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

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 metabol...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2012-04, Vol.22 (7), p.2376-2379
Hauptverfasser:	Sun, Lian-Qi, Qin, Bingjie, Huang, Li, Qian, Keduo, Chen, Chin-Ho, Lee, Kuo-Hsiung, Xie, Lan
Format:	Artikel
Sprache:	eng
Schlagworte:	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
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Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.02.055