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1.
J Med Chem ; 67(13): 11435-11449, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38889119

RESUMO

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.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2 , Cromanos , Desenho de Fármacos , Receptores Adrenérgicos alfa 2 , Animais , Receptores Adrenérgicos alfa 2/metabolismo , Cromanos/farmacologia , Cromanos/química , Cromanos/síntese química , Relação Estrutura-Atividade , Camundongos , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/química , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Masculino
2.
J Chem Inf Model ; 64(12): 4877-4896, 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38856697

RESUMO

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.


Assuntos
Antígeno B7-H1 , Cromanos , Desenho de Fármacos , Receptor de Morte Celular Programada 1 , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Humanos , Cromanos/química , Cromanos/farmacologia , Simulação de Dinâmica Molecular
3.
Food Chem ; 455: 139920, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-38850994

RESUMO

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 µÐœ-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.


Assuntos
Cromanos , Frutas , Grafite , Nitrogênio , Tantálio , Grafite/química , Frutas/química , Nitrogênio/química , Tantálio/química , Cromanos/química , Cromanos/análise , Teoria da Densidade Funcional , Técnicas Eletroquímicas , Limite de Detecção , Eletrodos , Ferro/química , Ferro/análise
4.
Chem Biodivers ; 21(7): e202400587, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38718104

RESUMO

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.


Assuntos
Antioxidantes , Simulação de Acoplamento Molecular , Triazóis , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/síntese química , Relação Estrutura-Atividade , NADPH Oxidases/metabolismo , NADPH Oxidases/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/síntese química , Cromanos/química , Cromanos/farmacologia , Cromanos/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/síntese química , Estrutura Molecular , Relação Dose-Resposta a Droga , Picratos/antagonistas & inibidores
5.
Bioorg Med Chem Lett ; 108: 129789, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38729318

RESUMO

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.


Assuntos
Antineoplásicos , Apoptose , Neoplasias da Mama , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Cromanos/farmacologia , Cromanos/síntese química , Cromanos/química , Simulação de Acoplamento Molecular , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/antagonistas & inibidores , Feminino , Estrutura Molecular , Células MCF-7 , Relação Dose-Resposta a Droga , Tamoxifeno/farmacologia , Tamoxifeno/síntese química , Tamoxifeno/química
6.
Org Biomol Chem ; 20(41): 8136-8144, 2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-36218163

RESUMO

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.


Assuntos
Alcenos , Quinolinas , Alcenos/química , Catálise , Cromanos/química , Quinolinas/química
7.
Molecules ; 27(3)2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35163847

RESUMO

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.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Cromanos/química , Fungos/efeitos dos fármacos , Compostos de Espiro/química , Antibacterianos/química , Antifúngicos/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxindóis/química , Relação Estrutura-Atividade
8.
Future Med Chem ; 14(5): 325-342, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34985322

RESUMO

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 ∼ two/∼fourfold 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.


Assuntos
Antineoplásicos/síntese química , Cromanos/química , Desenho de Fármacos , Compostos de Espiro/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Cromanos/metabolismo , Cromanos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Camundongos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
9.
Bioorg Med Chem ; 57: 116629, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35091169

RESUMO

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.


Assuntos
Antimaláricos/farmacologia , Cromanos/farmacologia , Malária/tratamento farmacológico , Plasmodium/efeitos dos fármacos , Compostos de Espiro/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Sobrevivência Celular/efeitos dos fármacos , Cromanos/síntese química , Cromanos/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade
10.
Chem Biodivers ; 19(1): e202100723, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34762766

RESUMO

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 3.70 µM) with standard 5-lipoxygenase inhibitor drug zileuton (IC50 2.41 µM). Noticeably, the index of anti-inflammatory selectivity of turbinochromanone (∼1.7) was considerably greater than that exhibited by the standard agent diclofenac (1.06). Antioxidant properties of turbinochromanone against oxidants (IC50 ∼24 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 -9.40 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.


Assuntos
Anti-Inflamatórios/química , Cromanos/química , Alga Marinha/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/metabolismo , Antioxidantes/química , Araquidonato 5-Lipoxigenase/química , Araquidonato 5-Lipoxigenase/metabolismo , Sítios de Ligação , Cromanos/isolamento & purificação , Cromanos/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Furanos/química , Conformação Molecular , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Estrutura Terciária de Proteína , Alga Marinha/metabolismo , Termodinâmica
11.
Molecules ; 26(23)2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34885681

RESUMO

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 (ABTS•+) 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 ABTS•+ 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 ABTS•+ 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.


Assuntos
Antioxidantes/química , Sequestradores de Radicais Livres/química , Lignanas/química , Peroxidação de Lipídeos/efeitos dos fármacos , Compostos Fitoquímicos/química , Animais , Antioxidantes/farmacologia , Benzotiazóis/química , Benzotiazóis/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Hidroxianisol Butilado/química , Hidroxitolueno Butilado/química , Butileno Glicóis/química , Cromanos/química , Cobre/química , Sequestradores de Radicais Livres/farmacologia , Íons/química , Ferro/química , Lignanas/farmacologia , Mamíferos , Masoprocol/química , Compostos Fitoquímicos/farmacologia , Picratos/síntese química , Picratos/farmacologia , Ácidos Sulfônicos/química , Ácidos Sulfônicos/farmacologia , Tetra-Hidronaftalenos/química
12.
J Nat Prod ; 84(11): 2953-2960, 2021 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-34787427

RESUMO

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.


Assuntos
Antibacterianos/isolamento & purificação , Cromanos/isolamento & purificação , Penicillium/metabolismo , Antibacterianos/química , Antibacterianos/farmacologia , Vias Biossintéticas , Cromanos/química , Cromanos/farmacologia , Staphylococcus aureus/efeitos dos fármacos
13.
J Med Chem ; 64(21): 16106-16131, 2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34723528

RESUMO

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.


Assuntos
Cromanos/química , Sistemas de Liberação de Medicamentos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Piranos/farmacologia , Sulfonamidas/farmacologia , Animais , Ciclização , Humanos , Células Jurkat , Camundongos , Simulação de Acoplamento Molecular , Piranos/administração & dosagem , Piranos/química , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/química
14.
Molecules ; 26(21)2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34771113

RESUMO

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.


Assuntos
Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Cromanos/farmacologia , Gênero Iris/química , Extratos Vegetais/farmacologia , Anti-Infecciosos/química , Antineoplásicos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cromanos/química , Relação Dose-Resposta a Droga , Humanos , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estrutura Molecular , Extratos Vegetais/química
15.
J Oleo Sci ; 70(10): 1461-1467, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34497177

RESUMO

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.


Assuntos
Ciclodextrinas/farmacologia , Sequestradores de Radicais Livres , Vitamina E/farmacologia , beta-Ciclodextrinas/farmacologia , Cromanos/química , Ciclodextrinas/química , Combinação de Medicamentos , Interações Medicamentosas , Solubilidade , Soluções , Vitamina E/química , Água , beta-Ciclodextrinas/química
16.
Angew Chem Int Ed Engl ; 60(46): 24456-24460, 2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34478225

RESUMO

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.


Assuntos
Cromanos/metabolismo , Oxirredutases/metabolismo , Tetra-Hidronaftalenos/metabolismo , Aminação , Aminas/química , Aminas/metabolismo , Biocatálise , Cromanos/química , Oxirredução , Estereoisomerismo , Tetra-Hidronaftalenos/química
17.
Molecules ; 26(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34361545

RESUMO

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.


Assuntos
Botrytis/crescimento & desenvolvimento , Cromanos , Phomopsis/crescimento & desenvolvimento , Xanthomonas axonopodis/crescimento & desenvolvimento , Xanthomonas/crescimento & desenvolvimento , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Cromanos/síntese química , Cromanos/química , Cromanos/farmacologia , Relação Estrutura-Atividade
18.
Molecules ; 26(16)2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34443516

RESUMO

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.


Assuntos
Antioxidantes/química , Aterosclerose/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Inflamação/tratamento farmacológico , Inibidores de Lipoxigenase/química , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/química , Antioxidantes/síntese química , Antioxidantes/farmacologia , Aterosclerose/patologia , Cromanos/química , Cromanos/farmacologia , Desenho de Fármacos , Humanos , Hiperlipidemias/patologia , Hipolipemiantes/síntese química , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Inflamação/patologia , Lipoxigenase/química , Lipoxigenase/efeitos dos fármacos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/farmacologia , Simulação de Acoplamento Molecular , Degeneração Neural/tratamento farmacológico , Degeneração Neural/patologia , Estresse Oxidativo/efeitos dos fármacos , Parabenos/química , Parabenos/farmacologia , Relação Estrutura-Atividade
19.
Molecules ; 26(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072598

RESUMO

Essential oils (EOs) were extracted from Eugenia patrisii, E. punicifolia, and Myrcia tomentosa, specimens A and B, using hydrodistillation. Gas chromatography coupled with mass spectrometry (GC/MS) was used to identify the volatile constituents present, and the antioxidant capacity of EOs was determined using diphenylpicryl-hydrazyl (DPPH) and trolox equivalent antioxidant capacity (TEAC) assays. For E. patrisii, germacrene D (20.03%), bicyclogermacrene (11.82%), and (E)-caryophyllene (11.04%) were identified as the major constituents of the EOs extracted from specimen A, whereas specimen B primarily comprised γ-elemene (25.89%), germacrene B (8.11%), and (E)-caryophyllene (10.76%). The EOs of E. punicifolia specimen A contained ß-Elemene (25.12%), (E)-caryophyllene (13.11%), and bicyclogermacrene (9.88%), while specimen B was composed of (E)-caryophyllene (11.47%), bicyclogermacrene (5.86%), ß-pinene (5.86%), and γ-muurolene (5.55%). The specimen A of M. tomentosa was characterized by γ-elemene (12.52%), germacrene D (11.45%), and (E)-caryophyllene (10.22%), while specimen B contained spathulenol (40.70%), α-zingiberene (9.58%), and γ-elemene (6.89%). Additionally, the chemical composition of the EOs was qualitatively and quantitatively affected by the collection period. Furthermore, the EOs of the studied specimens, especially specimen A of E. punicifolia, showed a greater antioxidant activity in DPPH rather than TEAC, as represented by a significantly high inhibition percentage (408.0%).


Assuntos
Antioxidantes/farmacologia , Eugenia/metabolismo , Myrtaceae/metabolismo , Óleos Voláteis/análise , Extratos Vegetais/farmacologia , Folhas de Planta/metabolismo , Antioxidantes/química , Compostos de Bifenilo/química , Técnicas de Química Analítica/métodos , Cromanos/química , Cromatografia Gasosa-Espectrometria de Massas , Óleos Voláteis/química , Picratos/química , Sesquiterpenos Policíclicos/análise , Sesquiterpenos/análise , Sesquiterpenos de Germacrano/análise
20.
J Med Chem ; 64(13): 9302-9320, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34152756

RESUMO

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.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Butirilcolinesterase/deficiência , Butirilcolinesterase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cromanos/síntese química , Cromanos/química , Cromanos/farmacologia , Cinamatos/síntese química , Cinamatos/química , Cinamatos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Masculino , Melatonina/síntese química , Melatonina/química , Melatonina/farmacologia , Camundongos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Picratos/antagonistas & inibidores , Relação Estrutura-Atividade
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