Design, synthesis and pharmacological evaluation of multitarget GPR40 agonists/HDAC6 inhibitors for Alzheimer's disease

The discovery of new therapeutic agents for the treatment of neurodegenerative diseases - particularly Alzheimer's disease (AD) - remains one of the most challenging areas in medicinal chemistry. Given the multifactorial nature of these disorders, the rational design of multitarget-directed ligands (MTDLs) is gaining increasing attention, underscoring the importance of exploring novel target combinations. In this study, we report the design of the first-in-class multitarget compounds that function as dual GPR40 agonists and HDAC6 inhibitors-a novel strategy aimed at modulating neuroinflammation in AD. Among them, compound 4e exhibited potent activity, with an EC50 of 22 nM for GPR40 activation and an IC50 of 73 nM for HDAC6 inhibition. This balanced dual profile was corroborated in cell-based assays, where compound 4e significantly increased acetylated tubulin and ERK phosphorylation levels in SH-SY5Y cells. Furthermore, compound 4e demonstrated immunomodulatory effects on microglia, highlighting its potential as a chemical starting point for targeting neuroinflammation and, ultimately, neurodegeneration.