A novel series of thiosemicarbazone hybrid scaffolds: Design, synthesis, DFT studies, metabolic enzyme inhibition properties, and molecular docking calculations

•New thiosemicarbazones bearing Schiff-bases have been synthesized.•Structures of the compounds have been clarified with spectroscopic methods.•Enzyme inhibitory activities (AChE, hCAI, hCAII) of the compounds have been studied.•Molecular docking studies have been performed.•DFT calculations have been investigated. The fourteen new thiosemicarbazone derivatives of Schiff base were synthesized from the condensation reactions of two different aldehydes (3‑hydroxy-4-methoxhybenzaldehyde and 3-ethoxhy-4-hydroxybenzaldehyde) with various substituted-thiosemicarbazides. Structures of the compounds (1-14) were characterized by using FT-IR, 1H NMR, and 13C NMR spectroscopic techniques, and elemental analysis. Furthermore, the enzyme inhibitory effect of the obtained hybrid scaffolds was studied. They exhibited highly potent inhibition effect on acetylcholinesterase (AChE) and carbonic anhydrases (hCAs) (KI values are in the range of 111.00 ± 12.12 to 381.60 ± 38.10 nM, 120.60 ± 20.45 to 338.90 ± 42.18 nM, and 100.60 ± 11.31 to 285.30 ± 45.27 nM for AChE, hCA I, and hCA II, respectively). DFT analyzes were performed to demonstrate the usability of some electronic parameters and nucleophilic-electrophilic attack abilities of the compounds in predicting enzyme inhibition properties. A correlation was seen between the HOMO energy eigenvalues of the compounds and the inhibition reactivity, and revealing that QTAIM calculations could also be used to predict the probability of electrophilic and nucleophilic attacks. Findings supporting that hCA I and AChE enzyme inhibition reactions primarily proceed through electrophilic attack, while hCA II reactions tend to occur via nucleophilic attack have been obtained. Also, molecular docking studies were conducted to confirm the outcomes of studies on binding affinities and the most powerful derivatives. The obtained results showed that the novel thiosemicarbazone derivatives may lead to the development of novel types of pharmacological agents in the treatment of patients with Alzheimer's disease, idiopathic intracranial hypertension, glaucoma, and related conditions. The fourteen new thiosemicarbazone derivatives of Schiff base were synthesized from the condensation reactions of two different aldehydes (3-hydroxy-4-methoxhybenzaldehyde and 3-ethoxhy-4-hydroxybenzaldehyde) with various substituted-thiosemicarbazides. Furthermore, the carbonic anhydrase and acetylcholinesterase enzymes inhibitory effect of the obtained hybrid scaf