title: Design, Synthesis, and Evaluation of Thiophene[3,2-d]pyrimidine Derivatives as HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with Significantly Improved Drug Resistance Profiles.
abstract: We designed and synthesized a series of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a piperidine-substituted thiophene[3,2-d]pyrimidine scaffold, employing a strategy of structure-based molecular hybridization and substituent decorating. Most of the synthesized compounds exhibited broad-spectrum activity with low (single-digit) nanomolar EC50 values toward a panel of wild-type (WT), single-mutant, and double-mutant HIV-1 strains. Compound 27 was the most potent; compared with ETV, its antiviral efficacy was 3-fold greater against WT, 5-7-fold greater against Y181C, Y188L, E138K, and F227L+V106A, and nearly equipotent against L100I and K103N, though somewhat weaker against K103N+Y181C. Importantly, 27 has lower cytotoxicity (CC50 > 227 μM) and a huge selectivity index (SI) value (ratio of CC50/EC50) of >159101. 27 also showed favorable, drug-like pharmacokinetic and safety properties in rats in vivo. Molecular docking studies and the structure-activity relationships provide important clues for further molecular elaboration.
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University , 44 West Culture Road, Jinan 250012, Shandong P.R. 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, Jinan 250012, Shandong P.R. China.|The Second Hospital, Shandong University , No. 247 Beiyuan Avenue, Jinan 250033, China.
authors.forename: Zengjun
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University , 44 West Culture Road, Jinan 250012, Shandong P.R. China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University , 44 West Culture Road, Jinan 250012, Shandong P.R. China.
authors.forename: Boshi
authors.initials: B
authors.lastname: Huang
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University , 44 West Culture Road, Jinan 250012, Shandong P.R. 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, Jinan 250012, Shandong P.R. China.
authors.forename: Xueyi
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University , 44 West Culture Road, Jinan 250012, Shandong P.R. China.
authors.forename: Haoran
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University , 44 West Culture Road, Jinan 250012, Shandong P.R. China.
authors.forename: Zhongxia
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University , 44 West Culture Road, Jinan 250012, Shandong P.R. China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Ding
authors.affiliation: Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Daelemans
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, Jinan 250012, Shandong P.R. China.
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, Jinan 250012, Shandong P.R. China.
authors.forename: Xinyong
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D009154:Mutation; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D019380:Anti-HIV Agents; D054303:HIV Reverse Transcriptase; D006574:Heterocyclic Compounds, 2-Ring; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D013449:Sulfonamides; D013876:Thiophenes; C000621126:4-((4-((4-(4-cyano-2,6-dimethylphenoxy)thieno(3,2-d)pyrimidin-2-yl)amino)piperidin-1-yl)methyl)benzenesulfonamide; D000096926:Benzenesulfonamides