Quinolizidinyl derivatives as potent inhibitors of acetyl- and butyryl-cholinesterase (ACHE and BCHE) of potential interest for the treatment of Alzheimer's disease

Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder characterized by a gradual decline of cognitive processes. The multifactorial pathogenesis of AD includes accumulation of aggregates of -amyloid and loss of cholinergic neurons, with consequent deficit of the neurotransmitter acetylcholine (ACh). The inhibition of AChE, that is responsible for the breakdown of ACh, has proven useful to relieve some cognitive and behavioral symptoms of AD. In advancing AD, AChE levels in the brain are declining, but a progressive increase (up to 90%)of BChE is observed , which too is able, even if at lower rate, to hydrolize ACh. Selective BChE inhibitors have already been reported to increase ACh levels in the brain, and,interestingly, to also reduce the formation of abnormal amyloid. Potent and selective BChE inhibitors are represented by some physostigmine derivatives as phenethylcymserine and MF-8622 and by some phenothiazine derivatives, as ethopropazine and Astra 1397, whose high activity, with respect to other phenothiazine-derived drugs, is related to their particular basic chains. In order to achieve novel cholinesterase inhibitors, either dual or, even better, selective for BChE, we have prepared and tested a number of derivatives of phenothiazine and related tricyclic systems, bearing a peculiar basic moiety, as the bulky quinolizidine ring, linked through different kinds of spacer. A few quinolizidinyl derivatives of 6-hydroxycoumarin were also included in the set of test compounds, as well as some well known tricyclic drugs(triflupromazine, methyxene, ethopropazine, Astra 1397 and quinacrine) serving as reference inhibitors. Compounds were evaluated for their inhibitory activities of AChE and BChE from bovine erythrocytes and equine serum, respectively. The tested compounds exhibited activity against both enzymes, but the inhibition of BChE was generally stronger than that of AChE, often with submicromolar IC50 values (9-lupinylthioxanthene: IC50, for AChE = 7.0 M; for BChE = 0.15 M). An inverted selectivity was observed for acridine and coumarin derivatives (6-chloro-9-[3-(lupinylthio)propylamino]-2-methoxyacridine: IC50, for AChE = 0.22 M; for BChE = 0.69 M); 6-[(3-lupinylthio)propoxy]coumarin: IC50, for AChE = 0.35 M; for BChE = 5.4 M). Molecular modeling studies provided valuable insights to interpret structure-affinity and structure-selectivity relationships and suggest appropriate structural modifications to improve the binding affinities at either one of the two enzymes.