title: Discovery of uracil-bearing DAPYs derivatives as novel HIV-1 NNRTIs via crystallographic overlay-based molecular hybridization.
abstract: A novel series of uracil-bearing DAPYs derivatives were designed and synthesized via structure-based molecular hybridization to discover compounds with improved anti-resistance profiles. Anti-HIV activity of the designed compounds was tested in MT-4 cell cultures. The most promising compound 16d showed excellent activity with EC50value of 5.6 nM against wide-type HIV-1 and low cytotoxicity (SI > 50000). Activity against the clinic prevalent mutant strains was also tested, suggesting that 16d was sensitive to E138K (EC50= 34.2 nM). Primary drug-like properties, such as water solubility and logP, were evaluated by experiment or calculation, which indicated that introducing an uracil can improve solubility. The molecular modeling accompanied with the preliminary SAR correlations paved the way for the next round of rational design of potent anti-HIV agents.
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Kang
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Huo
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China.
authors.forename: Zhongxia
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Institute of Pharmacology, School of Medicine, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Liu
authors.affiliation: Rega Institute for Medical Research, KU Leuven Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.affiliation: Rega Institute for Medical Research, KU Leuven Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhan
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
authors.forename: Xinyong
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D055808:Drug Discovery; D054303:HIV Reverse Transcriptase / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008958:Models, Molecular; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D014498:Uracil / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D014498:Uracil; D054303:HIV Reverse Transcriptase
keywords: DAPYs; Drug design; Molecular hybridization; NNRTIs; Physicochemical properties; Uracil