New Alkenyldiarylmethanes with Enhanced Potencies as Anti-HIV Agents Which Act as Non-Nucleoside Reverse Transcriptase Inhibitors

• Published in: Journal of medicinal chemistry Vol. 41; no. 12; pp. 2076 - 2089
• Main Authors: Cushman, Mark, Casimiro-Garcia, Agustin, Hejchman, Elzbieta, Ruell, Jeffrey A, Huang, Mingjun, Schaeffer, Catherine A, Williamson, Karen, Rice, William G, Buckheit, Robert W
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 04-06-1998
• Subjects: ADAM II; AIDS/HIV; Alkanes - chemical synthesis; Alkanes - chemistry; Alkanes - metabolism; Alkanes - pharmacology; alkenyldiarylmethane; Alkenyldiarylmethanes; Animals; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - metabolism; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Binding Sites; Biological and medical sciences; Caproates - chemical synthesis; Caproates - chemistry; Caproates - metabolism; Caproates - pharmacology; Cell Line; Cytopathogenic Effect, Viral - drug effects; Drug Evaluation, Preclinical; Drug Resistance, Microbial; HIV Reverse Transcriptase - genetics; HIV Reverse Transcriptase - metabolism; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 - genetics; HIV-1 - physiology; Human immunodeficiency virus; Human immunodeficiency virus 1; integrase; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - virology; Macrophages - drug effects; Macrophages - virology; Medical sciences; Mice; Models, Molecular; Mutation; nonnucleoside reverse transcriptase inhibitor; Pharmacology. Drug treatments; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - metabolism; Reverse Transcriptase Inhibitors - pharmacology; Structure-Activity Relationship; T-Lymphocytes - drug effects; T-Lymphocytes - virology; Virus Replication - drug effects; Zidovudine - pharmacology; RNA-directed DNA polymerase; HIV-1 virus; Non nucleoside compound; Binding site; Modeling; Benzoic acid derivatives; Structure activity relation; Chlorine Organic compounds; Molecular model; Antiviral; Infected cell; Inhibition; Mechanism of action; Chemical synthesis; Clinical isolate; Enzyme; Aliphatic compound; Transferases; Retroviridae; Enzyme inhibitor; Lentivirus; In vitro; Virus; Resistance; Nucleotidyltransferases; Replication; Human immunodeficiency virus; Mutation; Zidovudine; Ethylenic compound
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9800595

Twenty-two new alkenyldiarylmethanes (ADAMs) were synthesized and evaluated for inhibition of HIV-1 replication. The most potent compound proved to be methyl 3‘,3‘‘-dichloro-4‘,4‘‘-dimethoxy-5‘,5‘‘-bis(methoxycarbonyl)-6,6-diphenyl-5-hexenoate (ADAM II), which displayed an EC50 of 13 nM for inhibition of the cytopathic effect of HIV-1RF in CEM-SS cells. ADAM II inhibited HIV-1 reverse transcriptase with an IC50 of 0.3 μM but was inactive as an inhibitor of HIV-1 attachment/fusion to cells, protease, integrase, and the nucleocapsid protein. Molecular target-based and cell-based assays revealed that ADAM II acted biologically as a nonnucleoside reverse transcriptase inhibitor (NNRTI). ADAM II inhibited replication of a wide variety of laboratory, clinical, and clade-representative isolates of HIV-1 in T cell lines and cultures of peripheral blood mononuclear cells or monocyte/macrophages. Mutations that conferred resistance to ADAM II clustered at residues 101, 103, 108, 139, 179, 181, and 188, which line the nonnucleoside binding pocket of HIV-1 reverse transcriptase. However, HIV-1 NL4-3 strain expressing a mutation at residue 100 of reverse transcriptase, and an AZT-resistant virus, displayed increased sensitivity to ADAM II. Thus, ADAM II could serve as an adjunct therapy to AZT and NNRTIs that select for L100I resistance mutations.