UNLABELLED: In the current study, a novel route was established for the synthesis of hybrid benzothiazole derived thiazole bearing -thiazolidinone-chalcone (1-15) scaffolds. These compounds were screened for their biological potential as anti-Alzheimer therapeutic agents by inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. The biological evaluation and molecular docking studies revealed that most of the synthesized compounds exhibited significant inhibitory activity against both enzymes, outperforming the standard drug, donepezil. Among them, Analog 15 demonstrated remarkable therapeutic potential, with IC₅₀ values of 3.30 ± 0.70 µM and 3.80 ± 0.90 µM, as well as strong binding affinities/docking scores of - 8.97 and - 12.84 kcal/mol for AChE and BuChE, respectively. Additionally, enzyme kinetics analysis using Lineweaver-Burk plots confirmed the mode of inhibition of the synthesized analogs. Pharmacokinetic predictions further supported the drug-like properties of these compounds, highlighting favorable pharmacological profiles, including good water solubility, non-carcinogenicity, and biological safety. The findings presented in this study provide compelling evidence for the anti-Alzheimer potential of these novel scaffolds, warranting further investigation through in vivo studies and clinical exploration to assess their full therapeutic applicability. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-025-04313-6.