Design and synthesis of novel tacrine-dipicolylamine dimers that are multiple-target-directed ligands with potential to treat Alzheimer’s disease

Zhang, Panpan; Wang, Ze; Mou, Chenye; Zou, Jiamei; Xie, Yuning; Liu, Zhiwen; Naman, C. Benjamin; Mao, Yuechun; Wei, Jiaxin; Huang, Xinghan; Dong, Jiahui; Yang, Mengxiang; Wang, Ning; Jin, Haixiao; Liu, Fufeng; Lin, Dongdong; Líu, Hao; Fei, Zhou; He, Shan; Zhang, Bin; Cui, Wei

doi:10.1016/j.bioorg.2021.105387

Cited by 13 publications

(5 citation statements)

References 55 publications

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“…Pharmaceutics 2023, 15, x FOR PEER REVIEW 5 of 13 located on either side of an aromatic gorge within the enzyme, which is approximately 20 Å deep. For this reason, the number of atoms in the chemical bond in the structure of these dual interaction inhibitors is calculated to separate each of the two motifs by an adequate distance [21]. An example is donepezil, one of the anti-Alzheimer's drugs currently on the market, which inhibits the catalytic site of AChE and thus temporarily alleviates the cholinergic deficiency that marks the disease, and also interacts with the peripheral anion site of the enzyme, preventing it from aggregating with the beta-amyloid peptide (Figure 4).…”

Section: Non-dissociable Conjugatesmentioning

confidence: 99%

Conceptual Framework of the Design of Pleiotropic Drugs against Alzheimer’s Disease

Guiselin,

Lecoutey,

Rochais

et al. 2023

Pharmaceutics

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The multifactorial nature of some diseases, particularly neurodegenerative diseases such as Alzheimer’s disease, frequently requires the use of several drugs. These drug cocktails are not without drawbacks in terms of increased adverse effects, drug–drug interactions or low adherence to treatment. The use of pleiotropic drugs, which combine, within a single molecule, several activities directed against distinct therapeutic targets, makes it possible to overcome some of these problems. In addition, these pleiotropic drugs generally lead to the expression of a synergy of effects, sometimes greater than that observed with a combination of drugs. This article will review, through recent examples, the different kinds of pleiotropic drugs being studied or already present on the market of medicines, with a focus on the structural aspect of such drug design.

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Section: Non-dissociable Conjugatesmentioning

confidence: 99%

Conceptual Framework of the Design of Pleiotropic Drugs against Alzheimer’s Disease

Guiselin,

Lecoutey,

Rochais

et al. 2023

Pharmaceutics

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“…In neurodegenerative illnesses, the balance between proinflammatory and anti-inflammatory cytokines also has an impact on the course of the disease [ 15 , 45 ]. According to Zhang et al, hippocampal injection of a tacrine analogue known as 4-(bis(pyridin-2-ylmethyl)amino)-N-(3- ((1,2,3,4-tetrahydroacridin-9-yl) amino)propyl)butanamide could effectively attenuate A β 1-42 oligomers-induced cognitive dysfunction by activating the CREB/BDNF signaling pathway, decreasing tau phosphorylation [ 46 ]. According to the findings of a study conducted by Tyagi et al, tacrine may have an inhibitory effect on lipopolysaccharide (LPS-)-induced neuroinflammation in adult Swiss albino mice, as evidenced by a decrease in the high levels of IL-2 in the brain [ 42 ].…”

Section: Molecular Basis Of Tacrine Derivatives' Action Against Neuro...mentioning

confidence: 99%

Tacrine Derivatives in Neurological Disorders: Focus on Molecular Mechanisms and Neurotherapeutic Potential

Mitra

Muni

Shawon

et al. 2022

Oxidative Medicine and Cellular Longevity

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Tacrine is a drug used in the treatment of Alzheimer’s disease as a cognitive enhancer and inhibitor of the enzyme acetylcholinesterase (AChE). However, its clinical application has been restricted due to its poor therapeutic efficacy and high prevalence of detrimental effects. An attempt was made to understand the molecular mechanisms that underlie tacrine and its analogues influence over neurotherapeutic activity by focusing on modulation of neurogenesis, neuroinflammation, endoplasmic reticulum stress, apoptosis, and regulatory role in gene and protein expression, energy metabolism, Ca2+ homeostasis modulation, and osmotic regulation. Regardless of this, analogues of tacrine are considered as a model inhibitor of cholinesterase in the therapy of Alzheimer’s disease. The variety both in structural make-up and biological functions of these substances is the main appeal for researchers’ interest in them. A new paradigm for treating neurological diseases is presented in this review, which includes treatment strategies for Alzheimer’s disease, as well as other neurological disorders like Parkinson’s disease and the synthesis and biological properties of newly identified versatile tacrine analogues and hybrids. We have also shown that these analogues may have therapeutic promise in the treatment of neurological diseases in a variety of experimental systems.

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“…Novel hybrids in this category have been designed and synthesized by the covalent linking of tacrine and the Aβ aggregation inhibitor dipicolylamine. The products are dimers with a potent inhibitory effect on AChE and Aβ, decreasing tau phosphorylation, preventing synaptic toxicity, and inhibiting neuroinflammation [88]. MTDLs developed by structure-based drug design (SBDD) methods [90,91] have proven to be successful due to the increasing availability of structural data for key targets in AD (crystallographic, NMR, and CryoEM structures).…”

Section: Multi-target Directed Ligands (Mtdls) For Admentioning

confidence: 99%

New Drug Design Avenues Targeting Alzheimer’s Disease by Pharmacoinformatics-Aided Tools

et al. 2022

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Neurodegenerative diseases (NDD) have been of great interest to scientists for a long time due to their multifactorial character. Among these pathologies, Alzheimer’s disease (AD) is of special relevance, and despite the existence of approved drugs for its treatment, there is still no efficient pharmacological therapy to stop, slow, or repair neurodegeneration. Existing drugs have certain disadvantages, such as lack of efficacy and side effects. Therefore, there is a real need to discover new drugs that can deal with this problem. However, as AD is multifactorial in nature with so many physiological pathways involved, the most effective approach to modulate more than one of them in a relevant manner and without undesirable consequences is through polypharmacology. In this field, there has been significant progress in recent years in terms of pharmacoinformatics tools that allow the discovery of bioactive molecules with polypharmacological profiles without the need to spend a long time and excessive resources on complex experimental designs, making the drug design and development pipeline more efficient. In this review, we present from different perspectives how pharmacoinformatics tools can be useful when drug design programs are designed to tackle complex diseases such as AD, highlighting essential concepts, showing the relevance of artificial intelligence and new trends, as well as different databases and software with their main results, emphasizing the importance of coupling wet and dry approaches in drug design and development processes.

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Design and synthesis of novel tacrine-dipicolylamine dimers that are multiple-target-directed ligands with potential to treat Alzheimer’s disease

Cited by 13 publications

References 55 publications

Conceptual Framework of the Design of Pleiotropic Drugs against Alzheimer’s Disease

Conceptual Framework of the Design of Pleiotropic Drugs against Alzheimer’s Disease

Tacrine Derivatives in Neurological Disorders: Focus on Molecular Mechanisms and Neurotherapeutic Potential

New Drug Design Avenues Targeting Alzheimer’s Disease by Pharmacoinformatics-Aided Tools

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