Synthesis and structure-activity-relationship studies of thiazolidinediones as antiplasmodial inhibitors of the Plasmodium falciparum cysteine protease falcipain-2

Rajni Kant Sharma; Yassir Younis; Grace Mugumbate; Mathew Njoroge; Jiri Gut; Philip J Rosenthal; Kelly Chibale

doi:10.1016/j.ejmech.2014.11.061

Synthesis and structure-activity-relationship studies of thiazolidinediones as antiplasmodial inhibitors of the Plasmodium falciparum cysteine protease falcipain-2

Eur J Med Chem. 2015 Jan 27:90:507-18. doi: 10.1016/j.ejmech.2014.11.061. Epub 2014 Dec 2.

Authors

Rajni Kant Sharma¹, Yassir Younis¹, Grace Mugumbate¹, Mathew Njoroge¹, Jiri Gut², Philip J Rosenthal², Kelly Chibale³

Affiliations

¹ Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
² Department of Medicine, University of California, San Francisco, CA 94143, USA.
³ Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council, Drug Discovery and Development Unit, University of Cape Town, Rondebosch 7701, South Africa. Electronic address: Kelly.Chibale@uct.ac.za.

PMID: 25486422
DOI: 10.1016/j.ejmech.2014.11.061

Abstract

Following a structure-based virtual screening, a series of 2,4 thiazolidinediones was synthesized in order to explore structure activity relationships for inhibition of the Plasmodium falciparum cysteine protease falcipain-2 (FP-2) and of whole cell antiparasitic activity. Most compounds exhibited low micromolar antiplasmodial activities against the P. falciparum drug resistant W2 strain. The most active compounds of the series were tested for in vitro microsomal metabolic stability and found to be susceptible to hepatic metabolism. Subsequent metabolite identification studies highlighted the metabolic hot spots. Molecular docking studies of a frontrunner inhibitor were carried out to determine the probable binding mode of this class of inhibitors in the active site of FP-2.

Keywords: Antiplasmodial agents; Falcipain-2; Thiazolidinone.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antimalarials / chemical synthesis
Antimalarials / chemistry
Antimalarials / pharmacology*
Cysteine Endopeptidases / metabolism*
Cysteine Proteinase Inhibitors / chemical synthesis
Cysteine Proteinase Inhibitors / chemistry
Cysteine Proteinase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Molecular Structure
Parasitic Sensitivity Tests
Plasmodium falciparum / drug effects*
Plasmodium falciparum / enzymology
Structure-Activity Relationship
Thiazolidinediones / chemical synthesis
Thiazolidinediones / chemistry
Thiazolidinediones / pharmacology*

Substances

Antimalarials
Cysteine Proteinase Inhibitors
Thiazolidinediones
Cysteine Endopeptidases
falcipain 2