2-Amino-6-arylsulfonylbenzonitriles as Non-nucleoside Reverse Transcriptase Inhibitors of HIV-1

• Published in: Journal of medicinal chemistry Vol. 44; no. 12; pp. 1866 - 1882
• Main Authors: Chan, Joseph H, Hong, Jean S, Hunter, Robert N, Orr, G. Faye, Cowan, Jill R, Sherman, Douglas B, Sparks, Steven M, Reitter, Barbara E, Andrews, C. Webster, Hazen, Richard J, St Clair, Marty, Boone, Lawrence R, Ferris, Rob G, Creech, Katrina L, Roberts, Grace B, Short, Steven A, Weaver, Kurt, Ott, Ronda J, Ren, Jingshan, Hopkins, Andrew, Stuart, David I, Stammers, David K
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 07.06.2001; Amer Chemical Soc
• Subjects: 2-Amino-6-arylsulfonylbenzonitriles; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Binding Sites; Biological and medical sciences; Cell Line, Transformed; Chemistry, Medicinal; Crystallography, X-Ray; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - chemistry; Human immunodeficiency virus 1; Human T-lymphotropic virus 1 - genetics; Humans; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Conformation; Molecular Structure; Nitriles - chemical synthesis; Nitriles - chemistry; Nitriles - pharmacology; non-nucleoside reverse transcriptase inhibitors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Conformation; Science & Technology; Structure-Activity Relationship; Sulfones - chemical synthesis; Sulfones - chemistry; Sulfones - pharmacology; DESIGN; COMBINATIONS; REPLICATION; DATA-COLLECTION; NONNUCLEOSIDE INHIBITOR; RESOLUTION; ARYL SULFONES; CRYSTALLOGRAPHY; HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1; RNA-directed DNA polymerase; Nevirapine; Sulfone; HIV-1 virus; Non nucleoside compound; Modeling; Structure activity relation; Molecular model; Antiviral; Aromatic compound; Chemical synthesis; Enzyme; Transferases; Retroviridae; Enzyme inhibitor; Inhibitor enzyme complex; Lentivirus; X ray diffraction; In vitro; Virus; Nucleotidyltransferases; Benzenic compound; Human immunodeficiency virus; Aminonitrile; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0004906

A series of 2-amino-5-arylthiobenzonitriles (1) was found to be active against HIV-1. Structural modifications led to the sulfoxides (2) and sulfones (3). The sulfoxides generally showed antiviral activity against HIV-1 similar to that of 1. The sulfones, however, were the most potent series of analogues, a number having activity against HIV-1 in the nanomolar range. Structural−activity relationship (SAR) studies suggested that a meta substituent, particularly a meta methyl substituent, invariably increased antiviral activities. However, optimal antiviral activities were manifested by compounds where both meta groups in the arylsulfonyl moiety were substituted and one of the substituents was a methyl group. Such a disubstitution led to compounds 3v, 3w, 3x, and 3y having IC50 values against HIV-1 in the low nanomolar range. When gauged for their broad-spectrum antiviral activity against key non-nucleoside reverse transcriptase inhibitor (NNRTI) related mutants, all the di-meta-substituted sulfones 3u − z and the 2-naphthyl analogue 3ee generally showed single-digit nanomolar activity against the V106A and P236L strains and submicromolar to low nanomolar activity against strains E138K, V108I, and Y188C. However, they showed a lack of activity against the K103N and Y181C mutant viruses. The elucidation of the X-ray crystal structure of the complex of 3v (739W94) in HIV-1 reverse transcriptase showed an overlap in the binding domain when compared with the complex of nevirapine in HIV-1 reverse transcriptase. The X-ray structure allowed for the rationalization of SAR data and potencies of the compounds against the mutants.