Current Topics in Medicinal Chemistry - Volume 17, Issue 27, 2017

Alzheimer's Disease (AD) is one of the most common forms of dementia in elderly people. To date, efficacious therapeutic agent for the treatment of AD is still very limited, so it has long been a challenging and attractive task to discover new anti-AD drugs. Considering the multifactorial nature of AD, recently, the concept of Multi-Target-Directed Ligands (MTDLs) has emerged as a new strategy for designing therapeutic agents on AD. MTDLs are believed to exert their effects through simultaneously affecting multiple targets which contribute to etiology of AD. Therefore, MTDLs are considered to be more efficacious than mono-target agents. Tacrine is the first drug approved by Food and Drug Administration (FDA). Although the clinical use of tacrine is restricted because of its hepatotoxicity, the high Ligand Efficiency (LE) of this compound makes it an ideal component for designing MTDLs. This article provides an update review of the advances on the development of MTDLs based on tacrine. Case studies are carefully selected to show the detailed strategy on medicinal modification of Tacrine-Based MTDLs. Finally, several concerns and opinions on designing new MTDLs are discussed as well.

Alzheimer's Disease (AD) is a single major cause of dementia in middle to old age individuals involving several different etiopathological mechanisms that are yet to be properly characterized. Major invariant and characteristic features consist of the progressive cerebral deposition of the Amyloid β-protein (Aβ) and the neurofibrillary degeneration through Neurofibrillary Tangles (NFT) formed by hyperphosphorylation of the tau proteins in the regions of the brain that deal with memory and cognition. There are at least five subgroups of AD that can be identified by determining Cerebrospinal Fluid (CSF) levels of Aβ1-42, tau and ubiquitin. This multifactorial nature of the disease thus demands promising approaches for the development of rational disease-modifying drugs. A large number of agents have been discovered against individual targets but the success rate is very low and the number of compounds progressing to regulatory review is among the lowest found in any therapeutic area. A very promising modern approach solicits the design of Multi-Target-Directed Ligands (MTDLs) based on the “one molecule multiple targets” paradigm that has been specifically adopted for the treatment of disorders with complex pathological mechanisms. AD is one such disorder in which MTDL has found applicability. This review aims at providing an overview of the research carried out in discovering more efficient treatment against AD using MTDL, with a goal to ascertain safer drugs.

Alzheimer Diseases (AD) is a multifactorial pathology characterized by a complex etiology. The hallmarks of AD, such as Aβ deposits in senile plaque and Neurofibrillary Tangles (NFT), are strongly intertwined with Reactive Oxygen Species (ROS) production and oxidative stress (OS), which are considered the common effectors of the cascade of degenerative events. An increasing body of evidence reveals that both mitochondrial abnormalities and metal accumulations synergistically act as major producers of ROS, thus contributing to neuronal toxicity. Consequently, the detrimental role of ROS production together with the neurodegenerative events involved in AD has been widely investigated as new potential therapeutic strategies. This review will concisely summarize the link between OS and the hallmarks of AD, emphasizing on their strong correlation with neurodegenerative events and elucidating the pivotal role of ROS in AD pathology. Furthermore, through this review, we will provide a short account of some of the efforts, challenges and opportunities in developing multitarget drugs by addressing ROS production, metal accumulation and protein depositions.