Potent Alkaline Phosphatase Inhibitors, Pyrazolo-Oxothiazolidines: Synthesis, Biological Evaluation, Molecular Docking, and Kinetic Studies

To develop new alkaline phosphatase inhibitors (ALP), a series of pyrazolo-oxothiazolidine derivatives were synthesized and biologically assessed, and the results showed that all of the synthesized compounds significantly inhibited ALP. Specifically, compound 7g displayed the strongest inhibitory activity (IC50 = 0.045 +/- 0.004 mu M), which is 116-fold more active than monopotassium phosphate (IC50 = 5.242 +/- 0.472 mu M) as a standard reference. The most potent compound among the series (7g) was checked for its mode of binding with the enzyme and shown as non-competitively binding with the target enzyme. The antioxidant activity of these compounds was examined to investigate the radical scavenging effect. Moreover, the MTT assay method was performed to evaluate their toxic effects on the viability of MG-63 human osteosarcoma cells, and all compounds have no toxic effect on the cells at 4 mu M. Computational research was also conducted to examine the binding affinity of the ligands with alkaline phosphatase, and the results revealed that all compounds showed good binding energy values within the active site of the target. Therefore, these novel pyrazolo-oxothiazolidine derivatives might be employed as promising pharmacophores for potent and selective alkaline phosphatase inhibitors.

Automated summary

A series of pyrazolo-oxothiazolidine derivatives were synthesized and evaluated for their inhibitory activity against alkaline phosphatase. The most potent compound, 7g, demonstrated strong inhibition and non-competitive binding with the enzyme. These compounds also exhibited antioxidant activity and showed no toxicity to human osteosarcoma cells at a certain concentration. Computational research confirmed their good binding affinity with alkaline phosphatase, suggesting their potential as selective inhibitors.