Development of Potent and Selective PfCLK3 Inhibitors Based on GSK-TCMDC151 as a New Class of Antimalarials

Abstract

<p>The kinase <i>Pf</i>CLK3 plays a critical role in the regulation of malarial parasite RNA splicing and is essential for the survival of blood stage <i>Plasmodium falciparum</i>. We recently validated <i>Pf</i>CLK3 as a drug target in malaria that offers prophylactic, transmission blocking and curative potential. Herein we describe the synthesis of our initial hit TCMDC-135051 <b>1</b>and efforts to establish a SAR with a 7-azaindole-based series. A total of 14 analogues were assessed in a TR-FRET assay against the full recombinant protein kinase <i>Pf</i>CLK3 and 10 were further assessed in parasites 3D7 (chloroquine sensitive) strains of <i>P. falciparum</i>. SAR relating to rings A and B was established. These data suggest that TCMDC-135051 <b>1</b>is a promising lead compound for the development of new antimalarials with a novel mechanism of action targeting <i>Pf</i>CLK3.</p>