期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 17, 期 7, 页码 2925-2935出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2008.10.088
关键词
HIV-1 integrase inhibitors; Drug design; 4-Hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids; X-ray crystallography
资金
- Fondazione Banco di Sardegna
- Universite di Sassari
- Campbell Foundation
Previously, we discovered linomide analogues as novel HIV-1 integrase (IN) inhibitors. Here, to make possible structure-activity relationships, we report on the design and synthesis of a series of substituted dihydroquinoline-3-carboxylic acids. The crystal structure of the representative compound 2c has also been solved. Among the eight new analogues, 2e showed a potency in inhibiting IN strand transfer catalytic activity similar to the reference diketo acid inhibitor L-731,988 (IC50 = 0.9 mu M vs. 0.54 mu M, for 2e and L-731,988, respectively). Furthermore, none of the compounds showed significant cytotoxicity in two tested cancer cell lines. These compounds represent an interesting prototype of IN inhibitors, potentially involved in a metal chelating mechanism, and further optimization is warranted. (C) 2008 Elsevier Ltd. All rights reserved.
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