What question did this study set out to answer?

The aim is to develop effective pyrazole-based inhibitors targeting urease and thymidine phosphorylase enzymes.

March 15, 2026

Investigation of pyrazole linked carbonitrile based Schiff Bases through molecular dynamic simulation as promising urease and thymidine phosphorylase inhibitors: Synthesis in-vitro biological screening, DFT and computational approaches

Key Points

The aim is to develop effective pyrazole-based inhibitors targeting urease and thymidine phosphorylase enzymes.
Synthesis of twelve pyrazole-linked carbonitrile Schiff base derivatives.
In vitro screening of synthesized compounds for enzyme inhibition.
Molecular docking studies to evaluate binding interactions with target enzymes.
Molecular dynamics simulations for binding stability over 100 ns.
DFT calculations for electronic stability and drug-like property assessments.
Some compounds exhibited superior activity compared to standard inhibitors.
Compound 4 showed IC50 values of 13.47 μM for urease and 4.04 μM for thymidine phosphorylase.
Molecular docking revealed favorable interactions in the enzymes' active sites.
Molecular dynamics confirmed stable ligand-protein complexes for key compounds.

Abstract

Twelve new pyrazole-linked carbonitrile-based Schiff base derivatives have been prepared in the present study following a two-step pathway of reactions and tested as a dual inhibitor of urease and thymidine phosphorylase. The main target of this study was to develop structurally simple yet biologically active pyrazole-based scaffolds for targeting enzymes involved in bacterial infections and cancer-related angiogenesis. The originality of the present research lies in the rational synthesis of a pyrazole-carbonitrile core bearing Schiff base functionality, and in the thorough examination of the structure-activity relationship (SAR) through the in vitro, in silico, and quantum chemical studies. The compounds synthesized were structurally verified by the use of the NMR spectroscopy of 1 H and 13 C and screened against enzyme inhibition. Some of the derivatives showed better activity than the standard inhibitors, with compounds 4 (13.47 ± 1.12 μM for urease; 4.04 ± 1.78 μM for thymidine phosphorylase), 11 (14.75 ± 1.53 μM; 4.42 ± 0.98 μM), and 8 (17.93 ± 1.98 μM; 5.73 ± 2.16 μM). The results of molecular docking showed favorable binding interactions in the active sites of urease (PDB ID: 4UBP) and thymidine phosphorylase (PDB ID: 4EAD). In order to confirm binding stability, 100 ns molecular dynamics simulations were conducted, which confirmed stable ligand protein complexes, especially between compound 8 and urease and compound 4 and thymidine phosphorylase. DFT calculations were used to understand electronic stability and reactivity, and ADME analysis identified drug-like properties acceptable for the lead compounds.

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