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Jamieson_PfCLK3_ChemRxiv.pdf (1.41 MB)

Development of Potent and Selective PfCLK3 Inhibitors Based on GSK-TCMDC151 as a New Class of Antimalarials

submitted on 12.09.2019, 18:22 and posted on 13.09.2019, 15:25 by Amit Mahindra, Omar Janha, Kopano Mapesa, Ana Sanchez-Azqueta, Mahmood M. Alam, Andrew Tobin, Andrew Jamieson

The 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 1and efforts to establish a SAR with a 7-azaindole-based series. A total of 14 analogues were assessed in a TR-FRET assay against the full recombinant protein kinase PfCLK3 and 10 were further assessed in parasites 3D7 (chloroquine sensitive) strains of P. falciparum. SAR relating to rings A and B was established. These data suggest that TCMDC-135051 1is a promising lead compound for the development of new antimalarials with a novel mechanism of action targeting PfCLK3.


Email Address of Submitting Author


University of Glasgow


United Kingdom

ORCID For Submitting Author


Declaration of Conflict of Interest

No conflicts of interest

Version Notes

ChemRxiv version


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