Antileishmanial high-throughput drug screening reveals drug candidates with new scaffolds.
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.
Siqueira-Neto
Jair L
JL
Center for Neglected Diseases Drug Discovery (CND3), Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, South Korea.
Song
Ok-Ryul
OR
Oh
Hyunrim
H
Sohn
Jeong-Hun
JH
Yang
Gyongseon
G
Nam
Jiyoun
J
Jang
Jiyeon
J
Cechetto
Jonathan
J
Lee
Chang Bok
CB
Moon
Seunghyun
S
Genovesio
Auguste
A
Chatelain
Eric
E
Christophe
Thierry
T
Freitas-Junior
Lucio H
LH
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
D000981:Antiprotozoal Agents; D003577:Cytochrome P-450 Enzyme System
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