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• 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]

• Novel trifluoromethyl containing S-benzyl dithiocarbamates have been synthesized. • Crystallographic, Hirshfeld surface, FMO energy analyses were conducted. • Compounds showed good inhibition towards monoamine oxidases-A&B. • Docking studies showed a high binding affinity for both monoamine oxidases. Two novel trifluoromethyl containing S-benzyl dithiocarbamates (1-2) have been successfully synthesized and their structures were evaluated by means of 1H- and 13C-NMR spectroscopy, FT-IR spectroscopy, and single-crystal XRD analysis. Both S-benzyl dithiocarbamates, 1 and 2 , differ between them by the position of the trifluoromethyl group in the aromatic ring. The great molecular similarity is reflected in similar crystal structures with similar intermolecular interactions. Interestingly, the low temperature used in the XRD analysis showed that compound 1 is constituted by three conformers while compound 2 shows two independent conformers in the asymmetric unit. Considering that each conformer is organized in independent molecular sheets, compound 1 has a longer c parameter compared to compound 2. The position of the trifluoromethyl group also has implications in the chemical behavior which is demonstrated in the HOMO-LUMO orbitals computed by the B3LYP method with 3–21G* basis set. Bioassay outcome displays that both compounds 1 and 2 exhibit excellent inhibition potential against monoamine oxidases (MAO-A and MAO-B) with p -CF 3 S-benzyl dithiocarbamate 1 (IC 50 =16.02 ± 5.135 μg/mL, 1.284 ± 0.66 μg/mL) being more efficient than m -CF 3 S-benzyl dithiocarbamate 2 (IC 50 =18.37± 4.030 µM, 3.164 ± 0.456 µM) against MAO-A and MAO-B, respectively. The results of binding energy values computed via docking studies showed a remarkable agreement with in-vitro results. [Display omitted] [ABSTRACT FROM AUTHOR]