期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 92, 期 -, 页码 387-400出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.01.009
关键词
Benzothiazole derivatives; alpha-Glucosidase; DFf calculations; Docking studies; Physico-chemical properties
资金
- Ministry of Agriculture (MOA) Malaysia
- Universiti Teknologi MARA under MOA [100-RMI/MOA 16/6/2]
- Atta-ur-Rahman Institute for Natural product Discovery (RiND)
- Higher Education Commission (HEC) Pakistan under the National Research Program for Universitites [20-2073]
In an effort to design and synthesize a new class of alpha-glucosidase inhibitor, we synthesized benzothiazole hybrid having benzohydrazide moiety (5). Compound 5 was reacted with various substituted aryl aldehyde to generate a small library of compounds 6-35. Synthesis of compounds was confirmed by the spectral information. These compounds were screened for their alpha-glucosidase activity. They showed a varying degree of alpha-glucosidase inhibition with IC50 values ranging between 5.31 and 53.34 mu M. Compounds 6, 7, 9-16, 19, 21-30, 32-35 showed superior activity as compared to standard acarbose (IC50 = 906 +/- 6.3 mu M). This has identified a new class of alpha-glucosidase inhibitors. The predicted physicochemical properties indicated the drug appropriateness for most of these compounds, as they obey Lipinski's rule of five (RO5). A hybrid B3LYP density functional theory (DFT) was employed for energy, minimization of 3D structures for all synthetic compounds using 6-311 + G(d,p) basis sets followed by molecular docking to explore their interactions with human intestinal C- and N-terminal domains of alpha-glucosidase. All compounds bind to the prospective allosteric site of the C- terminal domain, and consequently, may be considered as mixed inhibitors. It was hypothesized that both the dipole moment and H-bond interactions govern the biological activation of these compounds. (C) 2015 Elsevier Masson SAS. All rights reserved.
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