Physicochemical property-driven optimization of diarylaniline compounds as potent HIV-1 non-nucleoside reverse transcriptase inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Liu, Na¹  Qin, Bingjie¹  Sun, Lian-Qi¹  Yu, Fei^2,3,4  Lu, Lu^2,3,4  Jiang, Shibo^2,3,4,5  Lee, Kuo-Hsiung^6,7  Xie, Lan¹ 

[1] Beijing Inst Pharmacol Toxicol, Beijing 100850, Peoples R China

[2] Fudan Univ, Shanghai Med Coll, Minist Educ, Key Lab Med Mol Virol, Shanghai 200032, Peoples R China

[3] Fudan Univ, Shanghai Med Coll, Minist Hlth, Shanghai 200032, Peoples R China

[4] Fudan Univ, Inst Med Microbiol, Shanghai 200032, Peoples R China

[5] New York Blood Ctr, Lindsley F Kimball Res Inst, New York, NY 10065 USA

[6] Univ N Carolina, UNC Eshelman Sch Pharm, Nat Prod Res Labs, Chapel Hill, NC 27599 USA

[7] China Med Univ & Hosp, Chinese Med Res & Dev Ctr, Taichung, Taiwan

关键词: Anti-HIV agents;    Diarylaniline;    NNRTIs;    Physicochemical property;   

DOI  :  10.1016/j.bmcl.2014.07.011

来源: Elsevier

【 摘 要 】

Using physicochemical property-driven optimization, twelve new diarylaniline compounds (DAANs) (7a-h, 11a-b and 12a-b) were designed and synthesized. Among them, compounds 12a-b not only showed high potency (EC50 0.96-4.92 nM) against both wild-type and drug-resistant viral strains with the lowest fold change (FC 0.91 and 5.13), but also displayed acceptable drug-like properties based on aqueous solubility and lipophilicity (LE > 0.3, LLE > 5, LELP < 10). The correlations between potency and physicochemical properties of these DAAN analogues are also described. Compounds 12a-b merit further development as potent clinical trial candidates against AIDS. (C) 2014 Elsevier Ltd. All rights reserved.

【 授权许可】

Free