Design, Synthesis, and In Silico Analyses of Nitroimidazole Derivatives Targeting Cholinesterases

Abstract The increasing incidence of diseases and the constraints of current treatments require expedited drug development. Drug repositioning presents an effective approach for discovering new therapeutic applications for drugs already in clinical use. This study examines the efficacy of metronidazole and secnidazole, which are presently utilized as antiprotozoal agents, in the treatment of Alzheimer's disease via ester modifications. The secondary alcohol group in nitroimidazole structures underwent esterification with acetyl, pivaloyl, cyclopropyl, and cyclohexyl carbonyl chlorides. The compounds exhibited significant inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with K i values between 52.40 ± 6.99 nM and 240.80 ± 45.56 nM for AChE and 77.82 ± 18.01 nM and 323.70 ± 56.21 nM for BChE. Molecular docking studies demonstrated significant interactions of the most active compounds (MNZ 8 and MNZ 4) with essential residues, including Trp84 and Phe330 in AChE, as well as Trp82 and active‐site water molecules in BChE. These findings corroborate their inhibitory potential, notwithstanding initial positional alterations observed during simulations. The synthesized compounds' absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties were also assessed in silico. All compounds demonstrated drug‐like properties and did not exhibit undesirable toxic effects. The findings indicate that repositioned derivatives of metronidazole and secnidazole may serve as promising lead compounds for the development of cholinesterase inhibitors aimed at treating Alzheimer's disease.