Exploring the potential of biphenyls as promising multi-enzyme inhibitors: Synthesis, molecular docking, and dynamic simulation studies

The continuous development of new drugs is essential due to emerging health threats, evolving drug-resistant diseases, and the need for safer, low-cost, and more effective treatments. The current research aimed to give insights into synthesizing and screening a series of biphenyl derivatives against (3-glucuronidase, superoxide dismutase, and urease enzymes. The newly synthesized compounds were corroborated by IR, NMR (1H and 13C), and EI-MS spectral data for structural confirmation. Compounds 9a showed excellent inhibitory activities against the urease and (3-glucuronidase, having IC50 values of 6.94 f 0.45 mu M and 21.25 f 0.86 mu M, respectively. The compounds 9a and 9b demonstrated radical scavenging activity of 87.3 f 0.9 % and 89.1 f 0.7 %, respectively. (3-glucuronidase, superoxide dismutase, and urease receptors were subjected to molecular docking to assess the compounds' binding affinities and potential binding modes. Following this, ADMET analysis was conducted to evaluate the pharmacokinetic profiles of the compounds. Molecular dynamics simulations and MMPBSA calculations were performed to validate the binding affinities and modes further. Trajectory analysis indicated that the compounds effectively bound to the active sites of the proteins, suggesting their potential role in inhibiting these enzymes. The findings offered invaluable details on the stability of the compounds, highlighting compounds 9a and 9b holding promise for addressing a broad spectrum of pathological disorders involving urease, (3-glucuronidase, and superoxidase enzymes.