Synthesis and biological evaluation of 4-(hydroxyimino)arylmethyl diarylpyrimidine analogues as potential non-nucleoside reverse transcriptase inhibitors against HIV

• Published in: Bioorganic & medicinal chemistry 2010-04, Vol.18 (7), p.2370-2374
• Main Authors: Feng, Xiao-Qing, Zeng, Zhao-Sen, Liang, Yong-Hong, Chen, Fen-Er, Pannecouque, Christophe, Balzarini, Jan, Clercq, Erik De
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - pharmacology; Cell Line - drug effects; Cell Survival - drug effects; DAPYs; HIV; HIV-1 - drug effects; HIV-1 - enzymology; HIV-2 - drug effects; Humans; Indicators and Reagents; NNRTIs; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - pharmacology; SAR; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.03.007

A series of novel diarylpyrimidine analogues featuring a hydroxyiminomethyl group between the pyrimidine scaffold and the aryl wing I have been synthesized and tested in MT-4 cells culture as non-nucleoside reverse transcriptase inhibitors against human immunodeficiency virus (HIV). Most of these new congeners exhibited moderate to excellent activity against wild-type virus with an EC50 value ranging from 0.569μM to 0.005μM. 4-(4-((Hydroxyimino) (3-methoxyphenyl)methyl)pyrimidin-2-ylamino)benzonitrile (12n) was identified as the most active compound of this new series (EC50=0.025μM, SI >1223) associated with moderate activity against HIV-1 double mutant strains (K103N+Y181C) (EC50=8.72μM) in addition to its anti-HIV-2 activity with an EC50 value of 8.31μM. Preliminary structure–activity relationship (SAR) among the newly synthesized DAPYs was also investigated.