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)

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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, Dr 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 > Institute of Molecular Cell and Systems Biology
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

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
305807Substrate Peptidomimetic Inhibitors (SPIs) of the COP9 signalosomeAndrew JamiesonEngineering and Physical Sciences Research Council (EPSRC)EP/N034260/2Chemistry