Development of Potent <i>Pf</i> CLK3 Inhibitors Based on TCMDC-135051 as a New Class of Antimalarials

Abstract

The protein 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 structure-activity relationship with a 7-azaindole-based series. A total of 14 analogues were assessed in a time-resolved fluorescence energy transfer assay against the full-length recombinant protein kinase <i>Pf</i>CLK3, and 11 analogues were further assessed in asexual 3D7 (chloroquine-sensitive) strains of <i>P. falciparum</i> parasites. SAR relating to rings A and B was established. These data together with analysis of activity against parasites collected from patients in the field 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.