Design, synthesis and biological evaluation of 2-styryl-5-hydroxy-4-pyrone derivatives and analogues as multiple functional agents with the potential for the treatment of Alzheimer’s disease

[Display omitted] A novel series of 2-styryl-5-hydroxy-4-pyrone derivatives and analogues were designed and synthesized as H3 receptor antagonism based multitarget-directed ligands (MTDLs) for AD therapy using pharmacophore-combine strategy. The 2-styryl-5-hydroxy-4-pyrone pharmacophore with metal ion chelation, antioxidation, and Aβ aggregation inhibition activities was employed as the “eastern part”, and a typical phenoxyalkylamine moiety was used as “central ring + western part” of the H3 receptor antagonist. The biological evaluation revealed that the majority of the target compounds demonstrated desirable multiple functions. The two most promising compounds 8a and 8b exhibited nanomolar IC50 values on H3 receptor antagonism, excellent metal ion chelating capability, more potent ABTS+ scavenging activity than Trolox, efficient Aβ self-aggregation and Cu2+-induced aggregation inhibitory activities, as well as disaggregation activities against Aβ self/Cu2+-induced aggregation.