期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 87, 期 -, 页码 52-62出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.09.054
关键词
HIV-1; NNRTIs; DANAs; Entrance channel; Molecular hybridization; Drug design
资金
- National Natural Science Foundation of China (NSFC) [81273354, 81102320, 30873133, 30772629, 30371686]
- Key Project of NSFC for International Cooperation [81420108027, 30910103908]
- Research Fund for the Doctoral Program of Higher Education of China [20110131130005, 20110131120037]
- Natural Science Foundation of Shandong Province [ZR2009CM016]
- KU Leuven [GOA 10/014]
Through a structure-based molecular hybridization approach, a novel series of diarylnicotinamide derivatives (DANAs) targeting the entrance channel of HIV-1 NNRTIs binding pocket (NNIBP) were rationally designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells together with the inhibition against the reverse transcriptase (RT) in an enzymatic assay. Encouragingly, most of the new DANAs were found to be active against wild-type HIV-1 with an EC50 in the range of 0.027-4.54 mu M, Among them, compound 6b11 (EC50 = 0.027 mu M, SI > 12518) and 6b5 (EC50 = 0.029 mu M, SI = 2471) were identified as the most potent inhibitors, which were more potent than the reference drugs nevirapine (EC50 = 0.31 mu M) and delavirdine (EC50 = 0.66 mu M). Some DANAs were also active at micromolar concentrations against the K103N + Y181C resistant mutant. Compound 6b11 exhibited the highest enzymatic inhibition activity (IC50 = 20 nM), which is equal to that of efavirenz (EC50 = 20 nM) and 31 times higher than that of nevirapine (EC50 = 0.62 mu M). Preliminary structure-activity relationships (SARs) and molecular modeling of these new DANAs have been discussed. (C) 2014 Elsevier Masson SAS. All rights reserved.
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