Hemi-synthesis of novel chiral benzodiazepine derivatives from Eucalyptus citriodora essential oil: 2D NMR experiments and differential scanning calorimetry study of diastereoisomers.

An efficient in situ condensation of citronellal, the main constituent of Eucalyptus citriodora essential oil (51%), with different amine derivatives of 2,3-diaminomaleonitrile and 3-[(2-aminoaryl)amino]dimedone has led to novel chiral benzodiazepine structures. All reactions were precipitated in ethanol and pure products were obtained in good yields (58-75%) without any purification. The synthesized benezodiazepines were characterized by spectroscopic techniques, namely 1H-NMR, 13C-NMR, 2D NMR and FTIR. Differential Scanning Calorimetry (DSC) and HPLC were used to confirm the formation diastereomeric mixtures of benzodiazepine derivatives.

Evaluation of In Vitro and In Silico Anti-Alzheimer Potential of Nonpolar Extracts and Essential Oil from Mentha piperita.

The anticholinesterase and antioxidant activities with chemical composition and molecular docking of essential oil and nonpolar extracts of Mentha piperita were evaluated using enzymatic and chemical methods. Molecular docking tools were used to explain the interaction of the major chemical constituents with the enzymes. GC/MS analyses revealed that the main compounds in M. piperita essential oil were l-menthone (43.601%) followed by pulegone (21.610%), linolenic acid (25.628%), and l-menthone (10.957%), representing the major compounds of the petroleum ether extract. Imidazoquinoline (7.767%) and 17-N-acetyl-oroidine (5.363%) were the major constituents of the chloroform extract. Linolenic acid (19.397%) and l-menthone (6.336%) were the most abundant compounds in the hexane extract. The M. piperita essential oil and nonpolar extracts showed moderate antioxidant activity. The essential oil showed the most promising anticholinesterase activity with IC50 = 10.66 ± 0.12 µg/mL and IC50 = 16.33 ± 0.03 µg/mL against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), respectively, close to galantamine in AChE and more active in BChE, followed by the interesting activity in the petroleum ether extract with IC50 = 23.42 ± 3.06 µg/mL in AChE and IC50 = 62.00 ± 3.22 µg/mL in BChE. The docking experiments showed that among the seven major identified compounds, N-acetyl-17-oroidine showed the highest binding score (63.01 in AChE and 63.68 in BChE). This compound was found to bind the catalytic and peripheral sites, resulting in more potent inhibitory activity than galantamine, which only binds to the catalytic site. These findings suggested the possible use of M. piperita essential oil and nonpolar extracts as a potential source of alternative natural anti-Alzheimer compounds.

Multifloral white honey outclasses manuka honey in methylglyoxal content: assessment of free and encapsulated methylglyoxal and anti-microbial peptides in liposomal formulation against toxigenic potential of Bacillus subtilis Subsp spizizenii strain.

The therapeutic virtues of honey no longer need to be proven. Honey, which is rich in nutrients, is an excellent nutritional food because of its many properties; however, honey has been diverted from this primary function and used in clinical research. Evidence has shown that honey still possesses unknown properties and some of these aspects have never been addressed. In this work, two bioactive compounds found in honey (methylglyoxal and antimicrobial peptides) were evaluated for their anti-Bacillus subtilis activity with particular attention to their dilution factor. Although this bacterial strain does not possess an indigenous virulence factor gene, it becomes virulent by transferring plasmids with B. thuringiensis or expression of toxins from Bordetella pertussis. As is known, methylglyoxal is a toxic electrophile present in many eukaryotic and prokaryotic cells, which is generated by enzymatic and non-enzymatic reactions. Its overexpression successfully kills bacteria by inducing membrane disruption. Also, AMPs show potent inhibitory action against Gram-positive bacteria. Because of the lack of information concerning the main ingredients of honey, the microencapsulation process was used. Both methylglyoxal (MGO) and peptide-loaded liposomes were synthesized, characterized and compared to their free forms. The liposomal formulations contained a mixture of eggPC, cholesterol, and octadecylamine and their particle sizes were measured and their encapsulation efficacy calculated. The results revealed that Algerian multifloral white honey contained higher levels of MGO compared to manuka honey, which prevented bacterial growth and free MGO was relatively less effective. In fact, MGO killed BS in the loaded form with the same bacteriostatic and bactericidal index. However, the action of AMPs was different. Indeed, the investigation into the reactivity of MGO in the solvent indicated that regardless of the level of water added, honey is active at a fixed dilution. This data introduces the notion of dilution and abolishes the concept of concentration. Moreover, the synergistic antibacterial effect of the compounds in honey was diminished by the matrix effect. The degree of liposome-bacteria-fusion and the delay effect observed could be explain by both the composition and nature of the lipids used. Finally, this study reinforces the idea that under certain conditions, the metalloproteinases in honey produce AMPs.

Molecular docking and dynamic studies of a potential therapeutic target inhibiting glyoxalase system: Metabolic action of the 3, 3 '- [3- (5-chloro-2-hydroxyphenyl) -3-oxopropane-1, 1-diyl] - Bis-4-hydroxycoumarin leads overexpression of the intracellular level of methylglyoxal and induction of a pro-apoptotic phenomenon in a hepatocellular carcinoma model.

Methylglyoxal is a dicarbonyl compound recruited as a potential cytotoxic marker, initially presents in cells and considered as a metabolite of the glycolytic pathway. Our aim is to demonstrate the inhibitory effect of 3, 3'-[3-(5-chloro-2-hydroxyphenyl)-3-oxopropane-1, 1-diyl] Bis (4-hydroxycoumarin) on the glyoxalase system, and indirectly its anticancer activity. The docking of OT-55 was conducted by using Flexible docking protocol, ChiFlex and libdock tools inside the active site of Glo-I indicated that both hydrogen bonding and hydrophobic interactions contributed significantly in establishing potent binding with the active site which is selected as a strong inhibitor with high scoring values and maximum Gibbs free energy. Coumarin-liposome formulation was characterized and evaluated in vivo against chemically induced hepatocarcinoma in Wistar rats. After Diethylnitrosamine (DEN) induction, microscopic assessment was realized; precancerous lesions were developed showing an increase of both tumor-associated lymphocyte and multiple tumor acini supported by the blood investigation. Our finding also suggested a preferential uptake of liposomes respectively in liver, kidney, lung, brain and spleen in the DEN-treated animals. OT-55 has also been shown to inhibit the activity of Glo-I in vitro as well as in DEN-treated rats. An abnormal high level of MGO of up to 50% was recorded followed by a reduction in glucose consumption and lactate dehydrogenase production validated in the positive control. MGO generates apoptosis as depicted by focal hepatic lesions. Also, no deleterious effects in the control group were observed after testing our coumarin but rather a vascular reorganization leading to nodular regenerative hyperplasia. Involved in the detoxification process, liver GSH is restored in intoxicated rats, while no changes are seen between controls. At the endothelial cell, OT-55 appears to modulate the release of NO only in the DEN-treated group. OT-55 would behave both as an anticancer agent but also as an angiogenic factor regarding results obtained.

Development of analytical methods GC-MS vs LC-UV for the serum monitoring of an inflammatory glycotoxin (methylglyoxal): A new biomarker of bovine hepatobiliary distomatosis.

Two analytical methods; high performance liquid chromatography and gas chromatography were used to determine the content of 2-methylquinoxaline, a methylglyoxal-derived agent in sera from cattle with fascioliasis. Methylglyoxal is a highly mutagenic and cytotoxic reactive dicarbonyl compound formed by non-enzymatic fragmentation of triose phosphate GAP and DHAP during glycolysis which regularly contributes to repositioning the energetic balance between physiological and pathological situations. The aim of this study was to propose the MGO as a new biomarker in the bovine fasciolosis. Strongly infected animals showed a correlation between the relatively high levels of Fasciola hepatica anti-f2 antibody and methylglyoxal compared to unharmed animals. Also, an acute hyperglycemia was recorded and closely related to hepatic parenchyma hyperplasia, inflammation, bile ducts obstruction and scléro-fibrous foci formation.Unlike HPLC, which has shown analytical flaws and irregularities, GC-MS remains an excellent diagnostic tool for detecting and quantifying methylglyoxal in biological fluids. The developed method has been validated under FDA guidelines. A full scan-range was set from m/z 39 to 144/999 and the molecular weight of the 2-methylquinoxaline was identified according to NIST Database and ES. Methylglyoxal was the only analyte successfully quantified in a relatively short run time. It was linear over a concentration range of 0.057-5.7  µg.ml-1with mean recoveries and RSD of 118% and 3.63% respectively. The intra and inter-day assays were satisfying and not exceed 3.00%. Results reflect the degree of precision of our method and indicate that MGO was an important contributor to understand the hepatic failure independently of other serum markers.