Revealing Protein Ligand Interactions via DFT Calculation, Molecular Docking, and ADMET: Insight into the Role of Imidazole with Anti‐Alzheimer Activity

Abstract Alzheimer's disease, a chronic neurological disease was targeted in search of therapeutic agents in the current study. We have synthesized a novel library of imidazole based hydrazone derivatives (1‐16) and assessed these compounds for anti‐Alzheimer's potential. These derivatives displayed excellent potency ranging between IC 50 = 3.10 ± 0.20 µM to 21.10 ± 0.30 µM against AChE and 3.40 ± 0.30 to 23.30 ± 0.30 µM against BuChE. The assessment of biological potency was brought about in contrast to control drug donepezil having IC 50 = 7.30 ± 0.90 and 7.50 ± 0.50 µM for AChE and BuChE. In this analogy, compound 8 with IC 50 = 3.10 ± 0.20 and 3.40 ± 0.30 µM was found as the lead candidate with surpassing potential than the standard drug. This compound was found to inhibit both the enzymes with much higher potential, engaging target proteins at greater extent than the standard drug. In silico molecular docking study strengthened the binding potency of the synthesized compounds against test enzymes by providing insight into the binding interactions with the receptor sites of the enzymes. Additionally, the nucleophilic and electrophilic sites of the potent compounds were also explored under density functional theory (DFT) which further displayed the reactive nature of the compounds. To verify the drug likeness and toxicity of the novel library, ADMET analysis was also conducted. Moreover, the structural validation of these compounds was achieved via spectroscopic techniques including 1 H‐NMR, 13 C‐NMR, and HREI‐MS.