title: Design, synthesis, and biological evaluation of novel trifluoromethyl indoles as potent HIV-1 NNRTIs with an improved drug resistance profile.
abstract: A novel series of trifluoromethyl indole derivatives have been designed, synthesized and evaluated for anti-HIV-1 activities in MT-2 cells. The hydrophobic constant, acute toxicity, carcinogenicity and mutagenicity were predicted. Trifluoromethyl indoles 10i and 10k showed extremely promising activities against WT HIV-1 with IC50 values at the low nanomolar level, similar to efavirenz, better than nevirapine, and also possessed higher potency towards the drug-resistant mutant strain Y181C than nevirapine. Preliminary SAR and docking studies of detailed binding mode provided some insights for discovery of more potent NNRTIs.
authors.affiliation: CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China. jiangb@mail.sioc.ac.cn zhangchen@mail.sioc.ac.cn.
authors.forename: Hai-Xia
authors.initials: HX
authors.lastname: Jiang
authors.forename: Dao-Min
authors.initials: DM
authors.lastname: Zhuang
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Xing-Xin
authors.initials: XX
authors.lastname: Cao
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Yao
authors.forename: Jing-Yun
authors.initials: JY
authors.lastname: Li
authors.forename: Jian-Yong
authors.initials: JY
authors.lastname: Wang
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.forename: Biao
authors.initials: B
authors.lastname: Jiang
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D000480:Alkynes; D048588:Benzoxazines / Q000737:chemistry / Q000494:pharmacology; D002273:Carcinogens / Q000633:toxicity; D002384:Catalysis; D002460:Cell Line; D003521:Cyclopropanes; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects*; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D009153:Mutagens / Q000633:toxicity; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000447:Aldehydes; D000480:Alkynes; D048588:Benzoxazines; D002273:Carcinogens; D003521:Cyclopropanes; D007211:Indoles; D008024:Ligands; D009153:Mutagens; D050505:Mutant Proteins; D018894:Reverse Transcriptase Inhibitors; C116609:3-hydroxybutanal; D054303:HIV Reverse Transcriptase; C098320:efavirenz