Novel Benzimidazole Derivatives as Effective Inhibitors of Prolyl Oligopeptidase: Synthesis, in Vitro and in Silico Analysis

Abstract

Background: This research aims to discover novel derivatives having potential therapeutic applications in treating conditions related to prolyl oligopeptidase (POP) dysfunction. Method: Novel benzimidazole derivatives have been synthesized, characterized and screened for their in vitro POP inhibition. Results: All these derivatives showed excellent-to-good inhibitory activities in the range of IC₅₀ values of 3.61 ± 0.15 to 43.72 ± 1.18 μM, when compared with standard Z-prolyl-prolinal. The docking analysis revealed the strong interactions between our compounds and the target enzyme, providing critical insights into their binding affinities and potential implications for drug development. Conclusion: The significance of these compounds in targeting POP enzyme offers promising prospects for future research in the field of neuropharmacology.

Graphical abstract

Keywords::

• benzimidazole
• HR-ESI–MS
• hydrazone–Schiff bases
• molecular docking
• NMR spectroscopy
• POP inhibitor
• propyl oligopeptidase

Author contributions

A Shakoor and A Alam synthesized the compounds, while S Ullah, A Al-Ghafri and A Khan screened the compounds against the prolyl oligopeptidase activity. A Alam and M Khan performed structural elucidation and wrote the original draft of the manuscript. F Jan, F Alasmari and A Abdullah F AlAsmari performed molecular docking study of the synthesized compounds. M Ali, M Khan and A Al-Harrasi supervised the project and assisted in the writing, the reviewing and the editing of the manuscript. All authors have read and agreed to the published version of the manuscript.

Acknowledgments

Authors are thankful to researchers supporting project no. (RSP2023R235), King Saud University, Riyadh, Saudi Arabia.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing assistance

No writing assistance was utilized in the production of this manuscript.