Synthesis, characterization, alkaline phosphatase inhibition assay and molecular modeling studies of 1-benzylidene-2-(4-tert- butylthiazol-2-yl) hydrazines

Alkaline phosphatases are homodimeric protein enzymes which removes phosphates from several types of molecules. These catalyze the hydrolysis of monoesters in phosphoric acid which in turn catalyze a transphosphorylation reaction. Thiazoles are a privileged class of heterocyclic compounds which may potentially serve as effective phosphatase inhibitors. In this regard, the present research paper reports the facile synthesis and characterization of substituted 1-benzylidene-2-(4-tert-butylthiazol-2-yl) hydrazines with excellent yields. The synthesized compounds were tested for inhibitory potential against alkaline phosphatases. The compound 1-(4-Hydroxy, 3-methoxybenzylidene)-2-(4-tert-butylthiazol-2-yl) hydrazine (5e)was found to be the most potent inhibitor of human tissue non-alkaline phosphatase in this group of molecules with an IC(50)value of 1.09 +/- 0.18 mu M. The compound 1-(3,4-dimethoxybenzylidene)-2-(4-tert-butylthiazol-2-yl) hydrazine(5d)exhibited selectivity and potency for human intestinal alkaline phosphatase with an IC(50)value of 0.71 +/- 0.02 mu M. In addition, structure activity relationship and molecular docking studies were performed to evaluate their binding modes with the target site of alkaline phosphatase. The docking analysis revealed that the most active inhibitors showed the important interactions within the binding pockets of human intestinal alkaline phosphatase and human tissue non-alkaline phosphatase and may be responsible for the inhibitory activity of the compound towards the enzymes. Therefore, the screened thiazole derivatives provided an outstanding platform for further development of alkaline phosphatase inhibitors. Alkaline phosphatase assay revealed compound5e(1-(4-Hydroxy, 3-methoxybenzylidene)-2-(4-tert-butylthiazol-2-yl) hydrazine) as the most active inhibitor ofh-TNAPwith an IC(50)value of 1.09 +/- 0.18 mu M. Computational evaluation clearly depicts several interactions within the binding pockets ofh-IAPandh-TNAPand maybe responsible for the inhibitory potential of the compound towards the enzymes.

Automated summary

Alkaline phosphatases are enzymes that remove phosphates from molecules, and thiazoles are a class of compounds that may serve as effective phosphatase inhibitors. The synthesized compounds showed promising inhibitory potential against different types of alkaline phosphatases, with specific compounds demonstrating high potency and selectivity. Molecular docking studies revealed important interactions between the inhibitors and the target sites of alkaline phosphatases, contributing to their inhibitory activity.