Tacrine Derivatives and Alzheimers Disease

Abstract

To date, the pharmacotherapy of Alzheimer's disease (AD) has relied on acetylcholinesterase (AChE) inhibitors (AChEIs) and, more recently, an N-methyl-D-aspartate receptor (NMDAR) antagonist. AD is a multifactorial syndrome with several target proteins contributing to its etiology. "Multi-target-directed ligands" (MTDLs) have great potential for treating complex diseases such as AD because they can interact with multiple targets. The design of compounds that can hit more than one specific AD target thus represents an innovative strategy for AD treatment. Tacrine was the first AChEI introduced in therapy. Recent studies have demonstrated its ability to interact with different AD targets. Furthermore, numerous tacrine homo- and heterodimers have been developed with the aim of improving and enlarging its biological profile beyond its ability to act as an AChEI. Several tacrine hybrid derivatives have been designed and synthesized with the same goal. This review will focus on and summarize the last two years of research into the development of tacrine derivatives able to hit AD targets beyond simple AChE inhibition.

Cholinesterases, a Target of Pharmacology and Toxicology

“…The main disadvantage of tacrine is its relatively high hepatotoxicity 98 . There is an effort underway to find less toxic derivatives of tacrine 99 . In the past, 7-methoxytacrine was extensively investigated as a promising substitute to tacrine.…”

Design, synthesis and neuroprotective evaluation of novel tacrine–benzothiazole hybrids as multi-targeted compounds against Alzheimer’s disease

“…11,12 Recent studies have demonstrated that homo-and hetero-dimers can improve the biological profile of tacrine and even overcome some of its side effects. 13 Afterwards, quite a number of tacrine derivatives, some of them as hybrid drugs, have been developed to improve its activity, as described in a recent review in this topic, 14 including tacrine-8-hydroxyquinoline hybrids, 15 mercapto-tacrine derivatives 16 , tacrine-fluorobenzoic acid hybrids 17 and tacrinemultialkoxybenzene hybrids. 18 Moreover, based on evidences that reduction of amyloid deposits lead to alleviation of the AD´s symptoms, 19,20 a considerable current effort has been directed towards the identification and the development of potential therapeutic agents able to reduce the soluble amyloid oligomers burden.…”

Neuroprotective Tri- and Tetracyclic BChE Inhibitors Releasing Reversible Inhibitors upon Carbamate Transfer

“…15,16 It was therefore tried to combine AChE inhibitors with compounds possessing antioxidant properties, for example, by forming covalently connected hybrids or physiologically more labile codrugs. 11,12,17,18 Albeit highly promising compounds, hybrids also suffer from some difficulties, such as their inherent high molecular mass and therefore reduced bioavailability.…”