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

ABSTRACT: The protein 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 (1) 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 PfCLK3, and 11 analogues were further assessed in asexual 3D7 (chloroquine-sensitive) strains of P. falciparum parasites. SAR relating to rings A and B

SUBMITTER: Mahindra A 

PROVIDER: S-EPMC7497403 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature