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

► Pyridonepezils1-8 were designed and synthesized as dual AChEI, binding the CAS and PAS of the enzyme. ► The biological evaluation of molecules 1-8 showed that most of these compounds are potent AChEI. ► Compound 7, the most potent, is 703-fold more selective for hAChE than for hBuChE. ► The ability of compound 7 to interact with the PAS and CAS of AChE was confirmed by molecular modeling. ► Inhibitors 2-8 are permeable as determined in the PAMPA-BBB assay.