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

Vinayak Singh, Angela Pacitto, Stefano Donini, Davide M. Ferraris, Sándor Boros, Eszter Illyés, Bálint Szokol, Menico Rizzi, Tom L. Blundell, David B. Ascher, Janos Pato, Valerie Mizrahi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)309-329
Number of pages21
JournalEuropean Journal of Medicinal Chemistry
Volume174
DOIs
Publication statusPublished - 15 Jul 2019

Keywords

  • GuaB2
  • IMPDH
  • SAR
  • Tuberculosis

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