Substituted tetrahydroquinolines as potent allosteric inhibitors of reverse transcriptase and its key mutants

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 17; pp. 5119 - 5123
• Main Authors: Su, Dai-Shi, Lim, John J., Tinney, Elizabeth, Wan, Bang-Lin, Young, Mary Beth, Anderson, Kenneth D., Rudd, Deanne, Munshi, Vandna, Bahnck, Carolyn, Felock, Peter J., Lu, Meiqing, Lai, Ming-Tain, Touch, Sinoeun, Moyer, Gregory, DiStefano, Daniel J., Flynn, Jessica A., Liang, Yuexia, Sanchez, Rosa, Prasad, Sridhar, Yan, Youwei, Perlow-Poehnelt, Rebecca, Torrent, Maricel, Miller, Mike, Vacca, Joe P., Williams, Theresa M., Anthony, Neville J.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.09.2009; Elsevier
• Subjects: AIDS VIRUS; Allosteric Site; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; BASIC BIOLOGICAL SCIENCES; Binding Sites; Biological and medical sciences; Crystal structure; Crystallography, X-Ray; ENZYME INHIBITORS; GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - metabolism; Human immunodeficiency virus 1; Medical sciences; Molecular Conformation; Molecular modeling; Mutant Proteins - antagonists & inhibitors; Mutant Proteins - metabolism; Mutant virus; MUTANTS; MUTATIONS; Non-nucleoside reverse transcriptase inhibitor (NNRTI); PHARMACOLOGY; Pharmacology. Drug treatments; QUINOLINES; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; SAR; Structure-Activity Relationship; STRUCTURE-ACTIVITY RELATIONSHIPS; SYNTHESIS; Tetrahydroquinoline; THERAPY; Thiocarbamates - chemistry; Thiocarbamates - pharmacology; Mutant virus; SAR; Molecular modeling; Non-nucleoside reverse transcriptase inhibitor (NNRTI); Crystal structure; Tetrahydroquinoline; RNA-directed DNA polymerase; HIV-1 virus; Nitrogen heterocycle; Non nucleoside compound; Modeling; Chlorine Organic compounds; Reverse transcriptase inhibitor; Molecular model; Bicyclic compound; Antiviral; Sulfonamide; Enzyme; Transferases; Benzene derivatives; Retroviridae; Quinoline derivatives; Enzyme inhibitor; Organic thiocarbamate; Inhibitor enzyme complex; Lentivirus; In vitro; Virus; Allosteric inhibitor; Nucleotidyltransferases; Carboxamide; Human immunodeficiency virus; Crystalline structure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.07.031

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key elements of multidrug regimens, called HAART (Highly Active Antiretroviral Therapy), that are used to treat HIV-1 infections. Elucidation of the structure–activity relationships of the thiocarbamate moiety of the previous published lead compound 2 provided a series of novel tetrahydroquinoline derivatives as potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells. The SAR optimization, mutation profiles, preparation of compounds, and pharmacokinetic profile of compounds are described.