title: Synthesis and anti-HIV activity of new alkenyldiarylmethane (ADAM) non-nucleoside reverse transcriptase inhibitors (NNRTIs) incorporating benzoxazolone and benzisoxazole rings.
abstract: The HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) constitute a large and structurally diverse set of compounds, several of which are currently used in the treatment of AIDS. A series of novel alkenyldiarylmethanes (ADAMs) were designed and synthesized as part of an ongoing investigation to replace the metabolically labile methyl ester moieties found in the ADAM pharmacophore with stable modifications that retain the potent anti-HIV activity of the parent compounds. Unsurprisingly, the rat plasma half-lives of the new ADAMs were not improved when compared to the parent compounds, but all of the synthesized ADAMs inhibited the cytopathic effect of HIV-1 in cell culture. The most potent compound identified was (E)-5-[1-(3,7-dimethyl-2-oxo-2,3-dihydro-benzoxazol-5-yl)-5-methoxycarbonyl-pent-1-enyl]-2-methoxy-3-methylbenzoic acid methyl ester (7), which inhibited the cytopathic effects of both HIV-1(RF) and HIV-1(IIIB) strains in cell cultures with EC50 values of 30 and 90 nM, respectively, and inhibited HIV-1 reverse transcriptase with an IC50 of 20 nM.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology and Purdue Cancer Center, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Bo-Liang
authors.initials: BL
authors.lastname: Deng
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Cullen
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Zhou
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Hartman
authors.forename: Robert W
authors.initials: RW
authors.lastname: Buckheit
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Fanwick
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001583:Benzoxazoles / Q000737:chemistry; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000737:chemistry; D008697:Methane / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C441200:1,2-benzisoxazole; D019380:Anti-HIV Agents; D001583:Benzoxazoles; D007555:Isoxazoles; D018894:Reverse Transcriptase Inhibitors; C017057:benzoxazolone; D008697:Methane