期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 23, 期 10, 页码 2435-2444出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.03.054
关键词
Alkaline phosphatase inhibitors; Tissue non-specific alkaline phosphatase; Intestinal alkaline phosphatase; Carbonic anhydrase inhibitors; Structure activity relationship (SAR); Bioisosteres; Homology modeling
资金
- German-Pakistani Research Collaboration Program
The effect of bioisosteric replacement of carboxamide linking group with sulfonamide linking group, on alkaline phosphatase (AP) and carbonic anhydrase (CA) inhibition activity of aromatic benzenesulfonamides was investigated. A series of carboxamide linked aromatic benzenesulfonamides 1a-1c, 2a-2d and their sulfonamide linked bioisosteres 3a-3d, 4a-4d was synthesized and evaluated for inhibitory activity against bovine tissue non-specific alkaline phosphatase (TNAP), intestinal alkaline phosphatase (IAP) and bCA II. A significant increase in CA inhibition activity was observed upon bioisosteric replacement of carboxamide linking group with a sulfonamide group. Some of these compounds were identified as highly potent and selective AP inhibitors. Compounds 1b, 2b, 3d, 4d 5b and 5c were found to be selective bTNAP inhibitors, whereas compounds 1a, 1c, 2a, 2c, 2d, 3a, 3c, 4a, 4b, 4c, 5a were found to be selective bIAP inhibitors. For most active AP inhibitor 3b, detailed kinetic studies indicated a competitive mode of inhibition against tissue non-specific alkaline phosphatase (TNAP) and non-competitive mode of inhibition against intestinal alkaline phosphatase (IAP). Molecular docking studies were carried out to rationalize important binding site interactions. (C) 2015 Elsevier Ltd. All rights reserved.
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