Article ID Journal Published Year Pages File Type
1376132 Bioorganic & Medicinal Chemistry Letters 2008 4 Pages PDF
Abstract

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

Related Topics
Physical Sciences and Engineering Chemistry Organic Chemistry
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