Synthesis, kinetic studies and in-silico investigations of novel quinolinyl-iminothiazolines as alkaline phosphatase inhibitors.

Deposition of hydroxyapatite (HA) or alkaline phosphate crystals on soft tissues causes the pathological calcification diseases comprising of end-stage osteoarthritis (OA), ankylosing spondylitis (AS), medial artery calcification and tumour calcification. The pathological calcification is symbolised by increased concentration of tissue non-specific alkaline phosphatase (TNAP). An efficient therapeutic strategy to eradicate these diseases is required, and for this the alkaline phosphatase inhibitors can play a potential role. In this context a series of novel quinolinyl iminothiazolines was synthesised and evaluated for alkaline phosphatase inhibition potential. All the compounds were subjected to DFT studies where N -benzamide quinolinyl iminothiazoline ( 6g ), N -dichlorobenzamide quinolinyl iminothiazoline ( 6i ) and N -nitrobenzamide quinolinyl iminothiazoline ( 6j ) were found as the most reactive compounds. Then during the in-vitro testing, the compound N -benzamide quinolinyl iminothiazoline ( 6g ) exhibited the maximum alkaline phosphatase inhibitory effect (IC 50 = 0.337 ± 0.015 µM) as compared to other analogues and standard KH 2 PO 4 (IC 50 = 5.245 ± 0.477 µM). The results were supported by the molecular docking studies, molecular dynamics simulations and kinetic analysis which also revealed the inhibitory potential of compound N -benzamide quinolinyl iminothiazoline ( 6g ) against alkaline phosphatase. This compound can be act as lead molecule for the synthesis of more effective inhibitors and can be suggested to test at the molecular level.