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Potent Alkaline Phosphatase Inhibitors, Pyrazolo-Oxothiazolidines: Synthesis, Biological Evaluation, Molecular Docking, and Kinetic Studies.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2022 Oct 31; Vol. 23 (21). Date of Electronic Publication: 2022 Oct 31. - Publication Year :
- 2022
-
Abstract
- 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 (IC <subscript>50</subscript> = 0.045 ± 0.004 μM), which is 116-fold more active than monopotassium phosphate (IC <subscript>50</subscript> = 5.242 ± 0.472 μM) 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 μM. 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.
- Subjects :
- Humans
Kinetics
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
Pyrazoles chemistry
Pyrazoles pharmacology
Thiazoles chemistry
Thiazoles pharmacology
Alkaline Phosphatase antagonists & inhibitors
Alkaline Phosphatase metabolism
Enzyme Inhibitors chemistry
Enzyme Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 23
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 36362051
- Full Text :
- https://doi.org/10.3390/ijms232113262