期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 159, 期 -, 页码 282-291出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.09.063
关键词
Chalcone; 1,2-Benzothiazine; Enzyme inhibition; Alkaline phosphatase; Aldol condensation
资金
- Higher Education Commission of Pakistan [NRPU 20-1582, 20-3733/NRPU/RD/14/520]
- Organization for the Prohibition of Chemical Weapons (OPCW), The Hague, The Netherlands [20-3733/NRPU/RD/14/520]
- Canadian Institutes of Health Research (CIHR)
- Chercheur National research award from the Fonds de recherche du Quebec - Sante (FRQS)
- IRSIP scholarship
Chalcones and 1,2-benzothiazines are two important classes of bioactive compounds, each scaffold endowed with diverse pharmacological activities. Combining both of these pharmacophores in a single molecule was aimed to yield multi-modal agents. Herein, we report a series of hybrid compounds 3a-3o derived from chalcones and 1,2-benzothiazine cores. They were synthesized from commercially available sodium saccharin, and the resulting 1,2-benzothiazine-derived ketone was then condensed with aromatic aldehydes in an aldol condensation to obtain the respective chalcones. The compounds were characterized using different analytical techniques including FT-IR, NMR spectroscopy, mass spectrometry and X-ray crystallography. Some synthesized chalcones revealed potent and/or selective inhibitory properties towards alkaline phosphatase isozymes transiently expressed in COS-7 cells. A detailed structure-activity and selectivity study was carried out with regard to the effect of different substituents at ortho-, meta- and para-positions of the phenyl residue. Compound 3c was the most effective human intestinal alkaline phosphatase (h-IAP) inhibitor (IC50 value of 1.04 mu M), while it was not active against human tissue non-specific alkaline phosphatase (h-TNAP) isozyme. In contrast, 3i was a selective inhibitor of h-TNAP with IC50 values of 0.25 +/- 0.01 mu M. The possible binding interactions of the most effective inhibitors of h-TNAP and h-IAP were obtained from molecular docking studies. (C) 2018 Elsevier Masson SAS. All rights reserved.
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