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Jamieson_PfCLK3_ChemRxiv.pdf (1.41 MB)
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Development of Potent and Selective PfCLK3 Inhibitors Based on GSK-TCMDC151 as a New Class of Antimalarials

preprint
submitted on 12.09.2019 and posted on 13.09.2019 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.

History

Email Address of Submitting Author

andrew.jamieson.2@glasgow.ac.uk

Institution

University of Glasgow

Country

United Kingdom

ORCID For Submitting Author

0000-0003-1726-7353

Declaration of Conflict of Interest

No conflicts of interest

Version Notes

ChemRxiv version

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