Synthesis, Theoretical, in Silico and in Vitro Biological Evaluation Studies of New Thiosemicarbazones as Enzyme Inhibitors

Eleven new thiosemicarbazone derivatives (1–11) were designed from nine different biologically and pharmacologically important isothiocyanate derivatives containing functional groups such as fluorine, chlorine, methoxy, methyl, and nitro at various positions of the phenyl ring, in addition to the benzyl unit in the molecular skeletal structure. First, their substituted-thiosemicarbazide derivatives were synthesized from the treatment of isothiocyanate with hydrazine to synthesize the designed compounds. Through a one-step easy synthesis and an eco-friendly process, the designed compounds were synthesized with yields of up to 95 % from the treatment of the thiosemicarbazides with aldehyde derivatives having methoxy and hydroxy groups. The structures of the synthesized molecules were elucidated with elemental analysis and FT–IR, 1H-NMR, and 13C-NMR spectroscopic methods. The electronic and spectroscopic properties of the compounds were determined by the DFT calculations performed at the B3LYP/6-311++G(2d,2p) level of theory, and the experimental findings were supported. The effects of some global reactivity parameters and nucleophilic-electrophilic attack abilities of the compounds on the enzyme inhibition properties were also investigated. They exhibited a highly potent inhibition effect on acetylcholinesterase (AChE) and carbonic anhydrases (hCAs) (KI values are in the range of 23.54±4.34 to 185.90±26.16 nM, 103.90±23.49 to 325.90±77.99 nM, and 86.15±18.58 to 287.70±43.09 nM for AChE, hCA I, and hCA II, respectively). Furthermore, molecular docking simulations were performed to explain each enzyme-ligand complex's interaction. © 2023 Wiley-VHCA AG, Zurich, Switzerland.