New deferiprone derivatives as multi-functional cholinesterase inhibitors: design, synthesis and in vitro evaluation

Bortolami, Martina; Pandolfi, Fabiana; Vita, Daniela De; Carafa, Camilla; Messore, Antonella; Santo, Roberto Di; Feroci, Marta; Costi, Roberta; Chiarotto, Isabella; Bagetta, Donatella; Alcaro, Stefano; Colone, Marisa; Stringaro, Annarita; Scipione, Luigi

doi:10.1016/j.ejmech.2020.112350

Cited by 40 publications

(30 citation statements)

References 45 publications

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“…After the alignment of Ee AChE (PDB code:1C2O) with the adopted h AChE structure (PDB code:4EY7), 94.7% of the identity of the aligned sequences within a range of 7 Å from the binding site is obtained ( Figure S15 ). According to a previous work 23 and the criteria for the identification of reliable complexes reported in the literature, 28 the selected models were considered as a good starting point for in silico investigation.…”

Section: Resultsmentioning

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: Resultsmentioning

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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“…Moreover, the Aβ plaques in the presence of free iron participate efficiently in the generation of ROS resulting in increased lipid peroxidation, protein oxidation and DNA damage [153]. Deferiprone derivatives act as acetylcholinesterase inhibitors and in iron chelation [154].…”

Section: Ferroptosis In Alzheimer's Diseasementioning

confidence: 99%

Ferroptosis Mechanisms Involved in Neurodegenerative Diseases

Reichert

Freitas

Sampaio-Silva

et al. 2020

IJMS

274

148

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Ferroptosis is a type of cell death that was described less than a decade ago. It is caused by the excess of free intracellular iron that leads to lipid (hydro) peroxidation. Iron is essential as a redox metal in several physiological functions. The brain is one of the organs known to be affected by iron homeostatic balance disruption. Since the 1960s, increased concentration of iron in the central nervous system has been associated with oxidative stress, oxidation of proteins and lipids, and cell death. Here, we review the main mechanisms involved in the process of ferroptosis such as lipid peroxidation, glutathione peroxidase 4 enzyme activity, and iron metabolism. Moreover, the association of ferroptosis with the pathophysiology of some neurodegenerative diseases, namely Alzheimer’s, Parkinson’s, and Huntington’s diseases, has also been addressed.

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“…Synthesis of the intermediate 3-(benzyloxy)-2-methyl-1-(4-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)butyl)pyridin-4(1H)-one. 1-(4-aminobutyl)-3-(benzyloxy)-2-methylpyridin-4(1H)-one (0.143 g, 0.5 mmol) was done as previously reported [ 38 ]. This was dissolved in 5.5 mL of MeOH.…”

Section: Methodsmentioning

confidence: 99%

“…Melting points were determined on FALC Mod. one (0.143 g, 0.5 mmol) was done as previously reported [38]. This was dissolved in 5.5 mL of MeOH.…”

Section: Dfp Derivatives and Fluorescent Compoundsmentioning

confidence: 99%

Salmonella Typhimurium and Pseudomonas aeruginosa Respond Differently to the Fe Chelator Deferiprone and to Some Novel Deferiprone Derivatives

Ammendola

Secli

Pacello

et al. 2021

IJMS

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The ability to obtain Fe is critical for pathogens to multiply in their host. For this reason, there is significant interest in the identification of compounds that might interfere with Fe management in bacteria. Here we have tested the response of two Gram-negative pathogens, Salmonella enterica serovar Typhimurium (STM) and Pseudomonas aeruginosa (PAO1), to deferiprone (DFP), a chelating agent already in use for the treatment of thalassemia, and to some DFP derivatives designed to increase its lipophilicity. Our results indicate that DFP effectively inhibits the growth of PAO1, but not STM. Similarly, Fe-dependent genes of the two microorganisms respond differently to this agent. DFP is, however, capable of inhibiting an STM strain unable to synthesize enterochelin, while its effect on PAO1 is not related to the capability to produce siderophores. Using a fluorescent derivative of DFP we have shown that this chelator can penetrate very quickly into PAO1, but not into STM, suggesting that a selective receptor exists in Pseudomonas. Some of the tested derivatives have shown a greater ability to interfere with Fe homeostasis in STM compared to DFP, whereas most, although not all, were less active than DFP against PAO1, possibly due to interference of the added chemical tails with the receptor-mediated recognition process. The results reported in this work indicate that DFP can have different effects on distinct microorganisms, but that it is possible to obtain derivatives with a broader antimicrobial action.

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New deferiprone derivatives as multi-functional cholinesterase inhibitors: design, synthesis and in vitro evaluation

Cited by 40 publications

References 45 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

Ferroptosis Mechanisms Involved in Neurodegenerative Diseases

Salmonella Typhimurium and Pseudomonas aeruginosa Respond Differently to the Fe Chelator Deferiprone and to Some Novel Deferiprone Derivatives

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