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

Abstract

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.