Leishmania donovani Growth Inhibitors from Pathogen Box Compounds of Medicine for Malaria Venture.

Publisher: Dove Press Limited Country of Publication: New Zealand NLM ID: 101475745 Publication Model: eCollection Cited Medium: Internet ISSN: 1177-8881 (Electronic) Linking ISSN: 11778881 NLM ISO Abbreviation: Drug Des Devel Ther Subsets: MEDLINE

Original Publication: [Auckland, N.Z.] : Dove Press Limited

Antiprotozoal Agents/*pharmacology ; Growth Inhibitors/*pharmacology ; Leishmania donovani/*drug effects ; Leishmaniasis/*drug therapy ; Malaria/*drug therapy; Adolescent ; Animals ; Antiprotozoal Agents/chemistry ; Cell Survival/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Female ; Growth Inhibitors/chemistry ; Humans ; Leishmania donovani/growth & development ; Leishmania donovani/isolation & purification ; Macrophages/drug effects ; Macrophages/parasitology ; Mice ; Molecular Structure ; Parasitic Sensitivity Tests ; Structure-Activity Relationship

Introduction: 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.
Competing Interests: The authors declare that they have no competing interests in this work.
(© 2020 Tadele et al.)

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Keywords: Leishmania donovani; Medicines for Malaria Venture; Pathogen Box compounds; drug discovery

0 (Antiprotozoal Agents)
0 (Growth Inhibitors)

Date Created: 20200414 Date Completed: 20210208 Latest Revision: 20231113

20231215

PMC7130106

10.2147/DDDT.S244903

32280200