title: Antileishmanial high-throughput drug screening reveals drug candidates with new scaffolds.
abstract: Drugs currently available for leishmaniasis treatment often show parasite resistance, highly toxic side effects and prohibitive costs commonly incompatible with patients from the tropical endemic countries. In this sense, there is an urgent need for new drugs as a treatment solution for this neglected disease. Here we show the development and implementation of an automated high-throughput viability screening assay for the discovery of new drugs against Leishmania. Assay validation was done with Leishmania promastigote forms, including the screening of 4,000 compounds with known pharmacological properties. In an attempt to find new compounds with leishmanicidal properties, 26,500 structurally diverse chemical compounds were screened. A cut-off of 70% growth inhibition in the primary screening led to the identification of 567 active compounds. Cellular toxicity and selectivity were responsible for the exclusion of 78% of the pre-selected compounds. The activity of the remaining 124 compounds was confirmed against the intramacrophagic amastigote form of the parasite. In vitro microsomal stability and cytochrome P450 (CYP) inhibition of the two most active compounds from this screening effort were assessed to obtain preliminary information on their metabolism in the host. The HTS approach employed here resulted in the discovery of two new antileishmanial compounds, bringing promising candidates to the leishmaniasis drug discovery pipeline.
authors.affiliation: Center for Neglected Diseases Drug Discovery (CND3), Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, South Korea.
authors.forename: Jair L
authors.initials: JL
authors.lastname: Siqueira-Neto
authors.forename: Ok-Ryul
authors.initials: OR
authors.lastname: Song
authors.forename: Hyunrim
authors.initials: H
authors.lastname: Oh
authors.forename: Jeong-Hun
authors.initials: JH
authors.lastname: Sohn
authors.forename: Gyongseon
authors.initials: G
authors.lastname: Yang
authors.forename: Jiyoun
authors.initials: J
authors.lastname: Nam
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Jang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cechetto
authors.forename: Chang Bok
authors.initials: CB
authors.lastname: Lee
authors.forename: Seunghyun
authors.initials: S
authors.lastname: Moon
authors.forename: Auguste
authors.initials: A
authors.lastname: Genovesio
authors.forename: Eric
authors.initials: E
authors.lastname: Chatelain
authors.forename: Thierry
authors.initials: T
authors.lastname: Christophe
authors.forename: Lucio H
authors.initials: LH
authors.lastname: Freitas-Junior
mesh_terms: D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004355:Drug Stability; D006801:Humans; D007891:Leishmania / Q000187:drug effects*; D008264:Macrophages / Q000469:parasitology; D050296:Microbial Viability / Q000187:drug effects; D008862:Microsomes, Liver / Q000201:enzymology; D009000:Monocytes / Q000187:drug effects
chemical_list: D000981:Antiprotozoal Agents; D003577:Cytochrome P-450 Enzyme System
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