Drug Design, Development and Therapy (Mar 2020)
Leishmania donovani Growth Inhibitors from Pathogen Box Compounds of Medicine for Malaria Venture
Abstract
Markos Tadele, 1,* Solomon M Abay, 2,* Eyasu Makonnen, 2, 3 Asrat Hailu 3, 4 1Animal Health Research Program, Ethiopian Institute of Agricultural Research, Holetta, Ethiopia; 2Department of Pharmacology and Clinical Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia; 3Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia; 4Department of Microbiology, Immunology and Parasitology, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia*These authors contributed equally to this workCorrespondence: Solomon M Abay P.O. Box 9086, Addis Ababa, EthiopiaTel +251 941 22 2169Email [email protected]: Leishmaniasis is a collective term used to describe various pathological conditions caused by an obligate intracellular protozoan of the genus Leishmania. It is one of the neglected diseases and has been given minimal attention by drug discovery and development stakeholders to narrow the safety and efficacy gaps of the drugs currently used to treat leishmaniasis. The challenge is further exacerbated by the emergence of drug resistance by the parasites.Methods: Aiming to look for potential anti-leishmanial hits and leads, we screened Medicines for Malaria Venture (MMV) Pathogen Box compounds against clinically isolated Leishmania donovani strain. In this medium-throughput primary screening assay, the compounds were screened against promastigotes, and then against amastigote stages.Results: From the total 400 compounds screened, 35 compounds showed > 50% inhibitory activity on promastigotes in the initial screen (1 μM). Out of these compounds, nine showed > 70% inhibition, with median inhibitory concentration (IC 50) ranging from 12 to 491 nM using the anti-promastigote assay, and from 53 to 704 nM using the intracellular amastigote assay. Identified compounds demonstrated acceptable safety profiles on THP-1 cell lines and sheep red blood cells, and had appropriate physicochemical properties suitable for further drug development. Two compounds (MMV690102 and MMV688262) were identified as leads. The anti-tubercular agent MMV688262 (delamanid) showed a synergistic effect with amphotericin B, indicating the prospect of using this compound for combination therapy.Conclusion: The current study indicates the presence of additional hits which may hold promise as starting points for anti-leishmanial drug discovery and in-depth structure–activity relationship studies.Keywords: Leishmania donovani, Pathogen Box compounds, Medicines for Malaria Venture, drug discovery
