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Development of Potent Pf CLK3 Inhibitors Based on TCMDC-135051 as a New Class of Antimalarials

Authors
  • Mahindra, Amit1
  • Janha, Omar1
  • Mapesa, Kopano1
  • Sanchez-Azqueta, Ana1
  • Alam, Mahmood M.1
  • Amambua-Ngwa, Alfred2
  • Nwakanma, Davis C.2
  • Tobin, Andrew B.1
  • Jamieson, Andrew G.1
  • 1 University of Glasgow, U.K.
  • 2 MRC Unit The Gambia at LSHTM, The Gambia
Type
Published Article
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Publication Date
Jul 28, 2020
Volume
63
Issue
17
Pages
9300–9315
Identifiers
DOI: 10.1021/acs.jmedchem.0c00451
PMID: 32787140
PMCID: PMC7497403
Source
PubMed Central
License
Unknown

Abstract

The protein kinase Pf CLK3 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 Pf 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 (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 Pf CLK3, 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 Pf CLK3.

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