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Bioorg Med Chem. 2012 Jul 15;20(14):4507-13. doi: 10.1016/j.bmc.2012.05.022. Epub 2012 May 17.

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

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1
Department of Pharmacology & Molecular Sciences, 725 North Wolfe Street, Baltimore, MD 21205, USA.

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.

PMID:
22704656
PMCID:
PMC3495175
DOI:
10.1016/j.bmc.2012.05.022
[Indexed for MEDLINE]
Free PMC Article
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