Synthesis and structure–activity relationship of 1-(5-isoquinolinesulfonyl)piperazine analogues as inhibitors of Mycobacterium tuberculosis IMPDH

Synthesis 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., Illyés, E., Szokol, B., Rizzi, M., Blundell, T. L., Ascher, D. B., Pato, J., & Mizrahi, V. European Journal of Medicinal Chemistry, 174:309–329, Elsevier Masson, jul, 2019.

Paper doi abstract bibtex

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.

@article{Singh2019,
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.},
author = {Singh, Vinayak and Pacitto, Angela and Donini, Stefano and Ferraris, Davide M and Boros, S{\'{a}}ndor and Illy{\'{e}}s, Eszter and Szokol, B{\'{a}}lint and Rizzi, Menico and Blundell, Tom L. and Ascher, David B. and Pato, Janos and Mizrahi, Valerie},
doi = {10.1016/J.EJMECH.2019.04.027},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Singh et al. - 2019 - Synthesis and structure–activity relationship of 1-(5-isoquinolinesulfonyl)piperazine analogues as inhibitors of i.pdf:pdf},
journal = {European Journal of Medicinal Chemistry},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jul},
pages = {309--329},
pmid = {31055147},
publisher = {Elsevier Masson},
title = {{Synthesis and structure–activity relationship of 1-(5-isoquinolinesulfonyl)piperazine analogues as inhibitors of \textit{Mycobacterium tuberculosis} IMPDH}},
url = {https://www.sciencedirect.com/science/article/pii/S0223523419303332?via{\%}3Dihub},
volume = {174},
year = {2019}
}

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