC50 > 25 µg/mL), all other tested crude extracts exhibited potent activities with IC50 < 5 µg/mL. The aqueous extracts from the stem bark of Terminalia mantaly (Tmsbw) and the leaf of Terminalia superba (Tslw) displayed the highest antiplasmodial activities (IC50: 0.26–1.26 µg/mL) and selectivity (SI > 158) on both resistant PfINDO and sensitive Pf3D7 strains. Four fractions upon further extraction with chloroform and ethyl acetate (TmlwChl, TmsbwChl, TmsbwEA, TsrmEA) afforded from three selected crude extracts (Tmlw, Tmsbw, Tsrm) exhibited highly potent activities against both P. falciparum strains (IC50 < 2 µg/mL) and high selectivity (SI > 109).ConclusionsThe results achieved in this work validate the reported traditional use of Terminalia mantaly and Terminalia superba to treat malaria. Moreover, the highly potent and selective fractions warrant further investigation to characterize the active antiplasmodial principles and progress them to rodent malaria models studies if activity and selectivity are evidenced.