Exploring new 5-Nitroimidazole Derivatives as Potent Acetylcholinesterase and Butyrylcholinesterase Enzyme Inhibitors.

Autor: Gursoy S; Department of Biohemistry, Faculty of Pharmacy, Erzincan Binali Yıldırım University, Erzincan, Türkiye., Satici D; Department of Pharmaceutical Sciences, Institute of Health Sciences, Erzincan Binali Yıldırım University, Erzincan, Türkiye., Kuzu B; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Van Yüzüncü Yıl University, Van, Türkiye., Turkmenoglu B; Department of Analytical Chemistry, Faculty of Pharmacy, Erzincan Binali Yıldırım University, Erzincan, Türkiye., Dilek E; Department of Biohemistry, Faculty of Pharmacy, Erzincan Binali Yıldırım University, Erzincan, Türkiye., Algul O; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erzincan Binali Yıldırım University, Erzincan, Türkiye.; Department of Pharmaceutical Chemistry, Mersin University, Faculty of Pharmacy, Mersin, Türkiye.
Jazyk: angličtina
Zdroj: Chemistry & biodiversity [Chem Biodivers] 2024 Oct; Vol. 21 (10), pp. e202400918. Date of Electronic Publication: 2024 Sep 13.
DOI: 10.1002/cbdv.202400918
Abstrakt: Discovering new compounds capable of inhibiting physiologically and metabolically significant drug targets or enzymes is of paramount importance in biological chemistry. With this aim, new 5-nitroimidazole derivatives (1-4) were designed and synthesized, and their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were discovered using acetyl (butyryl) thiocholine and Ellman's reagents for spectrophotometric assay. The inhibitory profiles of the synthesized compounds were assessed by comparing their IC 50 and K i values. Results demonstrate significant inhibitory activity of all synthesized compounds against both AChE and BuChE compared to the reference compound, donepezil. Notably, compound 4 exhibited dual inhibition of these enzymes, showing the highest activity against Electrophorus electricus AChE (EeAChE) with a K i value of 0.024±0.009 nM and against equine BuChE (eqBuChE) with a K i value of 0.087±0.017 nM. Furthermore, molecular modeling was conducted to study the interaction modes of the most potent compound (4) and donepezil in the active site of their related enzymes' crystal structures (PDB ID: 4EY7 and 4BDS, respectively). Additionally, drug-likeness, ADME, and toxicity profiles of the compounds and metronidazole were predicted. The above results indicated that the dual inhibition of these enzymes is considered as a promising strategy for the treatment of neurological disorder especially Alzheimer's disease.
(© 2024 Wiley-VHCA AG, Zurich, Switzerland.)
Databáze: MEDLINE
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