title: Synthesis and biological evaluation of CHX-DAPYs as HIV-1 non-nucleoside reverse transcriptase inhibitors.
abstract: A series of new diarylpyrimidines (DAPYs) characterized by a halogen atom on the methylene linker between wing I and the central pyrimidine ring was synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. The two most promising compounds 7f and 7g showed excellent activity against wild-type HIV-1 with low nanomolar EC50 values of 0.005 and 0.009 μM, respectively, which were comparable to or more potent than all the reference drugs zidovudine (AZT), lamivudine (3TC), nevirapine (NEV), efavirenz (EFV), delaviridine (DLV) and etravirine (ETV). In particular, 7g also displayed strong activity against the double mutant strain 103N + 181C with an EC50 value of 8.2 μM. The preliminary structure-activity relationship (SAR) and molecular docking analysis of this new series of CHX-DAPYs were also investigated.
authors.affiliation: Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China.
authors.forename: Zi-Hong
authors.initials: ZH
authors.lastname: Yan
authors.affiliation: Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China.
authors.forename: Hai-Qiu
authors.initials: HQ
authors.lastname: Wu
authors.affiliation: Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China.
authors.forename: Wen-Xue
authors.initials: WX
authors.lastname: Chen
authors.affiliation: College of Pharmacy, Yanbian University, Yanji 133000, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: College of Pharmacy, Yanbian University, Yanji 133000, People's Republic of China.
authors.forename: Hu-Ri
authors.initials: HR
authors.lastname: Piao
authors.affiliation: Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China. Electronic address: qqhe@fudan.edu.cn.
authors.forename: Qiu-Qin
authors.initials: QQ
authors.lastname: He
authors.affiliation: Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China; Institute of Biomedical Science, Fudan University, Shanghai 200433, People's Republic of China. Electronic address: rfchen@fudan.edu.cn.
authors.forename: Fen-Er
authors.initials: FE
authors.lastname: Chen
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, 10 Minderbroedersstraat, B-3000 Leuven, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, 10 Minderbroedersstraat, B-3000 Leuven, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009570:Nitriles; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects
chemical_list: C000601001:4-((4-((3-bromophenyl)chloromethyl)pyrimidin-2-yl)amino)benzonitrile; C000601000:4-((4-(chloro(3-chlorophenyl)methyl)pyrimidin-2-yl)amino)benzonitrile; D019380:Anti-HIV Agents; D001549:Benzamides; D009570:Nitriles; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: Antiviral activity; Diarylpyrimidine; HIV-1; NNRTIs; SAR