Journal article
Synthesis and Structure–Activity relationship of 1-(5-isoquinolinesulfonyl)piperazine analogues as inhibitors of Mycobacterium tuberculosis IMPDH
V Singh, A Pacitto, S Donini, DM Ferraris, S Boros, E Illyés, B Szokol, M Rizzi, TL Blundell, DB Ascher, J Pato, V Mizrahi
European Journal of Medicinal Chemistry | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER | Published : 2019
Abstract
Tuberculosis (TB) is a major infectious disease associated increasingly with drug resistance. Thus, new anti-tubercular agents with novel mechanisms of action are urgently required for the treatment of drug-resistant TB. In prior work, we identified compound 1 (cyclohexyl(4-(isoquinolin-5-ylsulfonyl)piperazin-1-yl)methanone) and showed that its anti-tubercular activity is attributable to inhibition of inosine-5′-monophosphate dehydrogenase (IMPDH) in Mycobacterium tuberculosis. In the present study, we explored the structure–activity relationship around compound 1 by synthesizing and evaluating the inhibitory activity of analogues against M. tuberculosis IMPDH in biochemical and whole-cell a..
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Awarded by South African Medical Research Council
Funding Acknowledgements
This work was supported by the European Community's Seventh Framework Programme (Grant 260872, More Medicines for Tuberculosis); the Howard Hughes Medical Institute (Senior International Research Scholar's grant to V.M.); the National Research Foundation of South Africa (to V.M.); and the South African Medical Research Council (to V.M.). D.B.A was funded by the Jack Brockhoff Foundation (JBF 4186, 2016), a C.J. Martin Research Fellowship from the National Health and Medical Research Council of Australia (APP1072476), and the Department of Biochemistry, University of Melbourne. D.B.A. and T.L.B received funding from the Newton Fund RCUK-CONFAP Grant awarded by The Medical Research Council and Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (MR/M026302/1). A.P and T.L.B were funded by the Bill and Melinda Gates Foundation. Special thanks to Gyorgyi Farkas (Vichem) for the technical assistance. We also thank medicinal chemists of Drug Discovery & Development Centre (H3D), University of Cape Town for the discussions.