RÉSUMÉ
Cavoxin (1) was isolated as the main phytotoxin produced by Phoma cava Schulzer, a toxigenic fungus isolated from Castanea spp. Its structure was determined by 1D NMR and MS in 1985 along with that of the corresponding chroman-4-one cavoxone (2), an artifact formed by acid treatment of 1. Since that time cavoxin was shown to be phytotoxic, antifungal, antifeedant, herbicidal, and antirust with potential application in agriculture and medicine. During a study aimed at improving cavoxin's production by P. cava, single crystals for X-ray diffractometric analysis were obtained. The X-ray crystallography characterization confirmed only in part the structure proposed for cavoxin (1), revealing a different substitution pattern on the aromatic ring, as depicted in the revised structure 3.
Sujet(s)
Mycotoxines , Cristallographie aux rayons X/méthodes , Structure moléculaire , Mycotoxines/composition chimique , Mycotoxines/pharmacologie , Ascomycota/composition chimique , Chromanes/composition chimique , Chromanes/pharmacologieRÉSUMÉ
Programmed death-ligand 1 (PD-L1) has emerged as a promising therapeutic target for various cancers due to its crucial role in promoting tumor immune evasion. Here, we report a novel class of chroman-like small-molecule PD-L1 inhibitors exhibiting significant activity in inhibiting the PD-1/PD-L1 interaction. Employing a "ring-close" strategy for conformational restriction, we have achieved compound C27, which demonstrates superior PD-1/PD-L1 inhibitory activity compared to the positive control. Molecular dynamics simulation and binding free energy calculation predict that (R)-C27 with inhibitory activity surpassed (S)-C27. The experimental results from bioassay and X-ray structural analysis corroborate these findings. All these results collectively indicate that (R)-C27 is a promising lead compound deserving further exploration.
Sujet(s)
Antigène CD274 , Chromanes , Conception de médicament , Récepteur-1 de mort cellulaire programmée , Antigène CD274/antagonistes et inhibiteurs , Antigène CD274/métabolisme , Récepteur-1 de mort cellulaire programmée/antagonistes et inhibiteurs , Récepteur-1 de mort cellulaire programmée/métabolisme , Humains , Chromanes/composition chimique , Chromanes/pharmacologie , Simulation de dynamique moléculaireRÉSUMÉ
This work presents a hydrothermal method followed by a sonochemical treatment for synthesizing tantalum decorated on iron selenide (Ta/FeSe2) integrated with nitrogen-doped graphene (NGR) as a susceptible electrode material for detecting trolox (TRX) in berries samples. The surface morphology, structural characterizations, and electrochemical performances of the synthesized Ta/FeSe2/NGR composite were analyzed via spectrophotometric and voltammetry techniques. The GCE modified with Ta/FeSe2/NGR demonstrated an impressive linear range of 0.1 to 580.3 µM for TRX detection. Additionally, it achieved a remarkable limit of detection (LOD) of 0.059 µM, and it shows a high sensitivity of 2.266 µA µÐ-1 cm-2. Here, we used density functional theory (DFT) to investigate the structures of TRX and TRX quinone and the locations of energy levels and electron transfer sites. The developed sensor exhibits significant selectivity, satisfactory cyclic and storage stability, and notable reproducibility. Moreover, the practicality of TRX was assessed in different types of berries, yielding satisfactory recoveries.
Sujet(s)
Chromanes , Fruit , Graphite , Azote , Tantale , Graphite/composition chimique , Fruit/composition chimique , Azote/composition chimique , Tantale/composition chimique , Chromanes/composition chimique , Chromanes/analyse , Théorie de la fonctionnelle de la densité , Techniques électrochimiques , Limite de détection , Électrodes , Fer/composition chimique , Fer/analyseRÉSUMÉ
Enhancing the selectivity of alpha2-adrenoceptor (α2A-AR) agonists remains an unresolved issue. Herein, we reported the design of an α2A-AR agonist using the conformation constraint method, beginning with medetomidine. The structure-activity relationship indicated that the 8-substituent of chromane derivatives exerted the most pronounced effect on α2A-AR agonistic activity. Compounds A9 and B9 were identified as the most promising, exhibiting EC50 values of 0.78 and 0.23 nM, respectively. Their selectivity indexes surpassed dexmedetomidine (DMED) by 10-80 fold. In vivo studies demonstrated that both A9 and B9 dose-dependently increased the loss of righting reflex in mice, with ED50 values of 1.54 and 0.138 mg/kg, respectively. Binding mode calculations and mutation studies suggested the indispensability of the hydrogen bond between ASP1283.32 and α2A-AR agonist. In particular, A9 and B9 showed no dual reverse pharmacological effect, a characteristic exhibited by DMED in α2A-AR activation.
Sujet(s)
Agonistes des récepteurs alpha-2 adrénergiques , Chromanes , Conception de médicament , Récepteurs alpha-2 adrénergiques , Animaux , Récepteurs alpha-2 adrénergiques/métabolisme , Chromanes/pharmacologie , Chromanes/composition chimique , Chromanes/synthèse chimique , Relation structure-activité , Souris , Agonistes des récepteurs alpha-2 adrénergiques/pharmacologie , Agonistes des récepteurs alpha-2 adrénergiques/composition chimique , Humains , Conformation moléculaire , Simulation de docking moléculaire , MâleRÉSUMÉ
A library of new chroman-4-one based 1,2,3-triazole analogues were synthesized involving a series of condensation, cyclization, Suzuki coupling and copper catalysed click chemistry protocols. The newly synthesized compounds 8a-l were screened for their invitro antioxidant and anti-inflammatory activities by employing Ascorbic acid and Diclofenac as reference drugs respectively. The compound without any substituent on benzyl ring (8a), compound with -Cl substituent in para position of benzyl ring (8i), and compound with ethoxy substituent in para position of benzyl ring (8k) exhibited potent antioxidant and anti-inflammatory activities with higher percentage of inhibition. To understand their binding affinities, molecular docking study of these three compounds performed against NADPH oxidase with presented outstanding docking scores and promising binding interactions like H-bond and hydrophobic.
Sujet(s)
Antioxydants , Simulation de docking moléculaire , Triazoles , Triazoles/composition chimique , Triazoles/pharmacologie , Triazoles/synthèse chimique , Antioxydants/pharmacologie , Antioxydants/composition chimique , Antioxydants/synthèse chimique , Relation structure-activité , NADPH oxidase/métabolisme , NADPH oxidase/antagonistes et inhibiteurs , Animaux , Anti-inflammatoires non stéroïdiens/pharmacologie , Anti-inflammatoires non stéroïdiens/composition chimique , Anti-inflammatoires non stéroïdiens/synthèse chimique , Chromanes/composition chimique , Chromanes/pharmacologie , Chromanes/synthèse chimique , Anti-inflammatoires/composition chimique , Anti-inflammatoires/pharmacologie , Anti-inflammatoires/synthèse chimique , Structure moléculaire , Relation dose-effet des médicaments , Picrates/antagonistes et inhibiteursRÉSUMÉ
Receptors are proteinous macromolecules which remain in the apo form under normal/unliganded conditions. As the ligand approaches, there are specific stereo-chemical changes in the apo form of the receptor as per the stereochemistry of a ligand. Accordingly, a series of substituted dimethyl-chroman-based stereochemically flexible and constrained Tamoxifen analogs were synthesized as anti-breast cancer agents. The synthesized compounds 19a-e, 20a-e, 21, and 22a-e, showed significant antiproliferative activity against estrogen receptor-positive (ER+, MCF-7) and negative (ER-, MDA MB-231) cells within IC50 value 8.5-25.0 µM. Amongst all, four potential molecules viz 19b, 19e, 22a, and 22c, were evaluated for their effect on the cell division cycle and apoptosis of ER+ and ER- cancer cells (MCF-7 & MDA MB-231cells), which showed that these compounds possessed antiproliferative activity through triggering apoptosis. In-silico docking experiments elucidated the possible affinity of compounds with estrogen receptors-α and -ß.
Sujet(s)
Antinéoplasiques , Apoptose , Tumeurs du sein , Prolifération cellulaire , Tests de criblage d'agents antitumoraux , Humains , Antinéoplasiques/pharmacologie , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Prolifération cellulaire/effets des médicaments et des substances chimiques , Stéréoisomérie , Relation structure-activité , Lignée cellulaire tumorale , Apoptose/effets des médicaments et des substances chimiques , Chromanes/pharmacologie , Chromanes/synthèse chimique , Chromanes/composition chimique , Simulation de docking moléculaire , Récepteur alpha des oestrogènes/métabolisme , Récepteur alpha des oestrogènes/antagonistes et inhibiteurs , Femelle , Structure moléculaire , Cellules MCF-7 , Relation dose-effet des médicaments , Tamoxifène/pharmacologie , Tamoxifène/synthèse chimique , Tamoxifène/composition chimiqueRÉSUMÉ
A new method for the stereoselective metal-, additive- and oxidant-free Friedel-Crafts-type halo-carbocyclization of N- and O-tethered arene-olefin substrates is reported, involving reaction with a suitable electrophilic halogenating reagent (NXS/DCDMH) in hexafluoroisopropanol. All halo (X = Br, I, Cl)-functionalized tetrahydroquinolines and chromans were obtained in excellent yields and with high levels of diastereocontrol (dr = >99 : 1), and these products were successfully transformed into synthetically useful compounds such as dihydroquinolines and partial or full azahelicene compounds.
Sujet(s)
Alcènes , Quinoléines , Alcènes/composition chimique , Catalyse , Chromanes/composition chimique , Quinoléines/composition chimiqueRÉSUMÉ
A novel series of 14 spiropyrrolidines bearing thiochroman-4-one/chroman-4-one, and oxindole/acenaphthylene-1,2-dione moieties were synthesized and characterized by spectroscopic techniques, as well as by three X-ray diffraction studies, corroborating the stereochemistry. Quantum chemical calculations studies, using the DFT approach, were performed to rationalize the stereochemical outcome. These N-heterocycles were evaluated for their antibacterial and antifungal activities against some pathogenic organisms. Several compounds displayed moderate to excellent activity towards the screened microbe strains in the study compared to Amoxicillin (AMX), Ampicillin (AMP), and Amphotericin B. Furthermore, a structural activity relationship (SAR) was established considering the synthesized compounds. Pharmacokinetic studies reveal that these derivatives exhibit an acceptable predictive ADMET profile (Absorption, Distribution, Metabolism, Excretion and Toxicity) and good drug-likeness.
Sujet(s)
Antibactériens/pharmacologie , Antifongiques/pharmacologie , Bactéries/effets des médicaments et des substances chimiques , Chromanes/composition chimique , Champignons/effets des médicaments et des substances chimiques , Spiranes/composition chimique , Antibactériens/composition chimique , Antifongiques/composition chimique , Tests de sensibilité microbienne , Simulation de docking moléculaire , Structure moléculaire , Oxindoles/composition chimique , Relation structure-activitéRÉSUMÉ
Aim: Literature reports suggest spirochromanone derivatives exhibit anticancer activity. Methodology: The authors designed and synthesized 18 spirochromanone derivatives (Csp 1-18). The compounds were characterized and evaluated for anticancer activity against human breast cancer (MCF-7) and murine melanoma (B16F10) cell lines. Results: The anticancer activity ranged from 4.34 to 29.31 µm. The most potent compounds, Csp 12 and Csp 18, were less toxic against the human embryonic kidney (HEK-293) cell line and â¼ two/â¼fourfold selective toward MCF-7 than B16F10 in comparison to the reference, BG-45. Csp 12 caused 28.6% total apoptosis, leading to significant cytotoxicity, and arrested the G2 phase of the cell cycle in B16F10 cells. A molecular docking study of Csp 12 exhibited effective binding at the active site of the epidermal growth factor receptor kinase domain. Conclusion: This study highlights the importance of spirochromanones as anticancer agents.
Sujet(s)
Antinéoplasiques/synthèse chimique , Chromanes/composition chimique , Conception de médicament , Spiranes/composition chimique , Animaux , Antinéoplasiques/métabolisme , Antinéoplasiques/pharmacologie , Apoptose/effets des médicaments et des substances chimiques , Sites de fixation , Domaine catalytique , Lignée cellulaire tumorale , Chromanes/métabolisme , Chromanes/pharmacologie , Tests de criblage d'agents antitumoraux , Récepteurs ErbB/antagonistes et inhibiteurs , Récepteurs ErbB/métabolisme , Points de contrôle de la phase G2 du cycle cellulaire/effets des médicaments et des substances chimiques , Humains , Souris , Simulation de docking moléculaire , Relation structure-activitéRÉSUMÉ
Malaria is a prevalent and lethal disease. The fast emergence and spread of resistance to current therapies is a major concern and the development of a novel line of therapy that could overcome, the problem of drug resistance, is imperative. Screening of a set of compounds with drug/natural product-based sub-structural motifs led to the identification of spirocyclic chroman-4-one 1 with promising antimalarial activity against the chloroquine-resistant Dd2 and chloroquine-sensitive 3D7 strains of the parasite. Extensive structure-activity and structure-property relationship studies were conducted to identify the essential features necessary for its activity and properties.
Sujet(s)
Antipaludiques/pharmacologie , Chromanes/pharmacologie , Paludisme/traitement médicamenteux , Plasmodium/effets des médicaments et des substances chimiques , Spiranes/pharmacologie , Antipaludiques/synthèse chimique , Antipaludiques/composition chimique , Survie cellulaire/effets des médicaments et des substances chimiques , Chromanes/synthèse chimique , Chromanes/composition chimique , Cristallographie aux rayons X , Relation dose-effet des médicaments , Cellules HepG2 , Humains , Modèles moléculaires , Structure moléculaire , Tests de sensibilité parasitaire , Spiranes/synthèse chimique , Spiranes/composition chimique , Relation structure-activitéRÉSUMÉ
Organic extract of the brown seaweed Turbinaria conoides (Sargassaceae) was chromatographically fractionated to yield an undescribed furanyl-substituted isochromanyl metabolite, named as turbinochromanone, which was characterized as methyl 4-[(3S)-8-{[(3R)-4-ethyl-2,3-dihydrofuran-3-yl]methyl}-1-oxo-3,4-dihydro-1H-2-benzopyran-3-yl]butanoate. The isochromanyl derivative possessed comparable attenuation potential against 5-lipoxygenase (IC50 3.70â µM) with standard 5-lipoxygenase inhibitor drug zileuton (IC50 2.41â µM). Noticeably, the index of anti-inflammatory selectivity of turbinochromanone (â¼1.7) was considerably greater than that exhibited by the standard agent diclofenac (1.06). Antioxidant properties of turbinochromanone against oxidants (IC50 â¼24â µM) further supported its potential anti-inflammatory property. Greater electronic properties (topological polar surface area of 61.8) along with comparatively lesser docking parameters of the studied compound with aminoacyl residues of targeted enzymes (cyclooxygenase-2 and 5-lipoxygenase) (binding energy of -11.05 and -9.40â kcal mol-1 , respectively) recognized its prospective anti-inflammatory potential. In an aim to develop seaweed-based natural anti-inflammatory leads, the present study isolated turbinochromanone as promising 5-lipoxygenase and cyclooxygenase-2 inhibitor, which could be used for pharmaceutical and biotechnological applications.
Sujet(s)
Anti-inflammatoires/composition chimique , Chromanes/composition chimique , Algue marine/composition chimique , Anti-inflammatoires/isolement et purification , Anti-inflammatoires/métabolisme , Antioxydants/composition chimique , Arachidonate 5-lipoxygenase/composition chimique , Arachidonate 5-lipoxygenase/métabolisme , Sites de fixation , Chromanes/isolement et purification , Chromanes/métabolisme , Cyclooxygenase 2/composition chimique , Cyclooxygenase 2/métabolisme , Furanes/composition chimique , Conformation moléculaire , Simulation de docking moléculaire , Extraits de plantes/composition chimique , Structure tertiaire des protéines , Algue marine/métabolisme , ThermodynamiqueRÉSUMÉ
In this study, the antioxidant and antiradical properties of some phyto lignans (nordihydroguaiaretic acid, secoisolariciresinol, secoisolariciresinol diglycoside, and α-(-)-conidendrin) and mammalian lignans (enterodiol and enterolactone) were examined by different antioxidant assays. For this purpose, radical scavenging activities of phyto and mammalian lignans were realized by 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) radical (ABTSâ¢+) scavenging assay and 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) scavenging assay. Additionally, the reducing ability of phyto and mammalian lignans were evaluated by cupric ions (Cu2+) reducing (CUPRAC) ability, and ferric ions (Fe3+) and [Fe3+-(TPTZ)2]3+ complex reducing (FRAP) abilities. Also, half maximal inhibitory concentration (IC50) values were determined and reported for DPPH⢠and ABTSâ¢+ scavenging influences of all of the lignan molecules. The absorbances of the lignans were found in the range of 0.150-2.320 for Fe3+ reducing, in the range of 0.040-2.090 for Cu2+ reducing, and in the range of 0.360-1.810 for the FRAP assay. On the other hand, the IC50 values of phyto and mammalian lignans were determined in the ranges of 6.601-932.167 µg/mL for DPPH⢠scavenging and 13.007-27.829 µg/mL for ABTSâ¢+ scavenging. In all of the used bioanalytical methods, phyto lignans, as secondary metabolites in plants, demonstrated considerably higher antioxidant activity compared to that of mammalian lignans. In addition, it was observed that enterodiol and enterolactone exhibited relatively weaker antioxidant activities when compared to phyto lignans or standard antioxidants, including butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), Trolox, and α-tocopherol.
Sujet(s)
Antioxydants/composition chimique , Piégeurs de radicaux libres/composition chimique , Lignanes/composition chimique , Peroxydation lipidique/effets des médicaments et des substances chimiques , Composés phytochimiques/composition chimique , Animaux , Antioxydants/pharmacologie , Benzothiazoles/composition chimique , Benzothiazoles/pharmacologie , Dérivés du biphényle/synthèse chimique , Dérivés du biphényle/pharmacologie , Hydroxyanisole butylé/composition chimique , Butylhydrotoluène/composition chimique , Butylène glycols/composition chimique , Chromanes/composition chimique , Cuivre/composition chimique , Piégeurs de radicaux libres/pharmacologie , Ions/composition chimique , Fer/composition chimique , Lignanes/pharmacologie , Mammifères , Masoprocol/composition chimique , Composés phytochimiques/pharmacologie , Picrates/synthèse chimique , Picrates/pharmacologie , Acides sulfoniques/composition chimique , Acides sulfoniques/pharmacologie , 1,2,3,4-Tétrahydro-naphtalènes/composition chimiqueRÉSUMÉ
Interleukin-17 (IL-17) is a proinflammatory cytokine that plays a dominant role in inflammation, autoimmunity, and host defense. RORγt is a key transcription factor mediating T helper 17 (Th17) cell differentiation and IL-17 production, which is able to activate CD8+ T cells and elicit antitumor efficacy. A series of sulfonamide derivatives as novel RORγt inverse agonists were designed and synthesized. Using GSK2981278 (phase II) as a starting point, we engineered structural modifications that significantly improved the activity and pharmacokinetic profile. In animal studies, oral administration of compound d3 showed a robust and dose-dependent inhibition of the IL-17A cytokine expression in a mouse imiquimod-induced skin inflammation model. Docking analysis of the binding mode revealed that the compound d3 occupied the active pocket suitably. Thus, compound d3 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases.
Sujet(s)
Chromanes/composition chimique , Systèmes de délivrance de médicaments , Membre-3 du groupe F de la sous-famille-1 de récepteurs nucléaires/agonistes , Pyrannes/pharmacologie , Sulfonamides/pharmacologie , Animaux , Cyclisation , Humains , Cellules Jurkat , Souris , Simulation de docking moléculaire , Pyrannes/administration et posologie , Pyrannes/composition chimique , Relation structure-activité , Sulfonamides/administration et posologie , Sulfonamides/composition chimiqueRÉSUMÉ
Penicisteckins A-D (1-4), two pairs of atropodiastereomeric biaryl-type hetero- and homodimeric bis-isochromans with 7,5'- and 7,7'-linkages and a pair of atropodiastereomeric 2-(isochroman-5-yl)-1,4-benzoquinone derivatives [penicisteckins E (5) and F (6)], were isolated from the Penicillium steckii HNNU-5B18. Their structures including the absolute configuration were determined by extensive spectroscopic and single-crystal X-ray diffraction analysis and TDDFT-ECD calculations. Both the bis-isochromans and the isochroman/1,4-benzoquinone conjugates represent novel biaryl scaffolds containing both central and axial chirality elements. The monomer anserinone B (8) exhibited potent antibacterial activities against Staphylococcus aureus ATCC 29213 and methicillin-resistant Staphylococcus aureus with minimal inhibition concentration values ranging from 2 to 8 µg mL-1. Plausible biosynthetic pathways of 1-6 are proposed, which suggest how the absolute configurations of the isolates were established during the biosynthetic scheme.
Sujet(s)
Antibactériens/isolement et purification , Chromanes/isolement et purification , Penicillium/métabolisme , Antibactériens/composition chimique , Antibactériens/pharmacologie , Voies de biosynthèse , Chromanes/composition chimique , Chromanes/pharmacologie , Staphylococcus aureus/effets des médicaments et des substances chimiquesRÉSUMÉ
Phytochemical investigation of the ethanol extract of underground parts of Iris tenuifolia Pall. afforded five new compounds; an unusual macrolide termed moniristenulide (1), 5-methoxy-6,7-methylenedioxy-4-O-2'-cycloflavan (2), 5,7,2',3'-tetrahydroxyflavanone (3), 5-hydroxy-6,7-dimethoxyisoflavone-2'-O-ß-d-glucopyranoside (9), 5,2',3'-dihydroxy-6,7-dimethoxyisoflavone (10), along with seven known compounds (4-8, 11-12). The structures of all purified compounds were established by analysis of 1D and 2D NMR spectroscopy and HR-ESI-MS. The antimicrobial activity of the compounds 1-3, 5, 9, and 10 was investigated using the agar diffusion method against fungi, Gram-positive and Gram-negative bacteria. In consequence, new compound 3 was found to possess the highest antibacterial activity against Enterococcus faecalis VRE and Mycobacterium vaccae. Cell proliferation and cytotoxicity tests were also applied on all isolated compounds and plant crude extract in vitro with the result of potent inhibitory effect against leukemia cells. In particular, the newly discovered isoflavone 10 was active against both of the leukemia cells K-562 and THP-1 while 4-6 of the flavanone type compounds were active against only THP-1.
Sujet(s)
Anti-infectieux/pharmacologie , Antinéoplasiques/pharmacologie , Chromanes/pharmacologie , Iris (plante)/composition chimique , Extraits de plantes/pharmacologie , Anti-infectieux/composition chimique , Antinéoplasiques/composition chimique , Lignée cellulaire , Survie cellulaire/effets des médicaments et des substances chimiques , Chromanes/composition chimique , Relation dose-effet des médicaments , Humains , Spectroscopie par résonance magnétique , Conformation moléculaire , Structure moléculaire , Extraits de plantes/composition chimiqueRÉSUMÉ
2-Aminotetralin and 3-aminochroman derivatives are key structural motifs present in a wide range of pharmaceutically important molecules. Herein, we report an effective biocatalytic approach towards these molecules through the enantioselective reductive coupling of 2-tetralones and 3-chromanones with a diverse range of primary amine partners. Metagenomic imine reductases (IREDs) were employed as the biocatalysts, obtaining high yields and enantiocomplementary selectivity for >15 examples at preparative scale, including the precursors to Ebalzotan, Robalzotan, Alnespirone and 5-OH-DPAT. We also present a convergent chemo-enzymatic total synthesis of the Parkinson's disease therapy Rotigotine in 63 % overall yield and 92 % ee.
Sujet(s)
Chromanes/métabolisme , Oxidoreductases/métabolisme , 1,2,3,4-Tétrahydro-naphtalènes/métabolisme , Amination , Amines/composition chimique , Amines/métabolisme , Biocatalyse , Chromanes/composition chimique , Oxydoréduction , Stéréoisomérie , 1,2,3,4-Tétrahydro-naphtalènes/composition chimiqueRÉSUMÉ
The precise understanding of the behaviour of vitamin E (α-tocopherol; Toc) complexed with cyclodextrin (CD) additives in aqueous solution is a fundamental issue for further development of their aqua-related biological applications. In this study, the solubilisation and complexation behaviours of Toc with methyl-substituted CD derivatives and the radical scavenging ability of the resulting complexes were precisely investigated in water media. Several problems were encountered upon pre-dissolving Toc in an organic solvent prior to the addition to the water media, such as enhancement of the dispersibility and decrease in the complexation capacity. Additionally, dispersions were obtained in some cases when mixing CD and Toc even in the absence of an organic solvent; therefore, to perform the measurements, a transparent solution was prepared via filtration with a nanopore filter. Consequently, unexpectedly, the addition of certain CD methylated derivatives did not always enhance the solubility of Toc significantly. However, 2,6-di-O-methylated ß-CD (2,6-DMCD) formed a water-soluble inclusion complex with Toc, effectively enhancing its solubility. A phase solubility study indicated the formation of 1:2 or 1:3 Toc/CD inclusion complexes, and the interaction of 2,6-DMCD with both the chromanol head and the phytol chain of Toc was revealed by 2D ROESY nuclear magnetic resonance analysis. The interaction between 2,6-DMCD and the chromanol head was also confirmed for a 2,6-DMCD-2,2,5,7,8-pentamethyl-6-chromanol inclusion complex. Additionally, a rapid scavenging effect for molecularly dissolved Toc was demonstrated even in a system comprising a chromanol head directly encapsulated by CD. Hence, this work elucidated the precise complexation and radical scavenging ability of 2,6-DMCD-Toc in an aqueous solution, which paves the way for its biological applications.
Sujet(s)
Cyclodextrines/pharmacologie , Piégeurs de radicaux libres , Vitamine E/pharmacologie , Cyclodextrines bêta/pharmacologie , Chromanes/composition chimique , Cyclodextrines/composition chimique , Association médicamenteuse , Interactions médicamenteuses , Solubilité , Solutions , Vitamine E/composition chimique , Eau , Cyclodextrines bêta/composition chimiqueRÉSUMÉ
Oxidative stress and inflammation are two conditions that coexist in many multifactorial diseases such as atherosclerosis and neurodegeneration. Thus, the design of multifunctional compounds that can concurrently tackle two or more therapeutic targets is an appealing approach. In this study, the basic NSAID structure was fused with the antioxidant moieties 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHB), its reduced alcohol 3,5-di-tert-butyl- 4-hydroxybenzyl alcohol (BHBA), or 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox), a hydrophilic analogue of α-tocopherol. Machine learning algorithms were utilized to validate the potential dual effect (anti-inflammatory and antioxidant) of the designed analogues. Derivatives 1-17 were synthesized by known esterification methods, with good to excellent yields, and were pharmacologically evaluated both in vitro and in vivo for their antioxidant and anti-inflammatory activity, whereas selected compounds were also tested in an in vivo hyperlipidemia protocol. Furthermore, the activity/binding affinity of the new compounds for lipoxygenase-3 (LOX-3) was studied not only in vitro but also via molecular docking simulations. Experimental results demonstrated that the antioxidant and anti-inflammatory activities of the new fused molecules were increased compared to the parent molecules, while molecular docking simulations validated the improved activity and revealed the binding mode of the most potent inhibitors. The purpose of their design was justified by providing a potentially safer and more efficient therapeutic approach for multifactorial diseases.
Sujet(s)
Antioxydants/composition chimique , Athérosclérose/traitement médicamenteux , Hyperlipidémies/traitement médicamenteux , Inflammation/traitement médicamenteux , Inhibiteurs de la lipoxygénase/composition chimique , Anti-inflammatoires/synthèse chimique , Anti-inflammatoires/composition chimique , Anti-inflammatoires/pharmacologie , Anti-inflammatoires non stéroïdiens/effets indésirables , Anti-inflammatoires non stéroïdiens/composition chimique , Antioxydants/synthèse chimique , Antioxydants/pharmacologie , Athérosclérose/anatomopathologie , Chromanes/composition chimique , Chromanes/pharmacologie , Conception de médicament , Humains , Hyperlipidémies/anatomopathologie , Hypolipémiants/synthèse chimique , Hypolipémiants/composition chimique , Hypolipémiants/pharmacologie , Inflammation/anatomopathologie , Lipoxygenase/composition chimique , Lipoxygenase/effets des médicaments et des substances chimiques , Inhibiteurs de la lipoxygénase/synthèse chimique , Inhibiteurs de la lipoxygénase/pharmacologie , Simulation de docking moléculaire , Dégénérescence nerveuse/traitement médicamenteux , Dégénérescence nerveuse/anatomopathologie , Stress oxydatif/effets des médicaments et des substances chimiques , Parabènes/composition chimique , Parabènes/pharmacologie , Relation structure-activitéRÉSUMÉ
In this study, using the botanical active component thiochromanone as the lead compound, a total of 32 new thiochromanone derivatives containing a carboxamide moiety were designed and synthesized and their in vitro antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo), Xanthomonas oryzae pv. oryzicolaby (Xoc), and Xanthomonas axonopodis pv. citri (Xac) were determined, as well as their in vitro antifungal activities against Botryosphaeria dothidea (B. dothidea), Phomopsis sp., and Botrytis cinerea (B. cinerea). Bioassay results demonstrated that some of the target compounds exhibited moderate to good in vitro antibacterial and antifungal activities. In particular, compound 4e revealed excellent in vitro antibacterial activity against Xoo, Xoc, and Xac, and its EC50 values of 15, 19, and 23 µg/mL, respectively, were superior to those of Bismerthiazol and Thiodiazole copper. Meanwhile, compound 3b revealed moderate in vitro antifungal activity against B. dothidea at 50 µg/mL, and the inhibition rate reached 88%, which was even better than that of Pyrimethanil, however, lower than that of Carbendazim. To the best of our knowledge, this is the first report on the antibacterial and antifungal activities of this series of novel thiochromanone derivatives containing a carboxamide moiety.
Sujet(s)
Botrytis/croissance et développement , Chromanes , Phomopsis (genre)/croissance et développement , Xanthomonas axonopodis/croissance et développement , Xanthomonas/croissance et développement , Antifongiques/synthèse chimique , Antifongiques/composition chimique , Antifongiques/pharmacologie , Chromanes/synthèse chimique , Chromanes/composition chimique , Chromanes/pharmacologie , Relation structure-activitéRÉSUMÉ
A series of multitarget-directed ligands (MTDLs) was designed by functionalizing a pseudo-irreversible butyrylcholinesterase (BChE) inhibitor. The obtained hybrids were investigated in vitro regarding their hBChE and hAChE inhibition, their enzyme kinetics, and their antioxidant physicochemical properties (DPPH, ORAC, metal chelating). In addition, in vitro assays were applied to investigate antioxidant effects using murine hippocampal HT22 cells and immunomodulatory effects on the murine microglial N9 cell line. The MTDLs retained their antioxidative properties compared to the parent antioxidant-moieties in vitro and the inhibition of hBChE was maintained in the submicromolar range. Representative compounds were tested in a pharmacological Alzheimer's disease (AD) mouse model and demonstrated very high efficacy at doses as low as 0.1 mg/kg. The most promising compound was also tested in BChE-/- mice and showed reduced efficacy. In vivo neuroprotection by BChE inhibition can be effectively enhanced by incorporation of structurally diverse antioxidant moieties.