Exploiting acylaminopyrazole scaffold for polypharmacology approach in Alzheimer's disease

Neurodegenerative diseases currently represent one of the most serious health pitfalls for the world population. Considering their multifactorial nature, research has focused on the study of small molecules able to simultaneously tackle different targets involved in their onset and progression. In this paper, two sets of acylaminopyrazole-based compounds were designed to exploit the aminopyrazole core as a privileged structure properly decorated with an acyl moiety and a further amide function, connected with a proper spacer. Indeed, acylated aminopyrazoles could be able to establish the appropriate hydrogen bond pattern to both bind GSK-3β, responsible for tau hyperphosphorylation, prevent the formation of insoluble Aβ-protein aggregates and have the structural features to show chelating properties towards metals involved in neuroinflammation. The collection of compounds was tested in vitro for GSK-3β inhibition activity, antiaggregating and chelating properties. Selected compounds were able to inhibit GSK-3β in the low micromolar range with a reversible and competitive mechanism of action, as established by Microfluidic Mobility Shift Assay (MMSA) and showed metal chelating ability. Preliminary Structure Activity Relationships (SARs) to hit these distinct and interconnected targets for neuromodulation were established. Finally, selected compounds showed good apparent permeability values in parallel artificial membrane permeability assay (PAMPA) together with good cellular safety profile. The collected results validated acylaminopyrazole as promising scaffold for the development of multitarget-directed ligands. Compounds 1c and 4c emerged as promising prototypes, and deserve further optimization in the search for drug candidates for polypharmacological approach in neurodegenerative disease.