Synthesis, in-vitro evaluation and in-silico analysis of new anticholinesterase inhibitors based on sulfinylbis(acylhydrazones) scaffolds

Abstract

The present research work is employed with the synthesis of 4,4ꞌ-sulfinyldiphenol-linked hydrazones, their in-vitro evaluation as cholinesterase inhibitors, and their molecular docking analysis. A total of 29 new bis(acylhydrazones) scaffolds (4–32) were recently synthesized in moderate to high yields utilizing 4,4-dithiophenol to serve as precursor. All the synthesized compounds were characterized through spectroscopic techniques such as ¹H NMR, ¹³C NMR and HRMS-ESI⁺. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were used as biological targets in order to conduct in-vitro anticholinesterase efficacy using these substances. Among all, compounds 11 (IC₅₀ = 66.3 ± 1.3 µM) and 13 (IC₅₀ = 62.3 ± 0.6 µM) showed the most significant AChE inhibitory potential as compared to the standard inhibitor, galantamine (IC₅₀ = 69.7 ± 0.18 µM). While compound 9 showed excellent inhibition of BChE (IC₅₀ = 53.9 ± 2.6 µM), and compounds 14, 25 and 32 exhibited the significant dual inhibition of AChE and BChE. The molecular docking of most active compounds (13 for AChE and 14 for BChE) indicates excellent binding potential of those inhibitors with their respective targets. The study reflect that those molecules can be considered as drug-like candidate upon further optimization.