Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays

作者：Huang, Boshi; Wang, Xueshun; Liu, Xinhao; Chen, Zihui; Li, Wanzhuo; Sun, Songkai; Liu, Huiqing; Daelemans, Dirk; De Clercq, Erik; Pannecouque, Christophe; Zhan, Peng^*; Liu, Xinyong^*

来源：Bioorganic & Medicinal Chemistry, 2017, 25(16): 4397-4406.

DOI：10.1016/j.bmc.2017.06.022

• HIV-1 inhibitors
• DAPY-IAS hybrids
• Crystallographic overlays
• Drug design
• SARs
• Molecular modeling

Crystallographic overlap studies and pharmacophoric analysis indicated that diarylpyrimidine (DAPY)based HIV-1 NNRTIs showed a similar binding mode and pharmacophoric features as indolylarylsulfones (IASs), another class of potent NNRTIs. Thus, a novel series of DAPY-IAS hybrid derivatives were identified as newer NNRTIs using structure-based molecular hybridization. Some target compounds exhibited moderate activities against HIV-1 IIIB strain, among which the two most potent inhibitors possessed EC50 values of 1.48 mu M and 1.61 mu M, respectively. They were much potent than the reference drug ddI (EC50 = 76.0 mu M) and comparable to 3TC (EC50 = 2.54 mu M). Compound 7a also exhibited the favorable selectivity index (SI = 80). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships, molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed.

• 出版日期2017-8-15
• 单位山东大学; 河北医科大学