Drug-134-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis Molecular Docking Pharmacokinetics and ADMET Evaluation

摘要

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.