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

• Published in: Bioorganic & medicinal chemistry Vol. 25; no. 16; pp. 4397 - 4406
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-08-2017
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Cell Line; Crystallographic overlays; Crystallography, X-Ray; DAPY-IAS hybrids; Dose-Response Relationship, Drug; Drug design; Drug Discovery; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - metabolism; HIV-1 - drug effects; HIV-1 inhibitors; Humans; Indoles - chemistry; Indoles - pharmacology; Microbial Sensitivity Tests; Molecular modeling; Molecular Structure; Pyrimidines - chemistry; Pyrimidines - pharmacology; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; SARs; Structure-Activity Relationship; Sulfones - chemistry; Sulfones - pharmacology; HIV-1 inhibitors; DAPY-IAS hybrids; SARs; Drug design; Crystallographic overlays; Molecular modeling
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.06.022

A novel series of DAPY-IAS hybrid derivatives were identified as newer HIV-1 NNRTIs using structure-based molecular hybridization.
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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 1.48μM and 1.61μM, respectively. They were much potent than the reference drug ddI (EC50=76.0μM) and comparable to 3TC (EC50=2.54μM). 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.