N-Propargylpyrrolidine-based butyrylcholinesterase and monoamine oxidase inhibitors

Butyrylcholinesterase (BChE) inhibitors are or could be used for the treatment of Alzheimer's disease, canine cognitive dysfunction, depression, multiple sclerosis, heroin abuse and metabolic disorders. Monoamine oxidase (MAO) inhibitors are or could be used for the treatment of depression, anxiety, Alzheimer's disease, Parkinson's disease, cancer, cardiovascular disease and chronic inflammatory diseases. We have designed, synthesized, and evaluated ten new N-propargylpyrrolidine-based inhibitors of these enzymes. Sulfonamide 10 is the most potent human (h)BChE (IC₅₀ = 0.203 μM) of the series, and secondary carboxamide 1 is a time-dependent and irreversible inhibitor of hMAO-A (IC₅₀ = 6.42 μM) and hMAO-B (IC₅₀ = 7.83 μM). The X-ray crystal structures of carboxamide 4 [IC₅₀(hBChE) = 3.89 μM] and sulfonamide 10 with hBChE confirmed our previous observation that carboxamides and sulfonamides have distinct binding poses in the active site of hBChE. The X-ray crystal structure of the complex of pyrrolidine 4 with hBChE also revealed a distinct binding pose compared to its direct piperidine analogue (PDB code 5LKR). Furthermore, compounds 1 and 10 should be able to cross the blood-brain barrier, exhibit low cytotoxicity (>50 μM) in two cell lines and protect against amyloid β_1-42-induced neuronal cell death.