Molecular modeling, design, synthesis, and biological evaluation of novel 3′,4′-dicamphanoyl-(+)-cis-khellactone (DCK) analogs as potent anti-HIV agents
| Autor: | Hai-Feng Chen, Lan Xie, Donglei Yu, Zhuo Yi Bao, Bo Tao Fan, Kuo Hsiung Lee, Zhaowen Lo, Jing Yun Li, Chun Hong Zhao, Jian Zhou Ma, Ting Zhou, Xian Hong Chen |
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| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular Quantitative structure–activity relationship Molecular model Anti-HIV Agents Stereochemistry Clinical Biochemistry Quantitative Structure-Activity Relationship Pharmaceutical Science Biochemistry Chemical synthesis Cell Line Coumarins Drug Discovery Humans Potency Molecular Biology Biological evaluation Anti hiv Chemistry Organic Chemistry Bridged Bicyclo Compounds Heterocyclic Models Chemical Design synthesis Drug Design Lipophilicity HIV-1 Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry. 13:6435-6449 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2005.06.057 |
| Popis: | Our current studies aimed at developing new potential anti-AIDS drug candidates have focused on the design and synthesis of new DCK analogs with improved molecular water solubility. Based on the structures and biodata of previous DCK analogs, 3D-QSAR studies have been performed which resulted in two reliable computational models, CoMFA and CoMSIA, with r(2) values of 0.995 and 0.987, and q(2) values of 0.662 and 0.657, respectively. In accord with these 3D-QSAR models, 15 new DCK analogs with polar functional groups at the 3-position were subsequently designed, synthesized, and evaluated against HIV-1 replication in H9 and MT4 cell lines. New DCK analogs 3b, 3c, 4b, 4c, 6a, 7c, and 9a showed promising potency with EC(50) values ranging from 0.09 to 0.0002 microM in both assays. Meanwhile, these promising compounds also showed a wide range of predicted logP values from 0.90 to 5.19, which increased the probability of identifying anti-HIV drug candidates from this class of compounds for clinical trials. Furthermore, both experimental and predicted values matched well, corroborating the reliability of the established 3D-QSAR models. |
| Databáze: | OpenAIRE |
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