期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 44, 期 4, 页码 1650-1663出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2008.09.024
关键词
O-(2-Phthalimidoethyl)-N-arylthiocarbamates; HIV-1; Non-nucleoside reverse transcriptase inhibitors; Parallel synthesis; Molecular docking
资金
- MURST (Cofinanziamento Nazionale)
- CNR (Rome)
- Ministero Italiano della Salute - Istituto Superiore di Sanita [40D.46]
- Fondazione Banca Carige
The structure-activity relationships (SARs) of N-aryl-O-(2-phthalimidoethyl)thiocarbamates (C-TCs) and their imide ring-opened congeners (O-TCs) as non-nucleoside HIV-1 reverse transcriptase inhibitors were further investigated. The SAR strategy involved modifications of the N-phenyl ring followed by the hybridization of the most promising N-aryl and O-(2-phthalimidoethyl)substructures. The role of stereochemistry and tert-butyl substitution of the phthalimidoethyl moiety on activity was also investigated. Seventy-six analogues were prepared by parallel solution-phase synthesis. Twenty-two C-TCs displayed nanomolar activity against wild-type HIV-1 and a number of analogues were effective against the Y181C mutant. Compound 56 combined the highest activity so far identified against Y181C (EC50=1.3 mu M) with good potency against the K103R mutant (EC50=4.8 mu M). Docking simulations helped to rationalize the SARs. (c) 2008 Elsevier Masson SAS. All rights reserved.
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