title: Hybrid chemistry. Part 4: Discovery of etravirine-VRX-480773 hybrids as potent HIV-1 non-nucleoside reverse transcriptase inhibitors.
abstract: A novel series of etravirine-VRX-480773 hybrids were designed using structure-guided molecular hybridization strategy and fusing the pharmacophore templates of etravirine and VRX-480773. The anti-HIV-1 activity and cytotoxicity was evaluated in MT-4 cell cultures. The most active hybrid compound in this series, N-(2-chlorophenyl)-2-((4-(4-cyano-2,6-dimethylphenoxy)pyrimidin-2-yl)thio)acetamide 3d (EC50=0.24 , SI>1225), was more potent than delavirdine (EC50=0.66 μM, SI>67) in the anti-HIV-1 in vitro cellular assay. Studies of structure-activity relationships established a correlation between anti-HIV activity and the substitution pattern of the acetanilide group.
authors.affiliation: Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China.
authors.forename: Zheng-Yong
authors.initials: ZY
authors.lastname: Wan
authors.affiliation: Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tao
authors.affiliation: Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China.
authors.forename: Ya-Feng
authors.initials: YF
authors.lastname: Wang
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.
authors.forename: Tian-Qi
authors.initials: TQ
authors.lastname: Mao
authors.affiliation: Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yin
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: Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, Yanbian University, Yanji 133000, People's Republic of China. Electronic address: piaohuri@aliyun.com.
authors.forename: Hu-Ri
authors.initials: HR
authors.lastname: Piao
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: Dirk
authors.initials: D
authors.lastname: Daelemans
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: D000083:Acetanilides / Q000737:chemistry; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D060326:Chemistry Techniques, Synthetic; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D056004:Molecular Dynamics Simulation; D009570:Nitriles; D011724:Pyridazines / Q000737:chemistry; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry
chemical_list: D000083:Acetanilides; D019380:Anti-HIV Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D014230:Triazoles; C519971:VRX-480773; C451734:etravirine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; C508827:acetanilide
keywords: Antiviral agent; Biological activity; Etravirine; Molecular hybridization; VRX-480773