“Clicking“ fragment leads to novel dual-binding cholinesterase inhibitors

Molęda, Zuzanna; Zawadzka, Anna; Czarnocki, Zbigniew; Monjas, Leticia; Hirsch, Anna K. H.; Budzianowski, Armand; Maurin, Jan K.

doi:10.1016/j.bmc.2021.116269

Cited by 8 publications

(6 citation statements)

References 32 publications

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“…In 2021, Molęda et al [34] reported the development of novel dual-binding inhibitors of ChE, designed to selectively target the catalytic and peripheral anionic sites (CAS and PAS) of AChE. Among the 12 hybrids synthesized and evaluated for their efficacy against both human enzymes, hAChE and hBChE, compound 1 (Figure 3) emerged as the most potent ChE inhibitor, exhibiting an IC50 value of 0.018 µM for hAChE and 0.963 µM for hBChE.…”

Section: Cholinesterase (Che) Inhibitorsmentioning

confidence: 99%

“…To achieve this, the neuroprotective qualities of Trp metabolites were investigated using both in vitro and in vivo experimental models. Trp metabolites, including indole, indole-3-acetic acid (32), indole-3propionic acid (33), indole-3-lactic acid (34), and indole-3-carboxyaldehyde (35) (Figure 21), exhibited significant reductions in oxidative stress, inflammation, and neuronal apoptosis induced by H 2 O 2 in HT-22 cells. Simultaneously, indoles upregulated the expressions of the (GPR30)/AMPK/SIRT1 pathway in vitro.…”

Section: Multifunctional Indole-based Compounds As Potential Anti-neu...mentioning

confidence: 99%

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Indole-Based Compounds in the Development of Anti-Neurodegenerative Agents

Barresi,

Baglini,

Poggetti

et al. 2024

Molecules

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Neurodegeneration is a gradual decay process leading to the depletion of neurons in both the central and peripheral nervous systems, ultimately resulting in cognitive dysfunctions and the deterioration of brain functions, alongside a decline in motor skills and behavioral capabilities. Neurodegenerative disorders (NDs) impose a substantial socio-economic strain on society, aggravated by the advancing age of the world population and the absence of effective remedies, predicting a negative future. In this context, the urgency of discovering viable therapies is critical and, despite significant efforts by medicinal chemists in developing potential drug candidates and exploring various small molecules as therapeutics, regrettably, a truly effective treatment is yet to be found. Nitrogen heterocyclic compounds, and particularly those containing the indole nucleus, which has emerged as privileged scaffold, have attracted particular attention for a variety of pharmacological applications. This review analyzes the rational design strategy adopted by different research groups for the development of anti-neurodegenerative indole-based compounds which have the potential to modulate various molecular targets involved in NDs, with reference to the most recent advances between 2018 and 2023.

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Section: Cholinesterase (Che) Inhibitorsmentioning

confidence: 99%

Section: Multifunctional Indole-based Compounds As Potential Anti-neu...mentioning

confidence: 99%

Indole-Based Compounds in the Development of Anti-Neurodegenerative Agents

Barresi,

Baglini,

Poggetti

et al. 2024

Molecules

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“…Click chemistry is a hot research area in synthetic organic chemistry with numerous advantages in drug discovery. In the year 2021, Moleda et al (2021) developed dual‐binding ChE inhibitors using “click chemistry” that selectively bind to the CAS and PAS of AChE. They systematically synthesized 12 hybrids and tested them against h AChE and h BChE.…”

Section: Multifunctional Tryptamine Hybrids As Potential Anti‐ad Drugsmentioning

confidence: 99%

Tryptamine: A privileged scaffold for the management of Alzheimer's disease

Singh,

Kumar

2023

Drug Development Research

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Alzheimer's disease (AD) is a chronic and irreversible neurodegenerative disease associated with aging. It is characterized by the progressive loss of memory and other cognitive functions. Although the exact etiology of AD is not well explored, several factors, such as the deposition of amyloid‐β (Aβ) plaques, hyperphosphorylation of tau protein, presence of low levels of acetylcholine, and generation of oxidative stress, are key mediators in the progression of AD. Currently, the clinical treatment options for AD are limited and are based on cholinesterase (ChE) inhibitors (e.g., donepezil, rivastigmine, and galantamine), N‐methyl‐d‐aspartic acid receptor antagonists (e.g., memantine), and the recently approved Aβ modulator (e.g., aducanumab). Tryptamine (2‐(1H‐indol‐3‐yl)ethan‐1‐amine) is a small molecule that contains an indole nucleus and an ethylamine side chain. It is also the active metabolite of tryptophan. It possesses a wide range of biological activities related to neurodegenerative disorders, such as ChE inhibition, Aβ aggregation inhibition, antioxidant effects, monoamine‐oxidase inhibition, and neuroprotection. Several tryptamine‐based hybrid analogs are currently being investigated as multifunctional agents for the development of novel hybrids for AD treatment. Thus, this review article aims to provide in‐depth insights into the research progress and strategies for designing multifunctional agents used in Alzheimer's therapy.

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“…Compound 14 also displayed good inhibition against the BuChE with IC 50 value of 0.963 μM. Structure–activity relationship suggested that up to four-carbon chain length between amide linkage and triazole nucleus was most appropriate for AChE inhibitory activity, while activity was decreased with decrease or increase in the carbons in chain length …”

Section: 23-triazole Containing Derivatives For Development Of Anti-a...mentioning

confidence: 99%

“…Structure−activity relationship suggested that up to four-carbon chain length between amide linkage and triazole nucleus was most appropriate for AChE inhibitory activity, while activity was decreased with decrease or increase in the carbons in chain length. 102 3.2. 1,2,3-Triazole Containing Derivatives Inspired from Natural Products.…”

Section: 23-triazole Containing Derivatives Inspired From Clinically ...mentioning

confidence: 99%

Pathogenesis of Alzheimer’s Disease and Diversity of 1,2,3-Triazole Scaffold in Drug Development: Design Strategies, Structural Insights, and Therapeutic Potential

Singh,

Kaur

et al. 2023

ACS Chem. Neurosci.

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Alzheimer’s disease is a most prevalent form of dementia all around the globe and currently poses a significant challenge to the healthcare system. Currently available drugs only slow the progression of this disease rather than provide proper containment. Identification of multiple targets responsible for this disease in the last three decades established it as a multifactorial neurodegenerative disorder that needs novel multifunctional agents for its management and the possible reason for the failure of currently available single target clinical drugs. 1,2,3-Triazole is a miraculous nucleus in medicinal chemistry and the first choice for development of multifunctional hybrid molecules. Apart from that, it is an integral component of various drugs in clinical trials as well as in clinical practice. This review is focused on the pathogenesis of Alzheimer’s disease and 1,2,3-triazole containing derivatives developed in recent decades as potential anti-Alzheimer’s agents. The review will provide (A) precise insight of various established targets of Alzheimer’s disease including cholinergic, amyloid, tau, monoamine oxidases, glutamate, calcium, and reactive oxygen species hypothesis and (B) design hypothesis, structure–activity relationships, and pharmacological outcomes of 1,2,3-triazole containing multifunctional anti-Alzheimer’s agents. This review will provide a baseline for various research groups working on Alzheimer’s drug development in designing potent, safer, and effective multifunctional anti-Alzheimer’s candidates of the future.

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“Clicking“ fragment leads to novel dual-binding cholinesterase inhibitors

Cited by 8 publications

References 32 publications

Indole-Based Compounds in the Development of Anti-Neurodegenerative Agents

Indole-Based Compounds in the Development of Anti-Neurodegenerative Agents

Tryptamine: A privileged scaffold for the management of Alzheimer's disease

Pathogenesis of Alzheimer’s Disease and Diversity of 1,2,3-Triazole Scaffold in Drug Development: Design Strategies, Structural Insights, and Therapeutic Potential

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