Unleashing new MTDL AChE and BuChE inhibitors as potential anti-AD therapeutic agents: In vitro, in vivo and in silico studies

• Published in: International journal of biological macromolecules 2024-05, Vol.268 (Pt 1), p.131740-131740, Article 131740
• Main Authors: Zaafar, Dalia, Elghazawy, Nehal H., Hassan, Afnan, Mahmoud, Mohamed Y., Bakr, Alaa F., Arafa, Reem K.
• Format: Article
• Language: English
• Subjects: Acetyl choline esterase and Butyryl choline esterase inhibitors; Acetylcholinesterase - chemistry; Acetylcholinesterase - metabolism; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animals; Brain - drug effects; Brain - metabolism; Butyrylcholinesterase - chemistry; Butyrylcholinesterase - metabolism; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Computer Simulation; Humans; Ligands; Male; Molecular Docking Simulation; Multi-target directed ligands; Oxidative Stress - drug effects; Rats; Rats, Wistar; Structure-Activity Relationship
• ISSN: 0141-8130; 1879-0003
• DOI: 10.1016/j.ijbiomac.2024.131740

Alzheimer's disease (AD) is challenging due to its irreversible declining cognitive symptoms and multifactorial nature. This work tackles targeting both acetylcholinesterase (AChE) and BuChE with a multitarget-directed ligand (MTDL) through design, synthesis, and biological and in silico evaluation of a series of twenty eight new 5-substituted-2-anilino-1,3,4-oxadiazole derivatives 4a-g, 5a-g, 9a-g and 13a-g dual inhibitors of the target biomolecules. In vitro cholinesterases inhibition and selectivity assay of the synthesized derivatives showed excellent nanomolar level inhibitory activities. Compound 5a, the most potent inhibitor, elicited IC50s of 46.9 and 3.5 nM against AChE and BuChE, respectively (SI = 0.07), 5 folds better than the known dual inhibitor Rivastagmine. In vivo and ex vivo investigation showed that 5a significantly inhibited MDA levels and increased GSH contents, thus, attenuating the brain tissue oxidative stress. Additionally, 5a significantly decreased AChE and BuChE levels and inhibited self-mediated β-amyloid aggregation in brains of treated rats. Histopathological and immunohistochemical evaluation demonstrated lessened damage and decreased caspase-3 and VEGF expression levels. In silico prediction of 5a's pharmacokinetics and toxicity profiles reflected promising results. Finally, 5a demonstrated tight binding interactions with the two target biomolecules upon docking along with stable complex formation with its bio-targets throughout the 100 ns MD trajectories. [Display omitted]