Design, Synthesis, and Preclinical Evaluations of Novel 4-Substituted 1,5-Diarylanilines as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Drug Candidates

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• 作者：Lian-Qi Sun ; Lei Zhu ; Keduo Qian ; Bingjie Qin ; Li Huang ; Chin Ho Chen ; Kuo-Hsiung Lee ; Lan Xie
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：August 23, 2012
• 年：2012
• 卷：55
• 期：16
• 页码：7219-7229
• 全文大小：372K
• 年卷期：v.55,no.16(August 23, 2012)
• ISSN：1520-4804

文摘

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 EC₅₀ 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 EC₅₀ values at the subnanomolar level (0.29鈥?.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 (EC₅₀ < 10 nM) have better aqueous solubility (>1鈥?0 渭g/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log聽P values (<5) and polar surface areas (PSA) (<140 脜²). These promising results warrant further development of this novel compound class as potential potent anti-AIDS clinical trial candidates.