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Development of Potent PfCLK3 Inhibitors Based on TCMDC-135051 as a New Class of Antimalarials

[Image: see text] 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...

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Detalles Bibliográficos
Autores principales: Mahindra, Amit, Janha, Omar, Mapesa, Kopano, Sanchez-Azqueta, Ana, Alam, Mahmood M., Amambua-Ngwa, Alfred, Nwakanma, Davis C., Tobin, Andrew B., Jamieson, Andrew G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497403/
https://www.ncbi.nlm.nih.gov/pubmed/32787140
http://dx.doi.org/10.1021/acs.jmedchem.0c00451
Descripción
Sumario:[Image: see text] 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.