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Development of Potent PfCLK3 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 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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Mahindra A,Janha O,Mapesa K,Sanchez-Azqueta A,Alam MM,Amambua-Ngwa A,Nwakanma DC,Tobin AB,Jamieson AG

doi

10.1021/acs.jmedchem.0c00451

subject

Has Abstract

pub_date

2020-09-10 00:00:00

pages

9300-9315

issue

17

eissn

0022-2623

issn

1520-4804

journal_volume

63

pub_type

杂志文章

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