Pyridonepezils, new dual AChE inhibitors as potential drugs for the treatment of Alzheimer's disease: synthesis, biological assessment, and molecular modeling.
The synthesis, biological assessment and molecular modeling of new pyridonepezils1-8, 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 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.
Laboratorio de Química Médica, Instituto de Química Orgánica General (CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain. samadi@iqog.csic.es
Abdelouahid
A
Samadi
Martín
M
Estrada
Concepción
C
Pérez
María Isabel
MI
Rodríguez-Franco
Isabel
I
Iriepa
Ignacio
I
Moraleda
Mourad
M
Chioua
José
J
Marco-Contelles
D000110:Acetylcholinesterase / Q000737:chemistry*; D000544:Alzheimer Disease / Q000188:drug therapy; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D000077265:Donepezil; D057075:Enzyme Assays; D006801:Humans; D007189:Indans / Q000737:chemistry*; D008954:Models, Biological; D008958:Models, Molecular; D009570:Nitriles / Q000737:chemistry*; D010539:Permeability; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry*; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry*; D013329:Structure-Activity Relationship
C580934:2-amino-6-((3-(1-benzylpiperidin-4-yl)propyl)amino)pyridine-3,5-dicarbonitrile; D000631:Aminopyridines; D002800:Cholinesterase Inhibitors; D007189:Indans; D009570:Nitriles; D010880:Piperidines; D011725:Pyridines; C071293:1-benzylpiperidine; D000077265:Donepezil; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase