Synthesis and Evaluation of Voltage‐Gated Sodium Channel Blocking Pyrroline Derivatives Endowed with Both Antiarrhythmic and Antioxidant Activities

Carocci, Alessia; Roselli, Mariagrazia; Budriesi, Roberta; Micucci, Matteo; Desaphy, Jean-François; Altamura, Concetta; Cavalluzzi, Maria Maddalena; Toma, Maddalena; Passeri, Giovanna Ilaria; Milani, Gualtiero; Lovece, Angelo; Catalano, Alessia; Bruno, Claudio; Palma, Annalisa De; Corbo, Filomena; Franchini, Carlo; Habtemariam, Solomon; Lentini, Giovanni

doi:10.1002/cmdc.202000692

Cited by 6 publications

(4 citation statements)

References 41 publications

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“…The same analysis was performed on the global minimum conformer of 22 , obtained through our previously developed conformational analysis procedure ( Figure 4 B). [ 23 , 24 ].…”

Section: Resultsmentioning

confidence: 99%

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Densely Functionalized 2-Methylideneazetidines: Evaluation as Antibacterials

et al. 2021

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Twenty-two novel, variously substituted nitroazetidines were designed as both sulfonamide and urethane vinylogs possibly endowed with antimicrobial activity. The compounds under study were obtained following a general procedure recently developed, starting from 4-nitropentadienoates deriving from a common β-nitrothiophenic precursor. While being devoid of any activity against fungi and Gram-negative bacteria, most of the title compounds performed as potent antibacterial agents on Gram-positive bacteria (E. faecalis and three strains of S. aureus), with the most potent congener being the 1-(4-chlorobenzyl)-3-nitro-4-(p-tolyl)azetidine 22, which displayed potency close to that of norfloxacin, the reference antibiotic (minimum inhibitory concentration values 4 and 1–2 μg/mL, respectively). Since 22 combines a relatively efficient activity against Gram-positive bacteria and a cytotoxicity on eucharyotic cells only at 4-times higher concentrations (inhibiting concentration on 50% of the cultured eukaryotic cells: 36 ± 10 μM, MIC: 8.6 μM), it may be considered as a promising hit compound for the development of a new series of antibacterials selectively active on Gram-positive pathogens. The relatively concise synthetic route described herein, based on widely available starting materials, could feed further structure–activity relationship studies, thus allowing for the fine investigation and optimization of the toxico-pharmacological profile.

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“…The same analysis was performed on the global minimum conformer of 22 , obtained through our previously developed conformational analysis procedure ( Figure 4 B). [ 23 , 24 ].…”

Section: Resultsmentioning

confidence: 99%

“…Calculations were performed according to the procedures we previously developed [ 23 , 24 ]. To check the reliability of the procedure, we verify if it was able to predict the cis / trans diastereomer equilibrium found in an apolar solvent ( 1 H NMR, CDCl 3 ).…”

Section: Methodsmentioning

confidence: 99%

Densely Functionalized 2-Methylideneazetidines: Evaluation as Antibacterials

et al. 2021

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“…Quantum mechanical calculations were performed for investigating the affinity of the most efficient inhibitors [ 41 ]. Briefly, the models of 6-hydroxycoumarin, 7-hydroxycoumarin (umbelliferone), and patulin were built and optimized by the Merck force field MMFF routine [ 42 ] implemented in the Spartan’16 suite (Wavefunction Inc., Irvine, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Targeting Penicillium expansum GMC Oxidoreductase with High Affinity Small Molecules for Reducing Patulin Production

Tragni

Cotugno

Grassi

et al. 2020

Biology

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Flavine adenine dinucleotide (FAD) dependent glucose methanol choline oxidoreductase (GMC oxidoreductase) is the terminal key enzyme of the patulin biosynthetic pathway. GMC oxidoreductase catalyzes the oxidative ring closure of (E)-ascladiol to patulin. Currently, no protein involved in the patulin biosynthesis in Penicillium expansum has been experimentally characterized or solved by X-ray diffraction. Consequently, nothing is known about P. expansum GMC oxidoreductase substrate-binding site and mode of action. In the present investigation, a 3D comparative model for P. expansum GMC oxidoreductase has been described. Furthermore, a multistep computational approach was used to identify P. expansum GMC oxidoreductase residues involved in the FAD binding and in substrate recognition. Notably, the obtained 3D comparative model of P. expansum GMC oxidoreductase was used for performing a virtual screening of a chemical/drug library, which allowed to predict new GMC oxidoreductase high affinity ligands to be tested in in vitro/in vivo assays. In vitro assays performed in presence of 6-hydroxycoumarin and meticrane, among the highly affinity predicted binders, confirmed a dose-dependent inhibition (17–81%) of patulin production by 6-hydroxycoumarin (10 µM–1 mM concentration range), whereas the approved drug meticrane inhibited patulin production by 43% already at 10 µM. Furthermore, 6-hydroxycoumarin and meticrane caused a 60 and 41% reduction of patulin production, respectively, in vivo on apples at 100 µg/wound.

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“…Despite the widely recognized multi-factorial profile of this disease, its etiology seems to be particularly linked to chronic oxidative stress, which can lead to tissue inflammation and cell death [ 2 ]. In fact, oxidative stress, caused by an imbalance between the production of ROS (Reactive Oxygen Species) and the natural antioxidant defenses of organisms such as scavengers or antioxidant enzymes, can cause DNA mutations, lipid peroxidation in the cell membrane, alterations and damage to cellular organelles, chiefly the mitochondria, and it has been linked to the pathogenesis of numerous conditions such as cancer [ 3 ], cardiovascular diseases (e.g., atherosclerosis and ischemia-reperfusion injury) [ 4 ], degenerating myopathies [ 5 ] and, in general, neurodegenerative diseases (NDs). While oxidative stress is not the only reason for the onset and progression of NDs, it is certainly an important link in the chain of events that lead to neuron loss [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Phenothiazine/Donepezil-like Hybrids Endowed with Antioxidant Activity for a Multi-Target Approach to the Therapy of Alzheimer’s Disease

et al. 2022

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Alzheimer’s disease (AD) is a complex multi-factorial neurodegenerative disorder for which only few drugs (including donepezil, DPZ) are available as symptomatic treatments; thus, researchers are focusing on the development of innovative multi-target directed ligands (MTDLs), which could also alter the course of the disease. Among other pathological factors, oxidative stress has emerged as an important factor in AD that could affect several pathways involved in the onset and progression of the pathology. Herein, we propose a new series of hybrid molecules obtained by linking a phenothiazine moiety, known for its antioxidant properties, with N-benzylpiperidine or N-benzylpiperazine fragments, mimicking the core substructure of DPZ. The investigation of the resulting hybrids showed, in addition to their antioxidant properties, their activity against some AD-related targets, such as the inhibition of cholinesterases (both AChE and BChE) and in vitro Aβ1-40 aggregation, as well as the inhibition of the innovative target fatty acid amide hydrolase (FAAH). Furthermore, the drug-likeness properties of these compounds were assessed using cheminformatic tools. Compounds 11d and 12d showed the most interesting multi-target profiles, with all the assayed activities in the low micromolar range. In silico docking calculations supported the obtained results. Compound 13, on the other hand, while inactive in the DPPH assay, showed the best results in the in vitro antioxidant cell assays conducted on both HepG2 and SHSY-5Y cell lines. These results, paired with the low or absent cytotoxicity of these compounds at tested concentrations, allow us to aim our future research at the study of novel and effective drugs and pro-drugs with similar structural characteristics.

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Synthesis and Evaluation of Voltage‐Gated Sodium Channel Blocking Pyrroline Derivatives Endowed with Both Antiarrhythmic and Antioxidant Activities

Cited by 6 publications

References 41 publications

Densely Functionalized 2-Methylideneazetidines: Evaluation as Antibacterials

Densely Functionalized 2-Methylideneazetidines: Evaluation as Antibacterials

Targeting Penicillium expansum GMC Oxidoreductase with High Affinity Small Molecules for Reducing Patulin Production

Novel Phenothiazine/Donepezil-like Hybrids Endowed with Antioxidant Activity for a Multi-Target Approach to the Therapy of Alzheimer’s Disease

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