title: Design, synthesis, and preclinical evaluations of novel 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) drug candidates.
abstract: Twenty-one new 4-substituted diarylaniline compounds (DAANs) (series 13, 14, and 15) were designed, synthesized, and evaluated against wild-type and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to subnanomolar EC(50) values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC(50) values at the subnanomolar level (0.29-0.87 nM) and were comparable to or more potent than the new NNRTI drug riplivirine (2) in the same assays. Druglike physicochemical property assessments revealed that the most active DAANs (EC(50) < 10 nM) have better aqueous solubility (>1-90 μg/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log P values (<5) and polar surface areas (PSA) (<140 Å(2)). These promising results warrant further development of this novel compound class as potential potent anti-AIDS clinical trial candidates.
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing 100850, China.
authors.forename: Lian-Qi
authors.initials: LQ
authors.lastname: Sun
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.forename: Keduo
authors.initials: K
authors.lastname: Qian
authors.forename: Bingjie
authors.initials: B
authors.lastname: Qin
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.forename: Chin Ho
authors.initials: CH
authors.lastname: Chen
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.forename: Lan
authors.initials: L
authors.lastname: Xie
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D015195:Drug Design; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014779:Virus Replication
chemical_list: D000814:Aniline Compounds; D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase