A Novel Series of Thiosemicarbazone Hybrid Scaffolds: Design, Synthesis, DFT Studies, Metabolic Enzyme Inhibition Properties, and Molecular Docking Calculations

Abstract

The fourteen new thiosemicarbazone derivatives of Schiff base were synthesized from the conden-sation 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, 1 H NMR, and 13 C NMR spectroscopic techniques, and elemental anal-ysis. Furthermore, the enzyme inhibitory effect of the obtained hybrid scaffolds was studied. They ex-hibited 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 at-tack abilities of the compounds in predicting enzyme inhibition properties. A correlation was seen be-tween 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 elec-trophilic 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.(c) 2023 Elsevier B.V. All rights reserved.