Towards Greener Pastures in Alzheimer's Therapy: Synthesis and XRD/HSA/DFT Mechanistic Investigation of Novel Trifluoromethylated Compounds

A concise, high‐yield one‐pot protocol afforded two novel trifluoromethylated Schiff base hybrids, (E)−2,2,2‐trifluoro‐N‐(2‐((2‐hydroxybenzylidene)amino)−2‐methylpropyl)acetamide ( 1 ) and its 2‐hydroxynaphthyl analogue ( 2 ). Both combine a branched diamine core, a phenolic/naphtholic imine, and a trifluoroacetamide fragment, giving fluorinated frameworks distinct from reported donepezil and galantamine analogues, which typically use extended benzyl–piperidine architectures. Both compounds were characterised by multinuclear NMR, IR, MS and elemental analysis; their purity was established by reverse‐phase HPLC (98.8% for 1 and > 99% for 2 after recrystallisation), and their structures were determined by single‐crystal X‐ray diffraction. Crystal structure and Hirshfeld surface analyses reveal a tautomerism‐controlled switch in supramolecular assembly: compound 1 adopts an enol–imine form, generating discrete amide–phenol dimers via a robust heterosynthon, while 2 exists as a keto–enamine, forming infinite N–H···O hydrogen‐bonded chains reinforced by π–π stacking of naphthalene rings. DFT calculations (B3LYP/6‐311 + G(d,p)) support these findings, showing distinct charge distributions and a reduced HOMO–LUMO gap for 2 , consistent with enhanced electronic polarizability. Molecular docking against acetylcholinesterase (PDB: 1EVE) predicted that both compounds adopt binding modes within the catalytic gorge, with 2 showing particularly favourable interactions within the catalytic gorge. These predictions were tested experimentally. In a colorimetric AChE inhibitor screening assay both compounds inhibit the enzyme in a concentration‐dependent manner, with IC 50 values of 22.5 µM (1) and 55.0 µM (2) against 15.0 µM for the galantamine reference measured alongside. Compound 1 is the more potent of the pair, by a factor of 2.4, and comes within 1.5‐fold of the reference inhibitor, identifying the compact phenolic scaffold rather than the extended naphthalenic one as the better lead for further development. Computational ADME/Tox profiling tentatively predicts compliance with Lipinski and Veber criteria, oral bioavailability, blood–brain barrier permeation, and acceptable toxicity classes, pending experimental confirmation. Overall, this work establishes a synthetically accessible, structurally tunable family of trifluoromethylated scaffolds whose solid‐state behaviour and preliminary computational pharmacology indicate potential as crystallography‐guided AChE inhibitor candidates warranting further investigation.