Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1376132 | Bioorganic & Medicinal Chemistry Letters | 2008 | 4 Pages |
Three new types of aryl diketo acid (ADK) isosteres were designed by conversion of the biologically labile 1,3-diketo unit into heteroaromatic motif such as isoxazole, isothiazole, or 1H-pyrazole to improve the physicochemical property of ADK-based HIV-1 integrase (IN) inhibitors. The synthesis of the heteroaromatic carboxylic acids was established by employing phenyl β-diketoester or benzaldehyde as the starting material and 1,3-dipolar cycloaddition as the key reaction. Of the compounds tested, the 3-benzyloxyphenyl-substituted isoxazole carboxylic acid displayed the best IN inhibitory and antiviral activities, with N-hydroxylamidation enhancing the in vitro and in vivo potency. These findings are important for further optimization of ADK-based IN inhibitors.
Graphical abstractThree types of aryl diketo acid isosteres were designed and synthesized by conversion of the biologically labile 1,3-diketo unit into isoxazole, isothiazole or 1H-pyrazole to improve the bioavailability of ADK-based HIV-1 integrase inhibitors, affording potent antiviral effect and high therapeutic index.Figure optionsDownload full-size imageDownload as PowerPoint slide