Benzimidazolone conjugated biscoumarins: Synthesis, molecular docking studies, urease, lipase, and acetylcholinesterase inhibitory activities

Abstract

New biscoumarin molecules bridged benzimidazolone were synthesized and then screened for their urease, lipase, and acetylcholinesterase inhibition properties. In this series, the best urease inhibition value belongs to compound 4f (IC₅₀: 0.05 ± 0.003 μM), the most effective lipase inhibition was shown by the compound 4s (IC₅₀: 0.05 ± 0.014 μM). Although the inhibition value of all compounds against acetylcholinesterase is remarkable, compound 4e showed the closest inhibition to tacrine (IC₅₀: 0.031 ± 0.013 μM) with an IC₅₀ value of 0.096 ± 0.018 μM. Molecular docking studies were performed using the Schrödinger Suite package using the IFD protocol to elucidate the interaction mode of the synthesized compounds with the binding site of urease, lipase and acetylcholine esterase enzymes. The molecular docking studies supported the in vitro inhibition results. It was shown that the compounds interacted with the important residues of the active site of the enzymes through hydrogen bonding, π–π stacking and hydrophobic interactions. 100 ns Molecular Dynamics (MD) simulations were performed on the top docking-scored complex to evaluate the stability of the ligand–protein interactions. The ADMET profiles of the most potent compounds were also evaluated to assess their pharmacokinetic and toxicity characteristics.