Samadi_2012_Eur.J.Med.Chem_57C_296

The synthesis biological assessment and molecular modeling of new pyridonepezils1-8 able to inhibit human acetylcholinesterase hAChE and human butyrylcholinesterase hBCHE 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 hBCHE Molecular modeling investigation on pyridonepezil7 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 pyridonepezils1-8 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.