PHOX 15 as a polypharmacological small molecule: synthetic optimization and development of novel derivatives targeting tau aggregation and hyperphosphorylation.

Tauopathies are a heterogeneous group of neurodegenerative disorders characterized by the accumulation of hyperphosphorylated tau protein in the form of neurofibrillary tangles in neurons and, in some cases, glial cells. Alzheimer’s disease represents the most prevalent tauopathy. Under physiological conditions, tau is a microtubule-associated protein participating in microtubule dynamics and axonal transport. Pathological post-translational modifications, particularly hyperphosphorylation mediated by kinases such as GSK3β and Cdk5, promote tau detachment from microtubules, conformational changes, and self-aggregation, leading to neuronal dysfunction and neurodegeneration. Despite encouraging results from preclinical studies, no effective cure for tauopathies is currently available. The identification of polypharmacological compounds capable of simultaneously inhibiting tau hyperphosphorylation and aggregation represents a promising therapeutic strategy. Such compounds may target multiple disease-relevant pathways, including tau aggregation, tau phosphorylation, and other tau-related functions impaired during disease progression. PHOX15 is a polypharmacological drug candidate able to restore physiological tau-microtubule interactions, by reducing the amyloid aggregation and hyperphosphorylation mediated by the kinases GSK3β and Cdk5. The aim of this thesis was the synthesis of new derivatives of PHOX15 and the optimization of its synthetic route. In this work, four PHOX15 derivatives bearing substituents on the aniline ring were synthesized to investigate structure-activity relationships and potential improvements in pharmacokinetic and pharmacodynamic properties. An optimized four-step synthetic route was developed, and future studies will focus on the biological evaluation of the synthesized compounds in vitro and in cellular models expressing pathological tau