Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 18, Issue 16, Pages 4521-4524Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2008.07.047
Keywords
HIV-1 integrase inhibitor; bioisostere; heteroaromatic carboxylic acid; isoxazole; isothiazole; 1H-pyrazole; bioavailability; antiviral effect
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Funding
- National Natural Science Foundation of China [30672528]
- Science and Technology Commission of Shanghai Municipality [07QH14018]
- Key Scientific and Technological Projects of China [200413A719A14]
- Yunnan province [2004NG12]
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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 beta-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. (c) 2008 Elsevier Ltd. All rights reserved.
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