Analogs of N′-hydroxy-N-(4H,5H-naphtho[1,2-d]thiazol-2-yl) methanimidamide inhibit Mycobacterium tuberculosis methionine aminopeptidases

Shridhar Bhat, Omonike Olaleye, Kirsten J. Meyer, Wanliang Shi, Ying Zhang, Jun O. Liu

Research output: Contribution to journalArticlepeer-review

Abstract

Our previous target validation studies established that inhibition of methionine aminopeptidases (MtMetAP, type 1a and 1c) from Mycobacterium tuberculosis (Mtb) is an effective approach to suppress Mtb growth in culture. A novel class of MtMetAP1c inhibitors comprising of N′-hydroxy-N-(4H,5H- naphtho[1,2-d]thiazol-2-yl)methanimidamide (4c) was uncovered through a high-throughput screen (HTS). A systematic structure-activity relationship study (SAR) yielded variants of the hit, 4b, 4h, and 4k, bearing modified A- and B-rings as potent inhibitors of both MtMetAPs. Except methanimidamide 4h that showed a moderate Mtb inhibition, a desirable minimum inhibitory concentration (MIC) was not obtained with the current set of MtMetAP inhibitors. However, the SAR data generated thus far may prove valuable for further tuning of this class of inhibitors as effective anti-tuberculosis agents.

Original languageEnglish (US)
Pages (from-to)4507-4513
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number14
DOIs
StatePublished - Jul 15 2012

Keywords

  • Methionine aminopeptidase
  • N′-Hydroxy-N-(thiazol-2-yl) methanimidamide
  • Tuberculosis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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