Development of potent PfCLK3 inhibitors based on TCMDC-135051 as a new class of antimalarials

Mahindra, A., Janha, O., Mapesa, K., Sanchez Azqueta, A., Alam, M. M. , Amambua-Ngwa, A., Nwakanma, D. C., Tobin, A. B. and Jamieson, A. G. (2020) Development of potent PfCLK3 inhibitors based on TCMDC-135051 as a new class of antimalarials. Journal of Medicinal Chemistry, 63(17), pp. 9300-9315. (doi: 10.1021/acs.jmedchem.0c00451) (PMID:32787140) (PMCID:PMC7497403)

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 (SAR) with a 7-azaindole-based series. A total of 14 analogues were assessed in a TR-FRET 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.

• Item Type: Articles
• Additional Information: The authors thank the University of Glasgow (A.G.J. and A.B.T.), EPSRC (Research Project Grant EP/N034295/1) (A.M.) and MRC Developmental Gap Fund (A.S.-A.) for financial support of this research. O.J. thanks MRC Toxicology Unit and MRC Unit the Gambia for a PhD studentship. K.M. thanks the University of Glasgow for a Lord Kelvin Adam Smith Studentship. M.M.A. thanks the University of Glasgow for a Lord Kelvin Adam Smith Fellowship.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Janha, Dr Omar and Mahindra, Dr Amit and Jamieson, Professor Andrew and Tobin, Andrew and Sanchez Azqueta, Dr Rer Nat Ana and Mapesa, Kopano and Alam, Dr Mahmood
• Authors: Mahindra, A., Janha, O., Mapesa, K., Sanchez Azqueta, A., Alam, M. M., Amambua-Ngwa, A., Nwakanma, D. C., Tobin, A. B., and Jamieson, A. G.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences; College of Medical Veterinary and Life Sciences > School of Life Sciences; College of Science and Engineering > School of Chemistry
• Journal Name: Journal of Medicinal Chemistry
• Publisher: American Chemical Society
• ISSN: 0022-2623
• ISSN (Online): 1520-4804
• Published Online: 28 July 2020
• Copyright Holders: Copyright © 2020 American Chemical Society
• First Published: First published in Journal of Medicinal Chemistry 63(17): 9300-9315
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
305807		Substrate Peptidomimetic Inhibitors (SPIs) of the COP9 signalosome	Andrew Jamieson	Engineering and Physical Sciences Research Council (EPSRC)	EP/N034260/2	Chemistry