Therapeutic Potential of Multifunctional Derivatives of Cholinesterase Inhibitors

Abstract

: The aim of this work is review of tacrine analogues from the last three years, which were not included in the latest review work, donepezil and galantamine hybrids from 2015 and rivastigmine derivatives from 2014. In this account we summarize the efforts toward the development and characterization of non-toxic inhibitors of cholinesterases based on mentioned drugs with various interesting additional properties such as antioxidant, decreasing β-amyloid plaque aggregation, nitric oxide production, pro-inflammatory cytokines release, monoamine oxidase-B activity, cytotoxicity and oxidative stress in vitro and in animal model that classify these hybrids as potential multifunctional therapeutic agents for Alzheimer’s disease. Moreover, herein, we have described the cholinergic hypothesis, mechanisms of neurodegeneration and current pharmacotherapy of Alzheimer’s disease which is based on the restoration of cholinergic function through blocking enzymes that break down acetylcholine.

Linking Cerebrovascular Dysfunction to Age-Related Hearing Loss and Alzheimer’s Disease—Are Systemic Approaches for Diagnosis and Therapy Required?

“…Multiple epidemiological studies have demonstrated a remarkable overlap among risk factors for cerebrovascular disorder and sporadic, late-onset AD [ 59 ]. For example, mid-life diabetes [ 60 ], hypertension [ 16 , 61 ], and obesity [ 62 ] have been shown to increase the risk for both AD and vascular dementia. It is now generally acknowledged that most AD cases have mixed vascular pathology and small-vessel disease [ 12 , 63 ].…”

“…The cholinergic hypothesis claims that AD is caused by cholinergic effects such as the reduced synthesis of the neurotransmitter acetylcholine or the initiation of the large-scale aggregation of amyloid and neuroinflammation [ 14 , 15 ]. Most currently available drug therapies are based on this hypothesis [ 16 ].…”

Design, synthesis and biological evaluation of novelN-phosphorylated andO-phosphorylated tacrine derivatives as potential drugs against Alzheimer’s disease

“…It should be mentioned that many other symptoms occur simultaneously with AD, like depression, psychosis or cognitive impairment 5–7 . The cause of this disease is still unknown, but the main therapeutic strategies are based on cholinergic hypothesis, so available drugs are cholinesterase inhibitors 8 , 9 . Regarding the hydrolysis of acetylcholine by acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) to choline and acetate, the concentration of this neurotransmitter in the central nervous system is insufficient to enable the proper work of brain 10–14 .…”

Design, Synthesis, and In Vitro, In Silico and In Cellulo Evaluation of New Pyrimidine and Pyridine Amide and Carbamate Derivatives as Multi-Functional Cholinesterase Inhibitors

“…During the last few years, scientific advances have inspired researchers to study new pharmacological therapies focused more on the pathophysiological events of the AD [24]. In particular, one of the central choices of medicinal chemistry research is the development of multitarget or multifunctional ChEIs [25][26][27]. Some of these studies suggest that a possible way forward could be the development of new therapeutic agents with anticholinesterasic activity that also mitigate oxidative stress both directly, by exerting antioxidant functions, and indirectly, through the chelation of the main metal ions involved in the generation of reactive oxygen species [28,29].…”