Tacrine hybrids as multi-target-directed ligands in Alzheimer's disease: influence of chemical structures on biological activities

Alzheimer's disease is a neurological disorder, which is the most common form of dementia affecting mostly elderly people. The number of patients is still rapidly increasing which results in negative impacts on population. The loss of cholinergic transmission is one of the signs of Alzheimer's disease; it is connected with cognition impairment and memory loss. Therefore, some drug therapies are based on restoring the cholinergic function. Therefore, drug therapies are based on the cholinergic hypothesis. Acetylcholinesterase inhibitors such as donepezil, galantamine, and rivastigmine are nowadays in medical use. Tacrine possesses a simple structure and strong activity, but despite these features, it was withdrawn from the market due to its side effects. Due to the multifactorial etiology of Alzheimer's disease, researchers have investigated multi-target-directed ligands based on tacrine structure to achieve better treatment efficacy. To broaden the therapeutic profile of the ligands, tacrine is bound to numerous moieties with various applications. The hybrids can be obtained in three ways: first, by conjugating; second, by fusing; third, by merging single molecules. The hybrids can target numerous disease pathways simultaneously. This is a promising concept, which will create multiple drugs that will minimize the symptoms of diseases in elderly populations. In this review, we will be describing differently synthesized series of tacrine compounds which were divided based on their biological activities.