title: DB-02, a C-6-cyclohexylmethyl substituted pyrimidinone HIV-1 reverse transcriptase inhibitor with nanomolar activity, displays an improved sensitivity against K103N or Y181C than S-DABOs.
abstract: 6-(cyclohexylmethyl)-5-ethyl-2-((2-oxo-2-phenylethyl)thio)pyrimidin-4(3H)-one (DB-02) is a member of the newly reported synthetic anti-HIV-1 compounds dihydro-aryl/alkylsulfanyl-cyclohexylmethyl-oxopyrimidines, S-DACOs. In vitro anti-HIV-1 activity and resistance profile studies have suggested that DB-02 has very low cytotoxicity (CC50>1mM) to cell lines and peripheral blood mononuclear cells (PBMCs). It displays potent anti-HIV-1 activity against laboratory adapted strains and primary isolated strains including different subtypes and tropism strains (EC50s range from 2.40 to 41.8 nM). Studies on site-directed mutagenesis, genotypic resistance profiles revealed that V106A was the major resistance contributor for the compound. Molecular docking analysis showed that DB-02 located in the hydrophobic pocket with interactions of Lys101, Val106, Leu234, His235. DB-02 also showed non-antagonistic effects to four approved antiretroviral drugs. All studies indicated that DB-02 would be a potential NNRTI with low cytotoxicity and improved activity.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, P. R. China ; University of Chinese Academy of Sciences, Beijing, P. R. China.
authors.forename: Xing-Jie
authors.initials: XJ
authors.lastname: Zhang
authors.forename: Li-He
authors.initials: LH
authors.lastname: Lu
authors.forename: Rui-Rui
authors.initials: RR
authors.lastname: Wang
authors.forename: Yue-Ping
authors.initials: YP
authors.lastname: Wang
authors.forename: Rong-Hua
authors.initials: RH
authors.lastname: Luo
authors.forename: Christopher
authors.initials: C
authors.lastname: Cong Lai
authors.forename: Liu-Meng
authors.initials: LM
authors.lastname: Yang
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: He
authors.forename: Yong-Tang
authors.initials: YT
authors.lastname: Zheng
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D002460:Cell Line; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D016297:Mutagenesis, Site-Directed; D011744:Pyrimidinones / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
chemical_list: C000590212:6-(cyclohexylmethyl)-5-ethyl-2-((2-oxo-2-phenylethyl)thio)pyrimidin-4(3H)-one; D000098:Acetophenones; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase