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Lerisetron Analogues with Antimalarial properties - Synthesis, Structure-Activity Relationship (SAR) studies and Biological Assessment

Mueller, Rufolf and Reddy, Virsinha and Nchinda, Aloysius and Mebrahtu, Fanuel and Taylor, Dale and Lawrence, Nina and Tanner, Lloyd and Barnabe, Marine and Eyermann, Charles and Zou, Bin and Kondireddi, Ravinder and Lakshminarayana, Suresh and Rottmann, Matthias and Street, Leslie and Chibale, Kelly (2020) Lerisetron Analogues with Antimalarial properties - Synthesis, Structure-Activity Relationship (SAR) studies and Biological Assessment. ACS Omega, 5 (12). pp. 6967-6982. ISSN 2470-13432470-1343

Abstract

A phenotypic whole cell high throughput screen against asexual blood and liver stages of the malaria parasite identified a benzimidazole chemical series. Among the hits were the antiemetic benzimidazole drug Lerisetron 1 (IC50 NF54 = 0.81 µM) and its methyl substituted analogue 2 (IC50 NF54 = 0.098 µM). A medicinal chemistry hit to lead effort led to the identification of chloro substituted analogue 3 with high potency against the drug sensitive NF54 (IC50 NF54 = 0.062 µM) and multidrug-resistant K1 (IC50 K1= 0.054 µM) strains of the human malaria parasite Plasmodium falciparum. Cardiotoxicity risks as expressed in strong inhibition of the hERG potassium channel was identified as major liability to address. This led to the synthesis and biological assessment of around sixty (60) analogues from which several compounds with more potent anti-plasmodium activity, relative to the lead compound 3, were identified.

Item Type: Article
Date Deposited: 17 Apr 2020 00:45
Last Modified: 17 Apr 2020 00:45
URI: https://oak.novartis.com/id/eprint/40563

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