Novel diarylpyridinones, diarylpyridazinones and diarylphthalazinones as potential HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs)

• Published in: Bioorganic & medicinal chemistry Vol. 19; no. 20; pp. 5924 - 5934
• Main Authors: Venkatraj, Muthusamy, Ariën, Kevin K., Heeres, Jan, Dirié, Bertrand, Joossens, Jurgen, Van Goethem, Sebastiaan, Van der Veken, Pieter, Michiels, Johan, Vande Velde, Christophe M.L., Vanham, Guido, Lewi, Paul J., Augustyns, Koen
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.10.2011; Elsevier
• Subjects: Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; chemistry; Diarylphthalazinones; Diarylpyridazinones; Diarylpyridinones; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - chemistry; HIV-1 reverse transcriptase; Human immunodeficiency virus 1; Humans; Medical sciences; Models, Molecular; mutants; NNRTIs; non-nucleoside reverse transcriptase inhibitors; Pharmacology. Drug treatments; Phthalazines - chemistry; Phthalazines - pharmacology; Pyridazines - chemistry; Pyridazines - pharmacology; Pyridones - chemistry; Pyridones - pharmacology; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; RNA-directed DNA polymerase; Diarylphthalazinones; Diarylpyridazinones; Diarylpyridinones; HIV-1 reverse transcriptase; NNRTIs; Nitrile; RNA-directed DNA polymerase; HIV-1 virus; Non nucleoside compound; Modeling; Pyridine derivatives; Reverse transcriptase inhibitor; Molecular model; Antiviral; Pyridazine derivatives; Benzonitrile derivatives; Chemical synthesis; Pyridone derivatives; Enzyme; Transferases; Retroviridae; Enzyme inhibitor; Lentivirus; In vitro; Biological activity; Virus; Phthalazine derivatives; Nucleotidyltransferases; Human immunodeficiency virus
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.08.060

In this Letter, we report on diarylpyridinone, diarylpyridazinone and diarylphthalazinone analogs as potential inhibitors of HIV-1 nonnucleoside reverse transcriptase (NNRTIs). The most promising compounds in these series are three diarylpyridazinones 25a, 25l and 25n which demonstrated submicromolar activity against wild-type HIV-1 and moderate activity against the single mutant strain Ba-L V106A.