Download MendeleySynthesis and Structure-Activity relationship of 1-(5-isoquinolinesulfonyl)piperazine analogues as inhibitors of Mycobacterium tuberculosis IMPDH.
Singh, V., Pacitto, A., Donini, S., Ferraris, D.M., Boros, S., Illyes, E., Szokol, B., Rizzi, M., Blundell, T.L., Ascher, D.B., Pato, J., Mizrahi, V.(2019) Eur J Med Chem 174: 309-329
- PubMed: 31055147
- DOI: https://doi.org/10.1016/j.ejmech.2019.04.027
- Primary Citation of Related Structures:
6D4Q, 6D4R, 6D4S, 6D4T, 6D4U, 6D4V, 6D4W - PubMed 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 assays. X-ray crystallography was performed to elucidate the mode of binding of selected analogues to IMPDH. We establish the importance of the cyclohexyl, piperazine and isoquinoline rings for activity, and report the identification of an analogue with IMPDH-selective activity against a mutant of M. tuberculosis that is highly resistant to compound 1. We also show that the nitrogen in urea analogues is required for anti-tubercular activity and identify benzylurea derivatives as promising inhibitors that warrant further investigation.
Organizational Affiliation:
H3D Drug Discovery and Development Centre, Department of Drug Discovery and Development & Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, 7701, Cape Town, South Africa; MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical TB Research & Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine & Department of Pathology, University of Cape Town, Anzio Road, Observatory, 7925, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, 7701, Cape Town, South Africa. Electronic address: [email protected].
