Teke_2025_Eur.J.Med.Chem_298_117986

Neurodegenerative diseases are multifactorial disorders characterized by protein misfolding, oxidative stress, and neuroinflammation, finally resulting in neuronal loss and cognitive dysfunctions. Nowadays, an attractive strategy to improve the classical treatments is the development of multitarget-directed molecules able to synergistically interact with different enzymes and/or receptors. A novel series of chiral carbamate and carbamothioate derivatives were designed, synthesized, and investigated as inhibition of cholinesterases and monoamine oxidases, anti-beta-amyloid aggregation and antioxidant activities against Alzheimer's disease. The enzymatic activity of butyrylcholinesterase (BChE) in the brain increases with the progression of Alzheimer's disease, thus classifying BChE as a promising drug target in advanced Alzheimer's disease. Two compounds, 4a-S and 4a-R, showed excellent and selective inhibitory activities against BChE (IC(50): 0.051 microM; IC(50): 0.059 microM). Compound 4a-S also exhibited selective hMAO-B (IC(50) = 0.45 +/- 0.02 microM) inhibitory activities. The molecular docking and dynamic simulations of compounds 4a-R and 4a-S in human BChE revealed that the piperidine and propargyl groups play crucial roles for the inhibition. Compound 1d-R had the greatest ability to hMAO-B inhibition (IC(50) = 0.09 microM). Compound 2b exhibited significant ability to inhibit self-induced beta-amyloid (Abeta(1-42); IC(50): 0.97 microM). Achiral carbamate derivatives 2c, 2j and 2a act as potential antioxidants. Among the compounds, 2c, 2i, 2j, 4a-S were selected for the PAMPA-BBB test. These compounds demonstrated excellent penetration into the central nervous system. Compounds 1d-R, 2b, 2c, 4a-S and 4a-R were assessed in vivo with Aluminium chloride induced Alzheimer mice model. Compounds 1d-R, 2b, and 4a-S increased learning according to Morris Water Maze test. Our preliminary findings may open-up the way for developing innovative carbamate and carbamothioate derivatives against neurodegenerative diseases.