Development of Potent PfCLK3 Inhibitors Based on TCMDC-135051 as a New Class of Antimalarials.
Mahindra, Amit;
Janha, Omar;
Mapesa, Kopano;
Sanchez-Azqueta, Ana;
Alam, Mahmood M;
Amambua-Ngwa, Alfred;
Nwakanma, Davis C;
Tobin, Andrew B;
Jamieson, Andrew G;
(2020)
Development of Potent PfCLK3 Inhibitors Based on TCMDC-135051 as a New Class of Antimalarials.
Journal of medicinal chemistry, 63 (17).
pp. 9300-9315.
ISSN 1520-4804
DOI: https://doi.org/10.1021/acs.jmedchem.0c00451
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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 was established. These data together with analysis of activity against parasites collected from patients in the field suggest that TCMDC-135051 (1) is a promising lead compound for the development of new antimalarials with a novel mechanism of action targeting PfCLK3.