Biological activities evaluation of enantiopure isoxazolidine derivatives: in vitro, in vivo and in silico studies

A series of enantiopure isoxazolidines (3a–c) were synthesized by 1,3-dipolar cycloaddition between a (−)-menthone-derived nitrone and various terminal alkenes. The screened compounds were evaluated for their antioxidant activity by two in vitro antioxidant assays, including β-carotene/linoleic acid bleaching, and inhibition of lipid peroxidation (thiobarbituric acid reactive species, TBARS). The results revealed that compound 3b (EC50 = 0.55 ± 0.09 mM) was the most potent antioxidant as compared to the standard drug (EC50 = 2.73 ± 0.07 mM) using the TBARS assay. Furthermore, the antimicrobial activity was assessed using disc diffusion and microdilution methods. Among the synthesized compounds, 3c was found to be the most potent antimicrobial agent as compared to the standard drug. Subsequently, the acute toxicity study has also been carried out for the newly synthesized compounds and the experimental studies revealed that all compounds were safe up to 500 mg/kg and no death of animals were recorded. The cytotoxicity of these compounds was assessed by the MTT cell proliferation assay against the continuous human cell lines HeLa and compound 3c (GI50 = 46.2 ± 1.2 μM) appeared to be more active than compound 3a (GI50 = 200 ± 2.8 μM) and 3b (GI50 = 1400 ± 7.8 μM). Interestingly, all tested compounds displayed a good α-amylase inhibitory activity in competitive manner with IC50 values ranging between 23.7 and 64.35 μM when compared to the standard drug acarbose (IC50 = 282.12 μM). In addition, molecular docking studies were performed to understand the possible binding and the interaction of the most active compounds to the α-amylase pocket.info:eu-repo/semantics/publishedVersio

Synthèse d'analogues de la 4-hydroxyisoleucine, un hypoglycémiant naturel

L étude des stéréoisomères de la 4-hydroxyisoleucine a montré que l isomère (2S,3R,4S) stimule efficacement la sécrétion d insuline, expliquant les propriétés hypoglycémiantes de cette plante. La synthèse de la 4-hydroxyisoleucine et de ses analogues est un domaine d étude pour lutter contre le diabète. Cette thèse concerne les synthèses de la 4-hydroxyisoleucine et ses analogues selon trois voies différentes. La chiralité du D-glucose a été exploitée par des réactions contrôlables, douces et stéréosélectives permettant la synthèse de 4 acides aminés et 3 hydroxy-acides. Une deuxième voie considérée concerne la cycloaddition 1,3-dipolaire de nitrones dérivées de ( )- et (+)-menthone sur des alcènes mono- et disubstitués pour créer simultanément 3 centres asymétriques. Cette voie a conduit à la (2S,3R,4R)-4-hydroxyisoleucine et à 12 autres aminoacides. Une troisième voie vise l attaque nucléophile de cétones par un carbanion fonctionnalisé issu de l isocyanoacétate d éthyle pour donner des précurseurs insaturés permettant l accès aux aminoacides. Cette méthodologie tout juste abordée a mené à la synthèse racémique d un acide aminé dihydroxylé. Des tests préliminaires suggèrent que deux de ces produits pourraient favoriser la sécrétion d insulineThe study of the stereoisomers of 4-hydroxyisoleucine has shown that the isomer (2S,3R,4S) stimulates the insulin secretion effectively, explaining its the hypoglycaemic properties of the plant. The synthesis of 4-hydroxyisoleucine and its analogues opens a new therapeutic approach of type 2 diabetes. This thesis focuses on the syntheses of 4-hydroxyisoleucine and its analogues according to three different ways. The chirality of D-glucose was exploited by mild and stereoselective reactions allowing the synthesis of 4 amino-acids and 3 hydroxy-acids. The second way rests on the 1,3-dipolar cycloaddition of nitrones derived from ( )- and (+)- menthone on mono- and di-substituted olefin hydrocarbons, to create simultaneously 3 asymmetric centers. This way led to (2S,3R,4R)-4-hydroxyisoleucine and 12 other amino-acids. The third route is based on the nucleophilic attack of the carbanion derived from ethyl isocyanoacetate on a ketone, to provide unsaturated precursors of amino-acids. This methodology led to the racemic synthesis of a dihydroxy-amino-acid. Preliminary biological evaluations suggest that two of these products could enhance the insulin secretionLYON1-BU.Sciences (692662101) / SudocSudocFranceF

In Vitro and In Silico Screening of Anti-<i>Vibrio</i> spp., Antibiofilm, Antioxidant and Anti-Quorum Sensing Activities of <i>Cuminum cyminum</i> L. Volatile Oil

Cuminum cyminum L. essential oil (cumin EO) was studied for its chemical composition, antioxidant and vibriocidal activities. Inhibition of biofilm formation and secretion of some virulence properties controlled by the quorum sensing system in Chromobacterium violaceum and Pseudomonas aeruginosa strains were also reported. The obtained results showed that cuminaldehyde (44.2%) was the dominant compound followed by β-pinene (15.1%), γ-terpinene (14.4%), and p-cymene (14.2%). Using the disc diffusion assay, cumin EO (10 mg/disc) was particularly active against all fifteen Vibrio species, and the highest diameter of growth inhibition zone was recorded against Vibrio fluvialis (41.33 ± 1.15 mm), Vibrio parahaemolyticus (39.67 ± 0.58 mm), and Vibrio natrigens (36.67 ± 0.58 mm). At low concentration (MICs value from 0.023–0.046 mg/mL), cumin EO inhibited the growth of all Vibrio strains, and concentrations as low as 1.5 mg/mL were necessary to kill them (MBCs values from 1.5–12 mg/mL). Using four antioxidant assays, cumin EO exhibited a good result as compared to standard molecules (DPPH = 8 ± 0.54 mg/mL; reducing power = 3.5 ± 0.38 mg/mL; β-carotene = 3.8 ± 0.34 mg/mL; chelating power = 8.4 ± 0.14 mg/mL). More interestingly, at 2x MIC value, cumin EO inhibited the formation of biofilm by Vibrio alginolyticus (9.96 ± 1%), V. parahaemolyticus (15.45 ± 0.7%), Vibrio cholerae (14.9 ± 0.4%), and Vibrio vulnificus (18.14 ± 0.3%). In addition, cumin EO and cuminaldehyde inhibited the production of violacein on Lauria Bertani medium (19 mm and 35 mm, respectively). Meanwhile, 50% of violacein inhibition concentration (VIC50%) was about 2.746 mg/mL for cumin EO and 1.676 mg/mL for cuminaldehyde. Moreover, elastase and protease production and flagellar motility in P. aeruginosa were inhibited at low concentrations of cumin EO and cuminaldehyde. The adopted in-silico approach revealed good ADMET properties as well as a high binding score of the main compounds with target proteins (1JIJ, 2UV0, 1HD2, and 3QP1). Overall, the obtained results highlighted the effectiveness of cumin EO to prevent spoilage with Vibrio species and to interfere with the quorum sensing system in Gram-negative bacteria by inhibiting the flagellar motility, formation of biofilm, and the secretion of some virulence enzymes

GC-MS Profiling, Vibriocidal, Antioxidant, Antibiofilm, and Anti-Quorum Sensing Properties of <i>Carum carvi</i> L. Essential Oil: In Vitro and In Silico Approaches

The main objectives of the present study were to investigate anti-Vibrio spp., antibiofilms, and anti-quorum-sensing (anti-QS) properties of caraway essential oil in relation to their phytochemical composition. The results obtained show the identification of twelve compounds, with carvone (58.2%) and limonene (38.5%) being the main ones. The obtained essential oil (EO) is particularly active against all Vibrio spp. species, with bacteriostatic action against all tested strains (MBC/MIC ratio ≥ 4) and with inhibition zones with high diameters of growth, ranging from 8.66 ± 0.58 mm for V. furnisii ATCC 35016 to 37.33 ± 0.58 mm for V. alginolyticus ATCC 17749. Caraway essential oil (Carvone/limonene chemotype) exhibits antioxidant activities by using four tests (DPPH = 15 ± 0.23 mg/mL; reducing power = 7.8 ± 0.01 mg/mL; β-carotene = 3.9 ± 0.025 mg/mL; chelating power = 6.8 ± 0.05 mg/mL). This oil is particularly able to prevent cell-to-cell communication by inhibiting swarming motility, production of elastase and protease in Pseudomonas aeruginosa PAO1, and violacein production in C. violaceum in a concentration-dependent manner. A molecular docking approach shows good interaction of the identified bioactive molecules in caraway EO, with known target enzymes involved in antioxidant, antibacterial, and anti-QS activities having high binding energy. Overall, the obtained results highlight the possible use of caraway essential oil against pathogenic Vibrio species and to attenuate the secretion of virulence-related factors controlled by QS systems in Gram-negative bacteria. Therefore, this oil can be used by food industries to prevent biofilm formation on abiotic surfaces by Vibrio strains

Unexpected synthesis of aziridines under CU(I) catalyzed kinugasa conditions assisted by microwave irradiation

International audienceCu(I)-catalyzed 1,3-dipolar cycloaddition between chiral nitrone and terminal alkynes under microwave irradiation afforded a series of enantiopure aziridines with the creation of two contiguous stereogenic centers

A stereoselective method for the synthesis of enantiopure 3-substituted 4-hydroxyproline derivatives via 1,3-Dipolar cycloadditions

International audienceThe stereoselective 1,3-dipolar cycloaddition between (Z)-1,4-dichloro-2-butene and a menthone-derived nitrone led to the corresponding isoxazolidine. Regioselective azidation of a single chlorine atom followed by another Cu(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC) induced enantiopure 1,2,3-triazolyl-functionalized isoxazolidines. The subsequent acidic cleavage of the menthone chiral auxiliary and reductive cleavage of the isoxazolidine N–O bond triggered an intramolecular cyclization through the displacement of the second chlorine. This rapid and stereoselective synthetic strategy provided reliable access to a series of enantiopure 3-substituted 4-hydroxyproline derivatives

Phytochemical Profiling, Antimicrobial and &alpha;-Glucosidase Inhibitory Potential of Phenolic-Enriched Extracts of the Aerial Parts from Echium humile Desf.: In Vitro Combined with In Silico Approach

The current study aimed to evaluate the naturally occurring antimicrobial and antidiabetic potential of various Echium humile (E. humile) solvent extracts (hexane, dichloromethane, ethyl acetate, methanol and aqueous). The bioactive compounds were identified using HPLC&ndash;MS, revealing the presence of sixteen phytochemical compounds, with the most abundant being p-coumaric acid, followed by 4,5-di-O-caffeoylquinic acid, trans-ferulic acid and acacetin. Furthermore, E. humile extracts showed marked antimicrobial properties against human pathogen strains, with MIC values for the most relevant extracts (methanol and ethyl acetate) ranging from 0.19 to 6.25 mg/mL and 0.39 to 12.50 mg/mL, respectively. Likewise, methanol was found to be bactericidal towards S. aureus, B. cereus and M. luteus, fungicidal against P. catenulatum and F. oxysporum and have a bacteriostatic/fungicidal effect for the other strains. In addition, the E. humile methanolic extract had the greatest &alpha;-glucosidase inhibitory effect (IC50 = 0.06 &plusmn; 0.29 mg/mL), which is higher than the standard drug, acarbose (IC50 = 0.80 &plusmn; 1.81 mg/mL) and the aqueous extract (IC50 = 0.70 &plusmn; 0.67 mg/mL). A correlation study between the major phytochemicals and the evaluated activities was investigated. Docking studies evidenced that most of the identified phenolic compounds showed strong interactions into the binding sites of S. aureus tyrosyl-tRNA synthetase and human lysosomal acid-&alpha;-glucosidase, confirming their suitable inhibitory effect. In summary, these results may provide rational support to explore the clinical efficacy of E. humile and its secondary metabolites in the treatment of dual diabetes and infections

Antimicrobial and Wound Healing Potential of a New Chemotype from <i>Piper cubeba</i> L. Essential Oil and In Silico Study on <i>S. aureus</i> tyrosyl-tRNA Synthetase Protein

Piper cubeba is an important plant commonly known as cubeb or Java pepper, and it is cultivated for its fruit and essential oils, largely used to treat various diseases. Up to today, there was no scientific report on wound healing activity. Thus, this study was initiated to evaluate for the first time the antimicrobial activity and wound healing potential of a new chemotype from Piper cubeba essential oil (PCEO) from fruits. Thirteen microbial strains have been selected to investigate the antimicrobial potential of PCEO. For the evaluation of the wound healing potential, sixteen rats were excised on the dorsal back and divided into four groups. The effect of PCEO on the malondialdehyde (MDA) and superoxide dismutase (SOD) activities in the healed wound area of rats and the biochemical parameters and skin histological analysis were also assessed. Results: Data showed that PCEO exhibited a powerful antimicrobial potential especially against Listeria monocytogenes and Staphylococcus aureus. In addition, the topical application of PCEO cream appears to increase the SOD level, wound healing and contraction but reduced the MDA amount suggesting an impressive and a rapid cutaneous healing power. Additionally, histopathological analysis of the granulation tissue revealed that the derma is properly restored and arranged after treatment with PCEO. The docking analysis of PCEO constituents against S. aureus tyrosyl-tRNA synthetase enzyme showed binding energies values in the range of −7.2 to −4.8 kcal/mol. In conclusion, the topic use of PCEO healing cream showed significant effect in accelerating the healing process, which may be attributed to the synergetic effect of antioxidant and antimicrobial properties of PCEO volatile constituents, making it a relevant therapeutic agent for the management of wounds and therefore confirming the popular traditional uses of this plant

cristal structure of 5-chloro-methyl-N-methyl-4-[(4-phenyl-1.2.3-triazol-1-yl)]isoxazolidine-3-carboxamide

International audienceThe title compound, C15H18ClN5O2, crystallizes with two independent mol­ecules (A and B) in the asymmetric unit. In both mol­ecules, the isoxazolidine rings have an envelope conformation with the O atoms at the flap positions. Each mol­ecule has three stereogenic centres with configurations 2(S), 3(S) and 4(R), confirmed by resonant scattering. Their conformations are significantly different, for example in mol­ecule A the phenyl ring is inclined to the triazole ring by 32.5 (2)°, while in mol­ecule B the corresponding dihedral angle is 10.7 (2)°. In the crystal, the A and B mol­ecules are linked via an N—H⋯O and a C—H⋯O hydrogen bond. These units are linked by C—H⋯O and C—H⋯N hydrogen bonds, forming slabs parallel to the ab plane. There are C—H⋯π inter­actions present within the slabs