The kinase PfCLK3 plays a critical role in the regulation of malarial parasite RNA splicing and is essential for the survival of blood stage Plasmodium falciparum. We recently validated PfCLK3 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 1and 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 PfCLK3 and 10 were further assessed in parasites 3D7 (chloroquine sensitive) strains of P. falciparum. SAR relating to rings A and B was established. These data suggest that TCMDC-135051 1is a promising lead compound for the development of new antimalarials with a novel mechanism of action targeting PfCLK3.
Development of Potent and Selective PfCLK3 Inhibitors Based on GSK-TCMDC151 as a New Class of Antimalarials
13 September 2019, Version 1
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