Benzimidazolone Bridged Triheterocyclic Compounds as Urease andLipase Inhibitors: A Study on Design, Synthesis, Molecular Docking, andStructure Activity Relationship (SAR) Studies

Introduction/Objective: The present work describes the synthesis, urease, and lipase inhibition, and Structure-Activity Relationship (SAR) studies of some novel benzimidazolonebridged heterocyclic compounds, including piperazine, thiophene, furan, thiosemicarbazide, thiadiazole, and triazole moieties. At the same time, this study also examines changes in urease and lipase enzyme inhibition activities resulting from the attachment of different heterocycles to the benzimidazolone ring. Methods: To elucidate the interactions of the synthesized compounds with the binding sites of urease and lipase enzymes, molecular docking studies were performed using the Schrödinger Suite package with the IFD protocol. These molecular docking studies supported the in vitro inhibition results. Results: All the synthesized compounds demonstrated excellent urease inhibition activity, with IC50 values between 0.16 ± 0.037 μM and 0.37±0.091 μM when compared with standard thiourea (0.51 ± 0.028 μM). Discussion: Compound 6a showed excellent lipase inhibition activity with an IC50 value of 0.003 ± 0.001 μM, while the standard drug Orlistat showed 0.25 ± 0.067 μM. Compounds 2b, 6a, 6b, 7a, 7b, and 8b showed higher lipase inhibition activity than the standard Orlistat, with IC50 values ranging from 0.003 ± 0.001 μM to 0.17 ± 0.021 μM. Conclusion: The compounds were observed to bind the active sites of both enzyme structures through various non-covalent interactions. Additionally, SAR studies demonstrate that triazolecontaining compounds (8a, b) showed the best urease inhibitory activity with IC50 values of 0.16 ± 0.037 μM and 0.26 ± 0.052 μM, and that thiosemicarbazide derivatives (6a, b) showed the best lipase inhibition with IC50 values of 0.003 ± 0.001 and 0.14 ± 0.02 μM.