New pyridine derivatives as inhibitors of acetylcholinesterase and amyloid aggregation

Pandolfi, Fabiana; Vita, Daniela De; Bortolami, Martina; Coluccia, Antonio; Santo, Roberto Di; Costi, Roberta; Andrisano, Vincenza; Alabiso, Francesco; Bergamini, Christian; Fato, Romana; Bartolini, Manuela; Scipione, Luigi

doi:10.1016/j.ejmech.2017.09.022

Cited by 32 publications

(19 citation statements)

References 46 publications

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“…19−21 In our previous studies, we synthesized and in vitro evaluated new series of dual binding site ChEIs, characterized by two small aromatic moieties separated by various functionalized linkers, some of which resulted in nanomolar mixed or uncompetitive inhibitors of both AChE and BChE, able to bind CAS and PAS, able to reduce Aβ aggregation, or endowed with metal chelating properties. 22,23 Based on these considerations and as a development of previous works, we decided to study a new series of pyrimidine and pyridine diamine derivatives and evaluate them both in vitro and in cellulo as potential ChEIs endowed with chelating and antioxidant activities as well as direct anti-amyloid aggregation properties, with the aim to develop new multifunctional compounds for AD. These molecules were designed as dual binding site inhibitors, based on the structure of the ChE enzymatic pocket, inserting two small aromatic groups separated by an aliphatic linker (Figure 1).…”

Section: ■ Introductionmentioning

confidence: 99%

New Pyrimidine and Pyridine Derivatives as Multitarget Cholinesterase Inhibitors: Design, Synthesis, and In Vitro and In Cellulo Evaluation

Bortolami

Pandolfi

Tudino

et al. 2021

ACS Chem. Neurosci.

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A new series of pyrimidine and pyridine diamines was designed as dual binding site inhibitors of cholinesterases (ChEs), characterized by two small aromatic moieties separated by a diaminoalkyl flexible linker. Many compounds are mixed or uncompetitive acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE) nanomolar inhibitors, with compound 9 being the most active on Electrophorus electricus AChE ( Ee AChE) ( K i = 0.312 μM) and compound 22 on equine BChE ( eq BChE) ( K i = 0.099 μM). Molecular docking and molecular dynamic studies confirmed the interaction mode of our compounds with the enzymatic active site. UV–vis spectroscopic studies showed that these compounds can form complexes with Cu 2+ and Fe 3+ and that compounds 18 , 20 , and 30 have antioxidant properties. Interestingly, some compounds were also able to reduce Aβ 42 and tau aggregation, with compound 28 being the most potent (22.3 and 17.0% inhibition at 100 μM on Aβ 42 and tau, respectively). Moreover, the most active compounds showed low cytotoxicity on a human brain cell line and they were predicted as BBB-permeable.

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Section: ■ Introductionmentioning

confidence: 99%

New Pyrimidine and Pyridine Derivatives as Multitarget Cholinesterase Inhibitors: Design, Synthesis, and In Vitro and In Cellulo Evaluation

Bortolami

Pandolfi

Tudino

et al. 2021

ACS Chem. Neurosci.

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“…4-AP was shown to improve the phenotypes of SMA in a Drosophila model, possibly through the pathway of motor circuits [114]. A phase 2/3 clinical trial assessing the efficacy in walking ability and endurance of type 3 adult SMA patients was completed in 2017, and the results are pending [115].…”

Section: Agents Targeting Neuromuscular Junction Synapse or Neurotrmentioning

confidence: 99%

New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand?

Chen

2020

IJMS

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Spinal muscular atrophy (SMA) is a congenital neuromuscular disorder characterized by motor neuron loss, resulting in progressive weakness. SMA is notable in the health care community because it accounts for the most common cause of infant death resulting from a genetic defect. SMA is caused by low levels of the survival motor neuron protein (SMN) resulting from SMN1 gene mutations or deletions. However, patients always harbor various copies of SMN2, an almost identical but functionally deficient copy of the gene. A genotype–phenotype correlation suggests that SMN2 is a potent disease modifier for SMA, which also represents the primary target for potential therapies. Increasing comprehension of SMA pathophysiology, including the characterization of SMN1 and SMN2 genes and SMN protein functions, has led to the development of multiple therapeutic approaches. Until the end of 2016, no cure was available for SMA, and management consisted of supportive measures. Two breakthrough SMN-targeted treatments, either using antisense oligonucleotides (ASOs) or virus-mediated gene therapy, have recently been approved. These two novel therapeutics have a common objective: to increase the production of SMN protein in MNs and thereby improve motor function and survival. However, neither therapy currently provides a complete cure. Treating patients with SMA brings new responsibilities and unique dilemmas. As SMA is such a devastating disease, it is reasonable to assume that a unique therapeutic solution may not be sufficient. Current approaches under clinical investigation differ in administration routes, frequency of dosing, intrathecal versus systemic delivery, and mechanisms of action. Besides, emerging clinical trials evaluating the efficacy of either SMN-dependent or SMN-independent approaches are ongoing. This review aims to address the different knowledge gaps between genotype, phenotypes, and potential therapeutics.

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“…[20,21] It is reported that in advanced stages of Alzheimer's, the activity of AChE may decrease up to 50 %, with a simultaneous significant enhancement of BuChE activity giving relevance to the anti-cholinesterase agent's selectivity. [20,22,23] Within this scientific framework, 1-methylpyridin-1-ium-2carboxylate (known as homarine) was selected as a suitable chemical structure to design new AChE inhibitors. Homarine, a naturally occurring molecule, is a quaternary ammoniumcontaining alkaloid used by diverse groups of marine invertebrates as methyl group reservoir, in osmoregulation, and for risk perception and predator detection, [24][25][26][27] suggesting potential to modulate cholinergic neuronal networks.…”

Section: Introductionmentioning

confidence: 99%

Homarine Alkyl Ester Derivatives as Promising Acetylcholinesterase Inhibitors

et al. 2021

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Reversible acetylcholinesterase (AChE) inhibitors are key therapeutic tools to modulate the cholinergic connectivity compromised in several degenerative pathologies. In this work, four alkyl esters of homarine were synthesized and screened by using Electrophorus electricus AChE and rat brain AChE-rich fraction. Results showed that all homarine alkyl esters are able to inhibit AChE by a competitive inhibition mode. The effectiveness of AChE inhibition increases with the alkyl side chain length of the homarine esters, being HOÀ C 16 (IC 50 = 7.57 � 3.32 μM and K i = 18.96 � 2.28 μM) the most potent inhibitor. The fluorescence quenching studies confirmed that HOÀ C 16 is the compound with higher selectivity and affinity for the tryptophan residues in the catalytic active site of AChE. Preliminary cell viability studies showed that homarine esters display no toxicity for human neuronal SH-SY5Y cells. Thus, the long-chain homarine esters emerge as new anti-cholinesterase agents, with potential to be considered for therapeutic applications development.

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New pyridine derivatives as inhibitors of acetylcholinesterase and amyloid aggregation

Cited by 32 publications

References 46 publications

New Pyrimidine and Pyridine Derivatives as Multitarget Cholinesterase Inhibitors: Design, Synthesis, and In Vitro and In Cellulo Evaluation

New Pyrimidine and Pyridine Derivatives as Multitarget Cholinesterase Inhibitors: Design, Synthesis, and In Vitro and In Cellulo Evaluation

New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand?

Homarine Alkyl Ester Derivatives as Promising Acetylcholinesterase Inhibitors

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