Derivatives of tenuazonic acid as potential new multi‐target anti‐alzheimer’s disease agents

Abstract

Alzheimer’s disease (AD) is generally recognized as a multifactorial neurodegenerative pathology with an increasing impact on society. Tenuazonic acid (TA) is a natural compound that was recently identified as a potential multitarget ligand with anti‐cholinesterase, anti-amyloidogenic and antioxidant activities. Using its structure as a chemical scaffold, we synthesized and evaluated new derivatives (1–5), including tenuazonic‐donepezil (TA‐DNP) hybrids (4 and 5) due to the clinical importance of the anti‐AD drug donepezil. These novel compounds all achieved activity in the micromolar range towards all selected targets and demonstrated to be potentially orally absorbed. Moreover, a selected compound (1) was further investigated as a chelating agent towards copper (II), zinc (II) and iron (III) and showed good chelating ability (pFe = 16.6, pCu = 11.6, pZn = 6.0 at pH 7.4). Therefore, the TA motif can be considered an interesting building block in the search for innovative multi‐functional anti‐neurodegenerative drugs, as exemplified by hybrid 5, a promising non‐cytotoxic lead compound adequate for the early stages of AD, and capable of ameliorating the oxidative status of SH‐SY5Y human neuroblastoma cells.