Pyridonepezils, new dual AChE inhibitors as potential drugs for the treatment of Alzheimer's disease: synthesis, biological assessment, and molecular modeling.

Abstract The synthesis, biological assessment and molecular modeling of new pyridonepezils 1 – 8 , able to inhibit human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBuChE), are described. The new compounds have been designed as hybrids resulting from a conjunctive approach that combines the N -benzylpiperidine moiety, present in donepezil, and the 2-amino-6-chloropyridine heterocyclic ring system, connected by an appropriate polymethylene linker. Compounds 1 – 8 were prepared by reaction of 2-amino-6-chloro-4-phenylpyridine-3,5-dicarbonitrile ( 13 ) [or 2-amino-6-chloropyridine-3,5-dicarbonitrile ( 14 )] with 2-(1-benzylpiperidin-4-yl)alkylamines ( 9 – 12 ). The biological evaluation of molecules 1 – 8 showed that compounds 1 – 6 are potent AChE inhibitors, in the submicromolar, while compounds 7 and 8 are on the nanomolar range, the most potent, 2-amino-6-((3-(1-benzylpiperidin-4-yl)propyl)amino)pyridine-3,5-dicarbonitrile ( 7 ), showing a IC 50 (hAChE) = 9.4 ± 0.4 nM. Inhibitors 2 – 8 are permeable as determined in the PAMPA assay. Compared to donepezil, compound 7 is in the same range of inhibitory activity for hAChE, and 703-fold more selective for hAChE than for hBuChE. Molecular modeling investigation on pyridonepezil 7 supports its dual AChE inhibitory profile, binding simultaneously at the catalytic active and at peripheral anionic sites of the enzyme. The theoretical ADME analysis of pyridonepezils 1 – 8 has been carried out. Overall, compound 7 , a potent and selective dual AChEI, can be considered as a candidate with potential impact for further pharmacological development in Alzheimer's therapy.