Screening of the Pan-African Natural Product Library Identifies Ixoratannin A-2 and Boldine as Novel HIV-1 Inhibitors

The continued burden of HIV in resource-limited regions such as parts of sub-Saharan Africa, combined with adverse effects and potential risks of resistance to existing antiretroviral therapies, emphasize the need to identify new HIV inhibitors. Here we performed a virtual screen of molecules from the pan-African Natural Product Library, the largest collection of medicinal plant-derived pure compounds on the African continent. We identified eight molecules with structural similarity to reported interactors of Vpu, an HIV-1 accessory protein with reported ion channel activity. Using in vitro HIV-1 replication assays with a CD4+ T cell line and peripheral blood mononuclear cells, we confirmed antiviral activity and minimal cytotoxicity for two compounds, ixoratannin A-2 and boldine. Notably, ixoratannin A-2 retained inhibitory activity against recombinant HIV-1 strains encoding patient-derived mutations that confer resistance to protease, non-nucleoside reverse transcriptase, or integrase inhibitors. Moreover, ixoratannin A-2 was less effective at inhibiting replication of HIV-1 lacking Vpu, supporting this protein as a possible direct or indirect target. In contrast, boldine was less effective against a protease inhibitor-resistant HIV-1 strain. Both ixoratannin A-2 and boldine also inhibited in vitro replication of hepatitis C virus (HCV). However, BIT-225, a previously-reported Vpu inhibitor, demonstrated antiviral activity but also cytotoxicity in HIV-1 and HCV replication assays. Our work identifies pure compounds derived from African plants with potential novel activities against viruses that disproportionately afflict resource-limited regions of the world

Identification of Bichalcones as Sirtuin Inhibitors by Virtual Screening and In Vitro Testing

Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent class III histone deacetylases, which have been linked to the pathogenesis of numerous diseases, including HIV, metabolic disorders, neurodegeneration and cancer. Docking of the virtual pan-African natural products library (p-ANAPL), followed by in vitro testing, resulted in the identification of two inhibitors of sirtuin 1, 2 and 3 (sirt1–3). Two bichalcones, known as rhuschalcone IV (8) and an analogue of rhuschalcone I (9), previously isolated from the medicinal plant Rhus pyroides, were shown to be active in the in vitro assay. The rhuschalcone I analogue (9) showed the best activity against sirt1, with an IC50 value of 40.8 µM. Based on the docking experiments, suggestions for improving the biological activities of the newly identified hit compounds have been provided

Cytotoxicity of seputhecarpan D, thonningiol and 12 other phytochemicals from African flora towards human carcinoma cells

PubMed:29378558Background: Despite the remarkable progress in cancer therapy in recent years, this disease still remains a serious public health concern. The use of natural products has been and continues to be one of the most effective ways to fight malignancies. The cytotoxicity of 14 compounds from African medicinal plants was evaluated in four human carcinoma cell lines and normal fibroblasts. The tested samples included: ?-spinasterol (1), friedelanone (2), 16?-hydroxylupeol (3), ?-amyrin acetate (4), lupeol acetate (5), sequoyitol (6), rhamnitrin (7), europetin 3-O-rhamnoside (8), thonningiol (9), glyasperin F (10), seputhecarpan B (11), seputhecarpan C (12), seputhecarpan D (13) and rheediaxanthone A (14). Methods: The neutral red uptake (NR) assay was used to evaluate the cytotoxicity of samples; caspase-Glo assay, flow cytometry for cell cycle analysis and mitochondrial membrane potential (MMP) as well as spectrophotometry to measure levels of reactive oxygen species (ROS) were performed to detect the mode of action of compounds 9 and 13 in MCF-7 breast adenocarcinoma cells. Results: Compounds 3, 9-13 displayed cytotoxic effects against the four tested cancer cell lines with IC50 values below 85 ?M. Compounds 9 and 13 had IC50 values below 10 ?M in 4/4 and 3/4 tested cell lines respectively. The IC50 values varied from 0.36 ?M (against MCF7 cells) to 5.65 ?M (towards colon carcinoma DLD-1 cells) for 9, from 9.78 ?M (against MCF7 cells) to 67.68 ?M (against HepG2 cells) for 13 and 0.18 ?M (towards HepG2 cells) to 72 ?M (towards Caco-2 cells) for the reference drug, doxorubicin. Compounds 9 and 13 induced cell cycle arrest in Go/G1 whilst doxorubicin induced arrest in G2/M. The two molecules (9 and 13) also induced apoptosis in MCF-7 cells through activation of caspases 3/7 and 9 as well as enhanced ROS production. Conclusion: Compounds 9 and 13 are good cytotoxic phytochemicals that should be explored more in future to develop a cytotoxic drug to fight human carcinoma.Firat University Scientific Research Projects Management Unit: 1507F563The study was funded by the Scientific and Technological Research Counsel of Turkey (TÜBİTAK) and to Scientific Research Projects Commission of Anadolu University, Eskisehir, Turkey (funding grant 1507F563). A grant for part of this work was also provided by International Science Programme, Uppsala University, Sweden (ISP)-KEN-02 project through the Network for Analytical and Bioassay Services in Africa (NABSA) at the University of Botswana

MOESM3 of Two new pterocarpans and a new pyrone derivative with cytotoxic activities from Ptycholobium contortum (N.E.Br.) Brummitt (Leguminosae): revised NMR assignment of mundulea lactone

Additional file 3. 1H and 13C NMR spectra of pythylopyrone A 3 showing the signals of the additional γ,γ-dimethylallyle group in position 4 of the molecule

Virtual Screening Identifies Chebulagic Acid as an Inhibitor of the M2(S31N) Viral Ion Channel and Influenza A Virus

The increasing prevalence of drug-resistant influenza viruses emphasizes the need for new antiviral countermeasures. The M2 protein of influenza A is a proton-gated, proton-selective ion channel, which is essential for influenza replication and an established antiviral target. However, all currently circulating influenza A virus strains are now resistant to licensed M2-targeting adamantane drugs, primarily due to the widespread prevalence of an M2 variant encoding a serine to asparagine 31 mutation (S31N). To identify new chemical leads that may target M2(S31N), we performed a virtual screen of molecules from two natural product libraries and identified chebulagic acid as a candidate M2(S31N) inhibitor and influenza antiviral. Chebulagic acid selectively restores growth of M2(S31N)-expressing yeast. Molecular modeling also suggests that chebulagic acid hydrolysis fragments preferentially interact with the highly-conserved histidine residue within the pore of M2(S31N) but not adamantane-sensitive M2(S31). In contrast, chebulagic acid inhibits in vitro influenza A replication regardless of M2 sequence, suggesting that it also acts on other influenza targets. Taken together, results implicate chebulagic acid and/or its hydrolysis fragments as new chemical leads for M2(S31N) and influenza-directed antiviral development.Medicine, Faculty ofScience, Faculty ofNon UBCBiochemistry and Molecular Biology, Department ofChemistry, Department ofEarth, Ocean and Atmospheric Sciences, Department ofReviewedFacult

Virtualizing the p-ANAPL Library: A Step towards Drug Discovery from African Medicinal Plants

<div><p>Background</p><p>Natural products play a key role in drug discovery programs, both serving as drugs and as templates for the synthesis of drugs, even though the quantities and availabilities of samples for screening are often limitted.</p><p>Experimental approach</p><p>A current collection of physical samples of > 500 compound derived from African medicinal plants aimed at screening for drug discovery has been made by donations from several researchers from across the continent to be directly available for drug discovery programs. A virtual library of 3D structures of compounds has been generated and Lipinski’s “Rule of Five” has been used to evaluate likely oral availability of the samples.</p><p>Results</p><p>A majority of the compound samples are made of flavonoids and about two thirds (2/3) are compliant to the “Rule of Five”. The pharmacological profiles of thirty six (36) selected compounds in the collection have been discussed.</p><p>Conclusions and implications</p><p>The p-ANAPL library is the largest physical collection of natural products derived from African medicinal plants directly available for screening purposes. The virtual library is also available and could be employed in virtual screening campaigns.</p></div

Chemical structures of natural products from the p-ANAPL library with log P > 8 units.

<p>Chemical structures of natural products from the p-ANAPL library with log P > 8 units.</p

Distribution of Lipinski parameters for the p-ANAPL library; (A) Bar chart showing the number of Lipinski violations, (B) Bar chart showing the MW parameter, (C) Plot of the lipophilicity parameter, (D) Plot of the HBA parameter, (E) Plot of the HBD parameter, and (F) Plot of the NRB parameter.

<p>Distribution of Lipinski parameters for the p-ANAPL library; (A) Bar chart showing the number of Lipinski violations, (B) Bar chart showing the MW parameter, (C) Plot of the lipophilicity parameter, (D) Plot of the HBA parameter, (E) Plot of the HBD parameter, and (F) Plot of the NRB parameter.</p