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

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 (IC₅₀ = 0.045 ± 0.004 μM), which is 116-fold more active than monopotassium phosphate (IC₅₀ = 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.

SUBMITTER: Hosseini Nasab N

PROVIDER: S-EPMC9654533 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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

Hosseini Nasab Narges N Raza Hussain H Shim Rok Su RS Hassan Mubashir M Kloczkowski Andrzej A Kim Song Ja SJ

International journal of molecular sciences 20221031 21

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 μM), which is 116-fold more active than monopotassium phosphate (IC50 = 5.242 ± 0.472 μM) as a standard reference. The most potent compound am ...[more]

PMID: 36362051

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Project description:The presence of alkaline phosphatases has been observed in several species and has been known to play a crucial role in various biological functions. Higher expressions of alkaline phosphatase have been found in several multifactorial disorders and cancer patients, which has led it to be an interesting target for drug discovery. A strong structural similarity exists between intestinal alkaline phosphatases (IAPs) and tissue-nonspecific alkaline phosphatases (TNAPs), which has led to the discovery of only a few selective inhibitors. Therefore, a series of 22 derivatives of 6-(chloromethyl)-4-(4-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1) and ethyl 6-(chloromethyl)-4-(2-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2) were synthesized to evaluate the anticancer potential of these compounds against breast cancer. The compounds were characterized through spectral and elemental analyses. The inhibitory effect of dihydropyrimidinone derivatives on alkaline phosphatases was evaluated using the calf alkaline phosphatase assay. The antioxidant activity of these compounds was performed to study the radical scavenging effect. In silico molecular docking and molecular dynamic simulations were performed to elucidate the binding mode of active compounds. Moreover, the two-dimensional qualitative-structure-activity relationship (2D-QSAR) was performed to study the structural requirements for enzyme inhibition. The calf alkaline phosphatase inhibitory assay revealed significant inhibition of the enzyme by compound 4d with IC50 1.27 μM at 0.1 mM concentration as compared to standard KH2PO4 having IC50 2.80 μM. The compounds 4f, 4e, and 4i also showed very good inhibition with IC50 values of 2.502, 2.943, and 2.132 μM, respectively, at the same concentration. The antioxidant assay revealed efficient radical scavenging activity of compounds 4f, 4e, and 4g at 100 μg/mL with IC50 values of 0.48, 0.61, and 0.75 μg/mL, respectively. The molecular docking and simulation studies revealed efficient binding of active compounds in the active binding site of the target enzyme. The final QSAR equation revealed good predictivity and statistical validation having R 2 = 0.958 and Q 2 = 0.903, respectively, for the generated model. The compound 4d showed the highest inhibitory activity with stable binding modes acting as a future lead for identifying alkaline phosphatase inhibitors. The molecular simulations suggested the stable binding of this compound, and the QSAR studies revealed the importance of autocorrelated descriptors in the inhibition of alkaline phosphatase. The investigated compounds may serve as potential pharmacophores for potent and selective alkaline phosphatase inhibitors. We intend to further investigate the biological activities of these compounds as alkaline phosphatase inhibitors.

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Dataset Information

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

Publications

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

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