Novel thiazole-carbohydrazone derivatives: Synthesis, characterization and multimodal evaluation as ache inhibitors

The progression of Alzheimer's disease underscores the urgent need for novel acetylcholinesterase (AChE) inhibitors capable of modulating cholinergic signaling with high specificity and low side effects. In this study, a series of ten 3-methyl-2-(phenylimino)-2,3-dihydrothiazole-4-carbohydrazone derivatives 24 a–j were designed to integrate the thiazole core and carbohydrazone pharmacophore known for dual‐site engagement of AChE. These novel compounds were fully characterized by FT-IR, 1H and 13C NMR, LC-QTOF-MS and LC-MS, confirming their structures and high purity. In vitro enzyme assays revealed submicromolar AChE inhibition for 21 (IC50 = 0.105 μM), 23 (0.233 μM), and notably 24b (0.052 μM), 24d (0.066 μM), 24f (0.076 μM), and 24h (0.114 μM), with negligible BChE activity (IC50 > 1 mM). Selected derivatives (24b and 24f) also inhibited MAO‑A (IC50 = 0.072 and 0.091 μM) and MAO‑B (0.064 and 0.081 μM), demonstrating a promising multi‑target profile. Molecular docking against human AChE corroborated these findings, predicting strong binding (–9.0 to -9.7 kcal/mol) at both catalytic and peripheral anionic sites. These results establish the thiazole‑carbohydrazone scaffold as compelling leads for further optimization and in vivo evaluation in Alzheimer's disease.