Development of Potent PfCLK3 Inhibitors Based on TCMDC-135051 as a New Class of Antimalarials.
Amit MahindraOmar JanhaKopano MapesaAna Sanchez-AzquetaMahmood M AlamAlfred Amambua-NgwaDavis C NwakanmaAndrew B TobinAndrew G JamiesonPublished in: Journal of medicinal chemistry (2020)
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.
Keyphrases
- plasmodium falciparum
- structure activity relationship
- energy transfer
- protein kinase
- end stage renal disease
- prognostic factors
- chronic kidney disease
- molecular docking
- ejection fraction
- escherichia coli
- quantum dots
- peritoneal dialysis
- high throughput
- electronic health record
- emergency department
- cancer therapy
- single molecule
- big data
- risk assessment
- deep learning
- drug induced
- patient reported
- human health
- single cell
- adverse drug
- free survival