标题：Design, synthesis and anti-HIV evaluation of novel diarylnicotinamide derivatives (DANAs) targeting the entrance channel of the NNRTI binding pocket through structure-guided molecular hybridization
作者：Liu, Zhaoqiang; Chen, Wenmin; Zhan, Peng; De Clercq, Erik; Pannecouque, Christophe; Liu, Xinyong
作者机构：[Liu, Zhaoqiang; Chen, Wenmin; Zhan, Peng; Liu, Xinyong] Shandong Univ, Sch Pharmaceut Sci, Dept Med Chem, Key Lab Chem Biol,Minist Educ, Jinan 250012 更多
通讯作者地址：[Zhan, P]Shandong Univ, Sch Pharmaceut Sci, Dept Med Chem, Key Lab Chem Biol,Minist Educ, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China.
来源：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
关键词：HIV-1; NNRTIs; DANAs; Entrance channel; Molecular hybridization; Drug; design
摘要：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.