TY - JOUR
T1 - Analogs of N′-hydroxy-N-(4H,5H-naphtho[1,2-d]thiazol-2-yl) methanimidamide inhibit Mycobacterium tuberculosis methionine aminopeptidases
AU - Bhat, Shridhar
AU - Olaleye, Omonike
AU - Meyer, Kirsten J.
AU - Shi, Wanliang
AU - Zhang, Ying
AU - Liu, Jun O.
N1 - Funding Information:
This work was supported in part by the Department of Pharmacology, Johns Hopkins School of Medicine and the Keck Foundation. We are grateful to ASDI, Inc. for the provision of the compound library. We thank Mr. Steve Fernandes for technical assistance.
PY - 2012/7/15
Y1 - 2012/7/15
N2 - 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.
AB - 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.
KW - Methionine aminopeptidase
KW - N′-Hydroxy-N-(thiazol-2-yl) methanimidamide
KW - Tuberculosis
UR - http://www.scopus.com/inward/record.url?scp=84863196769&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863196769&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2012.05.022
DO - 10.1016/j.bmc.2012.05.022
M3 - Article
C2 - 22704656
AN - SCOPUS:84863196769
SN - 0968-0896
VL - 20
SP - 4507
EP - 4513
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 14
ER -