Derivatives of Tenuazonic Acid as Potential New Multi-Target Anti-Alzheimer's Disease Agents.

Viviana Poliseno,Antonio Laghezza,Luca Piemontese,Sílvia Chaves,João D Magalhães,Fulvio Loiodice,Sandra M Cardoso,M Amélia Santos,Leonardo Brunetti,Antonio Carrieri,Paolo Tortorella

doi:10.3390/biom11010111

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.

Highlights

IntroductionAlzheimer’s disease (AD) is one of the most common neurodegenerative diseases, characterized by a drastic and progressive decline in memory and cognitive abilities [1]
Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases, characterized by a drastic and progressive decline in memory and cognitive abilities [1].It represents the main cause of dementia worldwide, and it is recognized as a socioeconomic problem especially due to the constant care needed by patients and their families [2]
The intermediate 6 was synthesized starting from the commercial N-aminoethylpiperazine as previously reported [12,29]

Summary

Introduction

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases, characterized by a drastic and progressive decline in memory and cognitive abilities [1]. It represents the main cause of dementia worldwide, and it is recognized as a socioeconomic problem especially due to the constant care needed by patients and their families [2]. The number of people affected by AD is substantial, reaching 46 million globally, and is poised to rise sharply in the coming decades, as a result of increasing life expectancies worldwide [3]. Five symptomatic drugs were approved in the EU and US, four acetylcholine esterase (AChE) inhibitors (tacrine, donepezil, Figure 1a, rivastigmine and galantamine), and memantine, an antagonist of the NMDA receptor [2]. 4.0/).

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