title: Synthesis, biological evaluation and molecular docking study of N-(2-methoxyphenyl)-6-((4-nitrophenyl)sulfonyl)benzamide derivatives as potent HIV-1 Vif antagonists.
abstract: Viral infectivity factor (Vif) is protective against APOBEC3G (A3G)-mediated viral cDNA hypermutations, and development of molecules that inhibit Vif mediated A3G degradation is a novel strategy for blocking HIV-1 replication. Through optimizations of the central ring of N-(2-methoxyphenyl)-2-((4-nitrophenyl)thio)benzamide (RN-18), we found a potent compound 12c with EC50value of 1.54 μM, enhancing the antiviral activity more than 150-fold compared with RN-18 in nonpermissive H9 cells. 12c protected A3G from degradation by inhibiting Vif function. Besides, 12c suppressed different HIV-1 clinical strains (HIV-1KM018, HIV-1TC-1and HIV-1WAN) and drug-resistant strains (NRTI, NNRTI, PI, and FI) with relatively high activities. Amidation of 12c with glycine gave a prodrug 13a, improving the water solubility about 2600-fold compared with 12c. Moreover, 13a inhibited the virus replication efficiently with an EC50value of 0.228 μM. These results suggested that the prodrug 13a is a promising candidate agent for the treatment of AIDS.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, PR China; Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education, Guizhou Medical University, Guiyang 550004, Guizhou, PR China; National Engineering Research Center of Miao's Medicines, Guizhou Medical University, Guiyang 550004, Guizhou, PR China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, PR China.
authors.forename: Rong-Hua
authors.initials: RH
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, PR China.
authors.forename: Xue-Yan
authors.initials: XY
authors.lastname: Hou
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, PR China.
authors.forename: Rui-Rui
authors.initials: RR
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, PR China.
authors.forename: Guo-Yi
authors.initials: GY
authors.lastname: Yan
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, PR China.
authors.forename: Huan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Tissue Engineering and Stem Cell Research Center, Guizhou Medical University, Guiyang 550004, Guizhou, PR China.
authors.forename: Rong-Hong
authors.initials: RH
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, PR China.
authors.forename: Jian-You
authors.initials: JY
authors.lastname: Shi
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, PR China. Electronic address: zhengyt@mail.kiz.ac.cn.
authors.forename: Yong-Tang
authors.initials: YT
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, PR China. Electronic address: lirui@scu.edu.cn.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, PR China.
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Wei
mesh_terms: D000071480:APOBEC-3G Deaminase / Q000378:metabolism; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral; D006801:Humans; D062105:Molecular Docking Simulation; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014779:Virus Replication / Q000187:drug effects; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors*
chemical_list: D019380:Anti-HIV Agents; D001549:Benzamides; D011355:Prodrugs; D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; D000071480:APOBEC-3G Deaminase
keywords: Antiviral activity; Nonpermissive; Vif antagonists; Vif mediated A3G degradation