MEDICINAL CHEMISTRY RESEARCH, cilt.32, sa.1, ss.189-204, 2023 (SCI-Expanded)
The development of novel analogues for the pancreatic lipase (PL)
inhibitors and antioxidant candidates remains a significant research
objective, as these studies are essential to our understanding of the
role of PL receptor in obesity. Herein, we report on the synthesis,
molecular docking, absorption, distribution, metabolism, excretion and
toxicity (ADMET) properties, and biological evaluation of ten
tetra-substituted pyrazole analogues as agents of PL inhibitors and
antioxidant activities. The tetra-substituted pyrazole analogues
displayed good binding affinity against Folin-Ciocalteu Reducing (FCR),
Ferric Reducing Antioxidant Power (FRAP). However, the synthesized
analogues displayed low binding affinity against Oxygen Radical
Absorbance Capacity (ORAC). The tetra-substituted pyrazole analogues
exhibited effective PL inhibition in the range of 2.0 ± 0.0 and
34.3 ± 0.3 μM according to the enzyme assays. Furthermore, the detailed
interactions and binding energies of the PL-tetra-substituted pyrazole
analogues’ complexes were determined using molecular docking studies.
The binding energies of the PL-tetra-substituted pyrazole analogues’
complexes were found in range of –9.4 to –13.2 kcal/mol.
In addition, the ADMET predictions of tetra-substituted pyrazole
analogues were carried out using PreADMET software. Overall, the
obtained results revealed that antioxidant and PL inhibitory activities
of tetra-substituted pyrazole analogues were in consensus with the ADMET
predictions results.