Title:Recent Developments in Tacrine-based Hybrids as a Therapeutic Option
for Alzheimer’s Disease
Volume: 23
Issue: 7
Author(s): Cem Yamali*Seyda Donmez
Affiliation:
- Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Cukurova University, Adana, Turkey
Keywords:
Alzheimer's disease, tacrine, multi-target directed ligands, MTDLs, β-amyloid, butyrylcholinesterase, acetylcholinesterase.
Abstract: Alzheimer's disease (AD) is a multifactorial, irreversible, and age-related neurodegenerative
disorder among the elderly. AD attracts attention due to its complex pathogenesis, morbidity and
mortality rates, and the limitations of drugs used in the treatment of AD. Cholinesterase inhibitors and
N-methyl-D-aspartate (NMDA) receptor antagonists are used in the clinic. While tacrine, donepezil,
galantamine, and rivastigmine are cholinesterase inhibitors, memantine is a non-competitive NMDA
receptor antagonist. However, these drugs could not delay the progress of AD. The traditional clinical
approach which is the one drug-one target concept is not entirely effective in the treatment of AD.
Also, it is of high-priority to develop potent and novel anti-AD drugs by the design concept of multitarget
directed ligands (MTDLs) which combine pharmacophores interacting with different pathways
in AD. This article provides an overview of the noteworthy structural modifications made to tacrine to
develop novel candidates for anti-Alzheimer drugs. Due to the complex pathology of AD, multifunctional
tacrine-based ligands targeting different hallmarks, β-amyloid, tau protein, N-methyl-Daspartate
receptor, cholinesterases, monoamine oxidases, secretases, have been studied. Here, tacrinebased
derivatives including heterocyclic structures such as dihydroxypyridine, chromene, coumarin,
pyrazole, triazole, tetrahydroquinolone, dipicolylamine, arylisoxazole were reported with promising
anti-AD effects compared to tacrine. In vitro and in vivo assays showed that new tacrine-based hybrids,
which are selective, neuroprotective, and non-hepatotoxic, might be considered as remarkable
anti-AD drug candidates for further clinical studies.
