Replacement of the metabolically labile methyl esters in the alkenyldiarylmethane series of non-nucleoside reverse transcriptase inhibitors with isoxazolone, isoxazole, oxazolone, or cyano substituents.
The alkenyldiarylmethanes (ADAMs) are a unique class of non-nucleoside reverse transcriptase inhibitors that have potential value in the treatment of HIV/AIDS. However, the potential usefulness of the ADAMs is limited by the presence of metabolically labile methyl ester moieties. A series of novel ADAMs were therefore designed and synthesized in order to replace the metabolically labile methyl ester moieties of the existing ADAM lead compounds with hydrolytically stable, fused isoxazolone, isoxazole, oxazolone, or cyano substituents on the aromatic rings. The methyl ester and methoxy substituents on both of the aromatic rings in the parent compound 1 were successfully replaced with metabolically stable moieties with retention of anti-HIV activity and a general decrease in cytotoxicity.
Deng
Bo-Liang
BL
Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue Cancer Center, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
Hartman
Tracy L
TL
Buckheit
Robert W
RW
Pannecouque
Christophe
C
De Clercq
Erik
E
Cushman
Mark
M
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003486:Cyanides / Q000737:chemistry*; D015195:Drug Design; D004952:Esters / Q000737:chemistry*; D006801:Humans; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010081:Oxazolone / Q000737:chemistry*; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D003486:Cyanides; D004952:Esters; D007555:Isoxazoles; D018894:Reverse Transcriptase Inhibitors; D010081:Oxazolone