Novel Xanthene Derivatives for Neuroprotection in Alzheimer's Disease—Synthesis and Biological Assessment

Alzheimer's disease (AD) is recognized by the World Health Organization as a global public health priority. There is an urgent need to develop disease‐modifying therapies or treatments (DMT's) to prevent, delay, or slow the progression and target the primary AD pathophysiology mechanisms. Following previous works on the activity of tricyclic compounds in neuroprotection, this work focuses on the synthesis of novel xanthene derivatives. Eighteen compounds were obtained and assessed regarding their cytotoxicity, central nervous system (CNS) penetration, P‐glycoprotein (P‐gp) modulation, and neuroprotective effects against iron‐ and amyloid‐beta (Aβ)‐induced cytotoxicity. Generally, the derivatives were well tolerated by differentiated human neuroblastoma SH‐SY5Y cells at concentrations up to 25 μM. Regarding their ability to activate P‐gp, compounds 5 , 7 , 9 , 11 , 12, and 16 showed the most significant increases in P‐gp activity. Neuroprotection assays demonstrated the ability of several xanthene derivatives to counteract iron (III)‐ and Aβ‐induced cytotoxicity. It was clearly demonstrated the P‐gp involvement in compound‐mediated ability to reverse the cytotoxicity induced by the Aβ _25–35 peptide. Additionally, parallel artificial membrane permeability assay (PAMPA) studies showed their potential to penetrate the blood‐brain barrier (BBB) and reach the CNS, which is a crucial requirement for their potential biological activity in AD.