Cosalane analogues 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. 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.
Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907.
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M
Cushman
W M
WM
Golebiewski
Y
Y
Pommier
A
A
Mazumder
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D
Reymen
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E
De Clercq
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L
Graham
W G
WG
Rice
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D001312:Aurintricarboxylic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004254:DNA Nucleotidyltransferases / Q000037:antagonists & inhibitors*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006564:Herpesviridae / Q000187:drug effects; D006801:Humans; D019426:Integrases; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; C083060:cosalane; D001312:Aurintricarboxylic Acid; D004254:DNA Nucleotidyltransferases; D019426:Integrases