Synthesis, anti-HIV activity, and metabolic stability of new alkenyldiarylmethane HIV-1 non-nucleoside reverse transcriptase inhibitors.

Abstract

Non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) are part of the combination therapy currently used to treat HIV infection. Based on analogy with known HIV-1 NNRT inhibitors, 18 novel alkenyldiarylmethanes (ADAMs) containing 5-chloro-2-methoxyphenyl, 3-cyanophenyl, or 3-fluoro-5-trifluoromethylphenyl groups were synthesized and evaluated as HIV inhibitors. Their stabilities in rat plasma have also been investigated. Although introducing 5-chloro-2-methoxyphenyl or 3-fluoro-5-trifluoromethylphenyl groups into alkenyldiarylmethanes does not maintain the antiviral potency, the structural modification of alkenyldiarylmethanes with a 3-cyanophenyl substituent can be made without a large decrease in activity. The oxazolidinonyl group was introduced into the alkenyldiarylmethane framework and found to confer enhanced metabolic stability in rat plasma.

• Authors: Bo-Liang Deng, Tracy L Hartman, Robert W Buckheit Jr, Christophe Pannecouque, Erik De Clercq, Phillip E Fanwick, Mark Cushman
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 19 Pg. 6140-55 (Sep 22 2005) ISSN: 0022-2623 [Print] United States
• PMID: 16162014 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-HIV Agents
• Reverse Transcriptase Inhibitors
• Methane

Topics

• Animals
• Anti-HIV Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line
• Crystallography, X-Ray
• Cytopathogenic Effect, Viral
• HIV-1 (drug effects, enzymology, pathogenicity)
• Methane (analogs & derivatives, blood, chemical synthesis, pharmacology)
• Rats
• Reverse Transcriptase Inhibitors (blood, chemical synthesis, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship