Optimization of 2,4-diarylanilines as non-nucleoside HIV-1 reverse transcriptase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 7; pp. 2376 - 2379
• Main Authors: Sun, Lian-Qi, Qin, Bingjie, Huang, Li, Qian, Keduo, Chen, Chin-Ho, Lee, Kuo-Hsiung, Xie, Lan
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.04.2012; Elsevier
• Subjects: Aniline Compounds - chemical synthesis; Aniline Compounds - pharmacology; Animals; Anti-HIV agents; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; antiviral properties; Biological and medical sciences; Cell Line, Tumor; Diarylaniline; Drug development; Drug Resistance, Viral; Drug Stability; Drugs; enzyme inhibitors; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - metabolism; HIV-1 - drug effects; HIV-1 - enzymology; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Inhibitory Concentration 50; Lead optimization; Medical sciences; Microsomes, Liver - metabolism; Molecular Structure; Nitriles - pharmacology; NNRTIs; Pharmacology. Drug treatments; Pyrimidines - pharmacology; Rats; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - pharmacology; Rilpivirine; RNA-directed DNA polymerase; Solubility; viruses; Lead optimization; Diarylaniline; Anti-HIV agents; NNRTIs; Drug; Antiretroviral agent; RNA-directed DNA polymerase; HIV-1 virus; Enzyme; Transferases; Non nucleoside compound; Retroviridae; Enzyme inhibitor; Pharmacotherapy; Lentivirus; Optimization; Research and development; Virus; Nucleotidyltransferases; Treatment; Reverse transcriptase inhibitor; Antiviral; Human immunodeficiency virus
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.02.055

The current optimization of 2,4-diarylaniline analogs (DAANs) on the central phenyl ring provided a series of new active DAAN derivatives 9a–9e, indicating an accessible modification approach that could improve anti-HIV potency against wild-type and resistant strains, aqueous solubility, and metabolic stability. A new compound 9e not only exhibited extremely high potency against wild-type virus (EC50 0.53nM) and several resistant viral strains (EC50 0.36–3.9nM), but also showed desirable aqueous solubility and metabolic stability, which were comparable or better than those of the anti-HIV-1 drug TMC278 (2). Thus, new compound 9e might be a potential drug candidate for further development of novel next-generation NNRTIs.