Cosalane Analogs with Enhanced Potencies as Inhibitors of HIV-1 Protease and Integrase

Several new analogues of the novel anti-HIV agent cosalane have been synthesized and evaluated as inhibitors of HIV-1 integrase and protease, HIV-1 replication, HIV-1 and HIV-2 cytopathicity, HIV-1- and HIV-2-mediated syncytium formation, and cytopathicity of a variety of human pathogenic viruses. T...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1995-02, Vol.38 (3), p.443-452
Main Authors: Cushman, Mark, Golebiewski, W. Marek, Pommier, Yves, Mazunder, Abhijit, Reymen, Diane, De Clercq, Erik, Grahm, Lisa, Rice, William G
Format: Article
Language:English
Subjects:
AIDS/HIV
Amino Acid Sequence
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Antiviral Agents - pharmacology
Aurintricarboxylic Acid - analogs & derivatives
Aurintricarboxylic Acid - chemistry
Aurintricarboxylic Acid - pharmacology
Biological and medical sciences
Cell Line
DNA Nucleotidyltransferases - antagonists & inhibitors
Herpesviridae - drug effects
HIV Protease Inhibitors - pharmacology
HIV-1 - drug effects
HIV-1 - enzymology
HIV-1 - physiology
human immunodeficiency virus 1
human immunodeficiency virus 2
Humans
Integrases
Medical sciences
Microbial Sensitivity Tests
Molecular Sequence Data
Pharmacology. Drug treatments
Virus Replication - drug effects
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Summary:Several new analogues of the novel anti-HIV agent cosalane have been synthesized and evaluated as inhibitors of HIV-1 integrase and protease, HIV-1 replication, HIV-1 and HIV-2 cytopathicity, HIV-1- and HIV-2-mediated syncytium formation, and cytopathicity of a variety of human pathogenic viruses. The congeners displayed enhanced potencies relative to cosalane itself as inhibitors of HIV-1 integrase and protease. The two most potent analogues against HIV-1 integrase displayed IC50 values of 2.2 microM, while the three most potent compounds against HIV-1 protease had IC50 values in the 0.35-0.39 microM range. In addition to its activity against HIV-1 and HIV-2 cytopathicity, cosalane inhibited the cytopathic effects of herpes simplex virus-1, herpes simplex virus-2, and human cytomegalovirus at concentrations that were well below the cytotoxic concentrations. Potentially useful antiviral activities were also revealed for some of the new cosalane congeners against influenza virus, Junin virus, and Tacaribe virus.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00003a007