Synthesis, biological evaluation and computational investigations of S-benzyl dithiocarbamates as the cholinesterase and monoamine oxidase inhibitors.

• Synthesis of S-benzyl dithiocarbamates derivatives via a single pot reaction setup. • Characterization of synthesized derivatives via NMR (1H and 13C), FT-IR and high resolution mass spectrometry. • In vitro enzyme inhibition assays against cholinesterase enzyme and monoamine oxidase. • Comprehensive in-silico investigations of synthesized derivatives. The current study was aimed to identify the selective and multi-targeted inhibitors of cholinesterase and monoamine oxidase enzymes. For this purpose, a novel class of multi-targeted compounds i.e., S -benzyl dithiocarbamates (1-30) was synthesized via a single pot reaction and the structures were characterized via NMR (1H and 13C), FT-IR and high-resolution mass spectrometry (HRMS). Moreover, the purity of the final products was determined using thin-layer chromatography (TLC). The compounds were evaluated for their inhibitory potential against cholinesterases (ChE) and monoamine oxidases (MAO). Among all derivatives, compound 5 (2-(trifluoromethyl) benzyl azepane-1-carbodithioate) depicted the maximum inhibition of AChE and BChE enzyme with an IC 50 value of 4.37±0.94 and 14.9±1.11, respectively. The derivative 11, expressed maximum inhibition of MAO-A and MAO-B with an IC 50 value of 1.14±0.03 and 1.01 ± 0.16 µM, respectively. Whereas, compound 16 exhibited maximum inhibitory potential against all four targeted enzymes i.e., AChE, BChE, MAO-A and MAO-B with an IC 50 value of 1.39±0.07 µg/ mL, 1.52±0.14 µg/ mL, 44.9±1.54 µM and 2.85±0.21 µM, respectively. The chemical reactivity profile of the potent derivatives were evaluated through density functional theory studies (DFT) where it was found that compound 5, 6 and 11 possessed reactive character due to narrow LUMO/HOMO energy gap. In addition, Molecular docking studies revealed excellent docking scores and produced sable protein-ligand complexes. The stability of protein-ligand complex was affirmed by molecular dynamic simulations which revealed stable and equilibrated trajectories of simulated complexes. The findings of in-vitro and in-silico studies suggested compound 16 as a promising multi-targeted compound that can be act as lead molecule for the treatment of AD. [Display omitted] [ABSTRACT FROM AUTHOR]