Development of cyanopyridine-triazine hybrids as lead multitarget anti-Alzheimer agents.

摘要: A series of new cyanopyridine-triazine hybrids were designed, synthesized and screened as multitargeted anti-Alzheimer's agents. These molecules designed while using computational techniques via a feasible concurrent synthetic route. Inhibition potencies compounds 4a-4h against cholinesterases, Aβ1-42 disaggregation, oxidative stress, cytotoxicity, neuroprotection Aβ1-42-induced toxicity the evaluated. Compounds 4d 4h showed promising inhibitory activity on acetylcholinesterase (AChE) with IC50 values 0.059 0.080μM, respectively, along good inhibition selectivity AChE over butyrylcholinesterase (BuChE). Molecular modelling studies revealed that these interacted simultaneously catalytic active site (CAS) peripheral anionic (PAS) AChE. The mixed type compound further confirmed their dual binding nature in kinetic studies. Furthermore, results from most potent indicate derivatives can reduce neuronal death induced by H2O2-mediated stress cytotoxicity. In addition, silico analysis absorption, distribution, metabolism excretion (ADME) profile best they have drug like properties. Overall, be considered candidate potential impact for pharmacological development Alzheimer's therapy.