Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation

Abstract

A small library of new drug-1,3,4-thiazidazole hybrid compounds (3a–3i) was synthesized, characterized, and assessed for their acetyl cholinesterase enzyme (AChE) inhibitory and free radical scavenging activities. The newly synthesized derivatives showed promising activities against AChE, especially compound 3b (IC50 18.1 ± 0.9 nM), which was the most promising molecule in the series, and was substantially more active than the reference drug (neostigmine methyl sulfate; IC50 2186.5 ± 98.0 nM). Kinetic studies were performed to elucidate the mode of inhibition of the enzyme, and the compounds showed mixed-type mechanisms for inhibiting AChE. The Ki of 3b (0.0031 µM) indicates that it can be very effective, even at low concentrations. Compounds 3a–3i all complied with Lipinski’s Rule of Five, and showed high drug-likeness scores. The pharmacokinetic parameters revealed notable lead-like properties with insignificant liver and skin-penetrating effects. The structure–activity relationship (SAR) analysis indicated π–π interactions with key amino acid residues related to Tyr124, Trp286, and Tyr341.

Potential thiosemicarbazone‐based enzyme inhibitors: Assessment of antiproliferative activity, metabolic enzyme inhibition properties, and molecular docking calculations

“…[14] Nonetheless, in recent years, some 1,3,4-thiadiazole hybrid compounds presented for acetylcholinesterase enzyme inhibitory and showed promising activities against AChE. [21] α-Glycosidase enzymes are located on the brushy surface of the small intestine. They are responsible for breaking down complex carbohydrates.…”

Biological and Computational Studies for Dual Cholinesterases Inhibitory Effect of Zerumbone

“…As shown in Table 4, zerumbone was predicted to possess good water solubility (−4.03 log mol/L), with appreciable absorption from the intestine (Caco-2 permeability > 0.90 × 10 −6 cm/s and human intestinal absorption >30%). The skin permeability value (−2.06 log Kp) of zerumbone, which defines the rate of a chemical passage through the stratum corneum, was comparable with that of the standard value (−2.5 log Kp), showing its potential as a lead structure and justifying its drug-likeliness behavior [17].…”

Cholinesterases and Their Inhibitors

“…Previous studies reported interactions with the AChE amino acid residues with various antipsychotic drugs. Recent studies reported interactions with critical residues such as Leu288, Ser292, Thr237, Val238, Gln368, Pi-cation interaction with Arg295, Pialkyl and alkyl interactions with Pro289, Val299, Pro367, 234 of AChE [42,43] Donepezil and Pimozide ligands showed the lowest energy and the best favorable interactions. The Galanthamine (À7.3 kcal/mol) and Risvagtimine (À7.95 kcal/mol) showed higher binding energies than Donepezil (À8.5 kcal/mol) ligands [44].…”