Iqbal, Jamshed El-Gamal, Mohammed I. Ejaz, Syeda Abida Lecka, Joanna Sevigny, Jean Oh, Chang-Hyun 2024-01-19T23:31:28Z 2024-01-19T23:31:28Z 2021-09-03 2018-02-02 1475-6366 https://pubs.kist.re.kr/handle/201004/121716 Tissue-nonspecific alkaline phosphatase (TNAP) is an important isozyme of alkaline phosphatases, which plays different pivotal roles within the human body. Most importantly, it is responsible for maintaining the balanced ratio of phosphate and inorganic pyrophosphate, thus regulates the extracellular matrix calcification during bone formation and growth. The elevated level of TNAP has been linked to vascular calcification and end-stage renal diseases. Consequently, there is a need to search for highly potent and selective inhibitors of alkaline phosphatases (APs) for treatment of disorders associated with the over-expression of APs. Herein, a series of tricyclic coumarin sulphonate 1a-za with known antiproliferative activity, was evaluated for AP inhibition against human tissue nonspecific alkaline phosphatase (h-TNAP) and human intestinal alkaline phosphatase (h-IAP). The methylbenzenesulphonate derivative 1f (IC50 = 0.38 +/- 0.01 mu M) was found to be the most active h-TNAP inhibitor. Another 4-fluorobenzenesulphonate derivative 1i (IC50 = 0.45 +/- 0.02 mu M) was found as the strongest inhibitor of h-IAP. Some of the derivatives were also identified as highly selective inhibitors of APs. Detailed structure-activity relationship (SAR) was investigated to identify the functional groups responsible for the effective inhibition of AP isozymes. The study was also supported by the docking studies to rationalise the most possible binding site interactions of the identified inhibitors with the targeted enzymes. English TAYLOR & FRANCIS LTD RAW 264.7 MACROPHAGES INDUCED NITRIC-OXIDE PGE(2) PRODUCTIONS HIGHLY POTENT IDENTIFICATION MECHANISMS SILICO ACID Tricyclic coumarin sulphonate derivatives with alkaline phosphatase inhibitory effects: in vitro and docking studies Article 10.1080/14756366.2018.1428193 1 JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, v.33, no.1, pp.479 - 484 JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY 33 1 479 484 scie scopus 000424262000001 2-s2.0-85041711145 Biochemistry & Molecular Biology Chemistry, Medicinal Biochemistry & Molecular Biology Pharmacology & Pharmacy Article RAW 264.7 MACROPHAGES INDUCED NITRIC-OXIDE PGE(2) PRODUCTIONS HIGHLY POTENT IDENTIFICATION MECHANISMS SILICO ACID Alkaline phosphatase inhibitor coumarin molecular docking structure-activity relationship Tricyclic coumarin sulfonate