Discovery and structure-activity relationships of pyrrolone antimalarials

  • J Med Chem. 2013 Apr 11;56(7):2975-90. doi: 10.1021/jm400009c.
Dinakaran Murugesan  1 ,  Alka Mital ,  Marcel Kaiser ,  David M Shackleford ,  Julia Morizzi ,  Kasiram Katneni ,  Michael Campbell ,  Alan Hudson ,  Susan A Charman ,  Clive Yeates ,  Ian H Gilbert
Affiliations
  • 1. Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee DD1 5EH, UK.
PMID: 23517371 DOI: 10.1021/jm400009c
Abstract

In the pursuit of new antimalarial leads, a phenotypic screening of various commercially sourced compound libraries was undertaken by the World Health Organisation Programme for Research and Training in Tropical Diseases (WHO-TDR). We report here the detailed characterization of one of the hits from this process, TDR32750 (8a), which showed potent activity against Plasmodium falciparum K1 (EC(50) ~ 9 nM), good selectivity (>2000-fold) compared to a mammalian cell line (L6), and significant activity against a rodent model of malaria when administered intraperitoneally. Structure-activity relationship studies have indicated ways in which the molecule could be optimized. This compound represents an exciting start point for a drug discovery program for the development of a novel antimalarial.