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

来源：European Journal of Medicinal Chemistry, 2014, 87: 52-62.

DOI：10.1016/j.ejmech.2014.09.054

• HIV-1
• NNRTIs
• DANAs
• Entrance channel
• Molecular hybridization
• Drug design

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.

• 出版日期2014-11-24
• 单位河北医科大学; 山东大学