Synthesis and anti-HIV activity of new metabolically stable alkenyldiarylmethane non-nucleoside reverse transcriptase inhibitors incorporating N-methoxy imidoyl halide and 1,2,4-oxadiazole systems.
The alkenyldiarylmethanes (ADAMs) are a unique class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that are capable of inhibiting HIV-1 reverse transcriptase (RT) through an allosteric mechanism. However, the potential usefulness of the ADAMs is limited by the presence of metabolically labile methyl ester moieties that are hydrolyzed by nonspecific esterases present in blood plasma, resulting in the formation of the inactive carboxylic acid metabolites. Therefore, to discover metabolically stable ADAMs, the design and synthesis of a new class of ADAMs with N-methoxy imidoyl halide and 1,2,4-oxadiazole systems were attempted. The resulting new ADAM 6 displayed enhanced metabolic stability in rat plasma (t1/2 = 61 h) along with the ability to inhibit HIV-1 reverse transcriptase and the cytopathic effect of HIV-1RF and HIV-1IIIB at submicromolar concentrations.
Sakamoto
Takeshi
T
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
Cullen
Matthew D
MD
Hartman
Tracy L
TL
Watson
Karen M
KM
Buckheit
Robert W
RW
Pannecouque
Christophe
C
De Clercq
Erik
E
Cushman
Mark
M
D000494:Allosteric Regulation; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D006219:Halogens / Q000737:chemistry*; D006801:Humans; D007094:Imides / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D010069:Oxadiazoles / Q000737:chemistry*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D055672:Static Electricity
D019380:Anti-HIV Agents; D006219:Halogens; D007094:Imides; D010069:Oxadiazoles; D018894:Reverse Transcriptase Inhibitors