The protein kinase CLK3 plays a critical role in the regulation of malarial parasite RNA splicing and is essential for the survival of blood stage . We recently validated 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 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 CLK3, and 11 analogues were further assessed in asexual 3D7 (chloroquine-sensitive) strains of 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 is a promising lead compound for the development of new antimalarials with a novel mechanism of action targeting CLK3.
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| http://dx.doi.org/10.1021/acs.jmedchem.0c00451 | DOI Listing |
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