Green synthesis of Tacrine modified Schiff bases as anti-Alzheimer Agents: An effective strategy validated through in-silico and in-vitro analysis

• Green chemistry Integration: emphasis on solvent-free synthesis to advance sustainable drug development, minimizing environmental impact and chemical waste. • Tacrine-modified Schiff base Inhibitors: developed as potential Alzheimer's disease treatments using the grindstone method, aligning with green chemistry principles. • In-Silico and in-vitro Validation: combined molecular docking studies and laboratory experiments confirmed the efficacy of the synthesized compounds as acetylcholinesterase (AChE) inhibitors. • Sustainable development goals (SDGs): the research supports SDGs related to health (SDG 3), responsible production (SDG 12), and clean water (SDG 6). • Broader Impact: demonstrates the feasibility of integrating green chemistry in medicinal chemistry, paving the way for environmentally responsible drug development. A variety of Tacrine-modified Schiff base analogues were developed via solvent free (green) method and structurally elucidated using 1H NMR, FTIR and UV–Vis analysis. High product yield was obtained from the synthesised molecules, which were produced efficiently at room temperature without the need of a solvent. The developed molecules were subsequently assessed for their potential to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). These molecules revealed effective inhibition of AChE and BChE enzymes with IC 50 values varying from 0.1 ± 0.02 to 0.3 ± 0.03 μM and 0.065 ± 0.01 to 0.3 ± 0.03 μM respectively. Compared to the standard Tacrine which has IC 50 values of 0.35 ± 0.02 μM for AChE and 0.1 ± 0.01 μM for BChE. Notably, compound 3f showed strong inhibition among others for both the enzymes. The structure–activity relationship of derivatives synthesized were verified and established through molecular docking studies. Theoretical ADME studies also predicted excellent drug-likeness for all the synthesized molecules. Antioxidant activities were also assessed because elevated oxidative stress levels are linked with cognitive loss in Alzheimer's disease (AD). These findings suggest that the lead compound is potentially an effective inhibitor for the therapeutic management of AD.