Pharmacophore Fusion-based Design,Synthesis And Biological Evaluation Of N-aryl-pyridinone Derivatives As Alzheimer’s Disease Therapeutic Agents

Alzheimer’s disease(AD)is the most common form of dementia and is characterized by progressive memory loss and cognitive impairments.Currently,treatments for AD only achieve limited clinical efficacy in symptomatic improvement but fail to address the underlying causes of the disease.Thus,multitarget-directed ligands(MTDLs)which raise as a potentially more effective strategy for AD therapy have attracted considerable attention in recent years.To develop a drug candidate capable of targeting multiple AD pathological factors,we undertook a rational pharmacophore-directed design and combined the amino-propoxyphenyl moiety of H3 receptor antagonists and Aβ aggregation inhibitors with marketed chelator deferiprone,which has desirable antioxidant capacity.Herein,we presented a series of 3-hydroxy-4-pyridinone derivatives as the first class of MTDLs integrating H3 receptor antagonism,anti-Aβ aggregation,metal chelation and radical scavenging activities.Most of the compounds demonstrated excellent activities.The most promising compound Ⅰ-29 displayed excellent selective H3 receptor antagonistic activity,effective inhibition of self-and copper-induced Aβ1-42 aggregation as well as the ability to disassemble the previously formed and highly structured Aβ1-42 fibrils.In addition,it showed no obvious cytotoxicity and possessed very low hERG potassium channel risk.Ⅰ-29 demonstrated suitable PK properties and acceptable BBB permeability in vivo.These results indicate that Ⅰ-29 is a potential lead for AD therapy.In order to improve the bioavailability of Ⅰ-29,a series of 3-alkoxy-4-pyridinone derivatives were designed and synthesized based on the hydroxyl group modified strategy.According to the results,most compounds showed excellent H3 receptor antagonistic activity and good Aβ1-40 and Aβ1-42 aggregation inhibitory activity.Representative compound Ⅰ-68 was chosen to evaluate further biological activities and druggability.Ⅰ-68 was a selective H3 antagonist with Aβ1-40 and Aβ1-42 disaggregation ability.Meanwhile,It has good stability in liver microsomes,suitable PK properties and efficient BBB permeability.Remarkablely,compared to Ⅰ-29,the bioavailability of Ⅰ-68 was significantly increased(F%=47.9).Furthermore,Ⅰ-68 could efficiently block RAMH-induced dipsogenia and reverse scopolamine-induced learning deficits of rats in the Morris water maze.Ⅰ-68 showed no obvious hERG toxicity and a minimum lethal dose of more than 500mg/kg.The above results suggested that Ⅰ-68 deserves further assessment and might to be a promising drug candidate.Based on the structural features of Ⅰ-68,a series of 2-phenyl-quinolinone and flavonoids derivatives were designed and synthesized according to rational drug design theory and the molecular alignment analysis.Most target compounds exhibited potent antagonistic activity towards H3 receptor and moderate anti-Aβ aggregation ability.Radical scavenger Edaravone was incorporated into the scaffold of Ⅰ-68 with the modification of substitutents in the pyrazolone ring,a series of pyrazolone derivatives were furnished as MDTLs with radical scavenging,H3 receptor antagonism and anti-Aβaggregation activities.Compounds Ⅲ-78 showed the most potent inhibitory activities(ABTS IC5O = 4.06 μM;H3R IC50 = 0.24 μM;Aβ1-42 Inh%:71.6%)in 14 tested compounds,which laid a foundation for further research.The above results provide new insights for the development of MTDLs as anti-Alzheimer agents.