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1.
Molecules ; 26(19)2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34641337

RESUMO

We report the design and synthesis of a series of new 5-chloropyridinyl esters of salicylic acid, ibuprofen, indomethacin, and related aromatic carboxylic acids for evaluation against SARS-CoV-2 3CL protease enzyme. These ester derivatives were synthesized using EDC in the presence of DMAP to provide various esters in good to excellent yields. Compounds are stable and purified by silica gel chromatography and characterized using 1H-NMR, 13C-NMR, and mass spectral analysis. These synthetic derivatives were evaluated in our in vitro SARS-CoV-2 3CLpro inhibition assay using authentic SARS-CoV-2 3CLpro enzyme. Compounds were also evaluated in our in vitro antiviral assay using quantitative VeroE6 cell-based assay with RNAqPCR. A number of compounds exhibited potent SARS-CoV-2 3CLpro inhibitory activity and antiviral activity. Compound 9a was the most potent inhibitor, with an enzyme IC50 value of 160 nM. Compound 13b exhibited an enzyme IC50 value of 4.9 µM. However, it exhibited a potent antiviral EC50 value of 24 µM in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral EC50 value of 2.4 µM in the same assay. We assessed the mode of inhibition using mass spectral analysis which suggested the formation of a covalent bond with the enzyme. To obtain molecular insight, we have created a model of compound 9a bound to SARS-CoV-2 3CLpro in the active site.


Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , SARS-CoV-2/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/farmacologia , Chlorocebus aethiops , Proteases 3C de Coronavírus/metabolismo , Ésteres/química , Ésteres/farmacologia , Halogenação , Humanos , Ibuprofeno/análogos & derivados , Ibuprofeno/farmacologia , Indometacina/análogos & derivados , Indometacina/farmacologia , Simulação de Acoplamento Molecular , Piridinas/química , Piridinas/farmacologia , SARS-CoV-2/metabolismo , Ácido Salicílico/química , Ácido Salicílico/farmacologia , Células Vero
2.
Molecules ; 26(19)2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34641627

RESUMO

Peganum harmala (P. harmala) belongs to the family Zygophyllaceae, and is utilized in the traditional medicinal systems of Pakistan, China, Morocco, Algeria, and Spain to treat several chronic health disorders. The aim of the present study was to identify the chemical constituents and to evaluate the antioxidant, anti-inflammatory, and toxicity effects of P. harmala extracts both in vitro and in vivo. Sequential crude extracts including 100% dichloromethane, 100% methanol, and 70% aqueous methanol were obtained and their antioxidant and anti-inflammatory effects evaluated both in vitro and in vivo. The anti-inflammatory effect of the extract was investigated using the carrageenan-induced paw edema method in mice, whereas the toxicity of the most active extract was evaluated using an acute and subacute toxicity rat model. In addition, we have used the bioassay-guided approach to obtain potent fractions, using solvent-solvent partitioning and reversed phase high performance liquid chromatography from active crude extracts; identification and quantification of compounds from the active fractions was achieved using electrospray ionization mass spectrometry and high performance liquid chromatography techniques. Results revealed that the 100% methanol extract of P. harmala exhibits significant in vitro antioxidant activity in DPPH assay with an IC50 of 49 µg/mL as compared to the standard quercetin with an IC50 of 25.4 µg/mL. The same extract exhibited 63.0% inhibition against serum albumin denaturation as compared to 97% inhibition by the standard diclofenac sodium in an in vitro anti-inflammatory assay, and in vivo anti-inflammatory against carrageenan-induced paw edema (75.14% inhibition) as compared to 86.1% inhibition caused by the standard indomethacin. Furthermore, this extract was not toxic during a 14 day trial of acute toxicity when given at a dose of 3 g/kg, indicating that the lethal dose (LD50) of P. harmala methanol extract was greater than 3 g/kg. P. harmala methanolic fraction 2 obtained using bioassay-guided fractionation showed the presence of quinic acid, peganine, harmol, harmaline, and harmine, confirmed by electrospray ionization mass spectrometry and quantified using external standards on high performance liquid chromatography. Taken all together, the current investigation further confirms the antioxidant, anti-inflammatory, and safety aspects of P. harmala, which justifies its use in folk medicine.


Assuntos
Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Carragenina/efeitos adversos , Edema/tratamento farmacológico , Peganum/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Modelos Animais de Doenças , Edema/induzido quimicamente , Indometacina/farmacologia , Dose Letal Mediana , Camundongos , Extratos Vegetais/química , Quercetina/farmacologia , Ratos , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
3.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443416

RESUMO

Acylhydrazones are still an important framework to the design of new bioactive compounds. As treatment of chronic pain represents a clinical challenge, we decided to modify the structure of LASSBio-1514 (1), previously described as anti-inflammatory and analgesic prototype. Applying the homologation as a strategy for molecular modification, we designed a series of cyclopentyl- (2a-e), cyclobutyl- (3a-e), and cyclopropylacylhydrazones (4a-e) that were synthetized and evaluated in murine models of inflammation and pain. A comparison of their in silico physicochemical and drug-like profile was conducted, as well as their anti-inflammatory and analgesic effect. Compounds 4a (LASSBio-1755) and 4e (LASSBio-1757) displayed excellent in silico drug-like profiles and were identified as new analgesic lead-candidates in acute and chronic model of pain, through oral administration.


Assuntos
Simulação por Computador , Desenho de Fármacos , Hidrazonas/síntese química , Hidrazonas/farmacologia , Preparações Farmacêuticas/síntese química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Aspirina/farmacologia , Células CACO-2 , Humanos , Hidrazonas/química , Hiperalgesia/patologia , Indometacina/farmacologia , Masculino , Camundongos , Conformação Molecular , Peso Molecular , Preparações Farmacêuticas/química , Ratos Wistar
4.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360951

RESUMO

Epidemiological studies have implied that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows the development and progression of Alzheimer's disease (AD). However, the underlying mechanisms are notably understudied. Using a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) (APP/PS1) expressing transgenic (Tg) mice and neuroblastoma (N) 2a cells as in vivo and in vitro models, we revealed the mechanisms of indomethacin in ameliorating the cognitive decline of AD. By screening AD-associated genes, we observed that a marked increase in the expression of α2-macroglobulin (A2M) was markedly induced after treatment with indomethacin. Mechanistically, upregulation of A2M was caused by the inhibition of cyclooxygenase-2 (COX-2) and lipocalin-type prostaglandin D synthase (L-PGDS), which are responsible for the synthesis of prostaglandin (PG)H2 and PGD2, respectively. The reduction in PGD2 levels induced by indomethacin alleviated the suppression of A2M expression through a PGD2 receptor 2 (CRTH2)-dependent mechanism. Highly activated A2M not only disrupted the production and aggregation of ß-amyloid protein (Aß) but also induced Aß efflux from the brain. More interestingly, indomethacin decreased the degradation of the A2M receptor, low-density lipoprotein receptor-related protein 1 (LRP1), which facilitated the brain efflux of Aß. Through the aforementioned mechanisms, indomethacin ameliorated cognitive decline in APP/PS1 Tg mice by decreasing Aß production and clearing Aß from the brains of AD mice.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Indometacina/farmacologia , Placa Amiloide/tratamento farmacológico , alfa-Macroglobulinas/metabolismo , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Humanos , Indometacina/uso terapêutico , Oxirredutases Intramoleculares/metabolismo , Lipocalinas/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Placa Amiloide/metabolismo , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Regulação para Cima , alfa-Macroglobulinas/genética
5.
PLoS One ; 16(8): e0254606, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34428217

RESUMO

Acetylsalicylic acid is a globally used non-steroidal anti-inflammatory drug (NSAID) with diverse pharmacological properties, although its mechanism of immune regulation during inflammation (especially at in vivo relevant doses) remains largely speculative. Given the increase in clinical perspective of Acetylsalicylic acid in various diseases and cancer prevention, this study aimed to investigate the immunomodulatory role of physiological Acetylsalicylic acid concentrations (0.005, 0.02 and 0.2 mg/ml) in a human whole blood of infection-induced inflammation. We describe a simple, highly reliable whole blood assay using an array of toll-like receptor (TLR) ligands 1-9 in order to systematically explore the immunomodulatory activity of Acetylsalicylic acid plasma concentrations in physiologically relevant conditions. Release of inflammatory cytokines and production of prostaglandin E2 (PGE2) were determined directly in plasma supernatant. Experiments demonstrate for the first time that plasma concentrations of Acetylsalicylic acid significantly increased TLR ligand-triggered IL-1ß, IL-10, and IL-6 production in a dose-dependent manner. In contrast, indomethacin did not exhibit this capacity, whereas cyclooxygenase (COX)-2 selective NSAID, celecoxib, induced a similar pattern like Acetylsalicylic acid, suggesting a possible relevance of COX-2. Accordingly, we found that exogenous addition of COX downstream product, PGE2, attenuates the TLR ligand-mediated cytokine secretion by augmenting production of anti-inflammatory cytokines and inhibiting release of pro-inflammatory cytokines. Low PGE2 levels were at least involved in the enhanced IL-1ß production by Acetylsalicylic acid.


Assuntos
Aspirina/farmacologia , Citocinas/genética , Inflamação/tratamento farmacológico , Receptores Toll-Like/genética , Adjuvantes Imunológicos/farmacologia , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/farmacologia , Celecoxib/farmacologia , Ciclo-Oxigenase 2/sangue , Ciclo-Oxigenase 2/genética , Citocinas/biossíntese , Dinoprostona/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Indometacina/farmacologia , Inflamação/sangue , Inflamação/patologia , Interleucina-10/genética , Interleucina-1beta/genética , Interleucina-6/genética , Leucócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Receptores Toll-Like/sangue , Adulto Jovem
6.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206628

RESUMO

Black rice is a type of rice in the Oryza sativa L. species. There are numerous reports regarding the pharmacological actions of black rice bran, but scientific evidence on its gastroprotection is limited. This study aimed to evaluate the gastroprotective activities of black rice bran ethanol extract (BRB) from the Thai black rice variety Hom Nil (O. sativa L. indica) as well as its mechanisms of action, acute oral toxicity in rats, and phytochemical screening. Rat models of gastric ulcers induced by acidified ethanol, indomethacin, and restraint water immersion stress were used. After pretreatment with 200, 400, and 800 mg/kg of BRB in test groups, BRB at 800 mg/kg significantly inhibited the formation of gastric ulcers in all gastric ulcer models, and this inhibition seemed to be dose dependent in an indomethacin-induced gastric ulcer model. BRB could not normalize the amount of gastric wall mucus, reduce gastric volume and total acidity, or increase gastric pH. Although BRB could not increase NO levels in gastric tissue, the tissue MDA levels could be normalized with DPPH radical scavenging activity. These results confirm the gastroprotective activities of BRB with a possible mechanism of action via antioxidant activity. The major phytochemical components of BRB comprise carotenoid derivatives with the presence of phenolic compounds. These components may be responsible for the gastroprotective activities of BRB. The 2000 mg/kg dose of oral BRB showed no acute toxicity in rats and confirmed, in part, the safe uses of BRB.


Assuntos
Antiulcerosos , Etanol/química , Indometacina/efeitos adversos , Oryza/química , Fitoterapia , Extratos Vegetais , Úlcera Gástrica , Animais , Antiulcerosos/química , Antiulcerosos/farmacologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Indometacina/farmacologia , Masculino , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patologia
7.
Molecules ; 26(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205704

RESUMO

The discovery of drugs capable of inhibiting SARS-CoV-2 is a priority for human beings due to the severity of the global health pandemic caused by COVID-19. To this end, repurposing of FDA-approved drugs such as NSAIDs against COVID-19 can provide therapeutic alternatives that could be utilized as an effective safe treatment for COVID-19. The anti-inflammatory activity of NSAIDs is also advantageous in the treatment of COVID-19, as it was found that SARS-CoV-2 is responsible for provoking inflammatory cytokine storms resulting in lung damage. In this study, 40 FDA-approved NSAIDs were evaluated through molecular docking against the main protease of SARS-CoV-2. Among the tested compounds, sulfinpyrazone 2, indomethacin 3, and auranofin 4 were proposed as potential antagonists of COVID-19 main protease. Molecular dynamics simulations were also carried out for the most promising members of the screened NSAID candidates (2, 3, and 4) to unravel the dynamic properties of NSAIDs at the target receptor. The conducted quantum mechanical study revealed that the hybrid functional B3PW91 provides a good description of the spatial parameters of auranofin 4. Interestingly, a promising structure-activity relationship (SAR) was concluded from our study that could help in the future design of potential SARS-CoV-2 main protease inhibitors with expected anti-inflammatory effects as well. NSAIDs may be used by medicinal chemists as lead compounds for the development of potent SARS-CoV-2 (Mpro) inhibitors. In addition, some NSAIDs can be selectively designated for treatment of inflammation resulting from COVID-19.


Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/uso terapêutico , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Anti-Inflamatórios não Esteroides/metabolismo , Antivirais/química , Antivirais/farmacologia , Auranofina/química , Auranofina/farmacologia , Sítios de Ligação , COVID-19/complicações , Biologia Computacional , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Bases de Dados de Compostos Químicos , Humanos , Indometacina/química , Indometacina/farmacologia , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Ligação Proteica , SARS-CoV-2/química , SARS-CoV-2/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfimpirazona/química , Sulfimpirazona/farmacologia , Estados Unidos , United States Food and Drug Administration
8.
Microb Pathog ; 158: 105097, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34284088

RESUMO

The current failure of antimicrobials in treating life-threatening diseases, the high rate of multidrug resistant pathogens and the slow progress in the development of new antibiotics directed scientists to develop antivirulence drugs that targets quorum sensing (QS). In many microbes, QS acts as a communication system which control pathogenicity of microbes. Analgesics can be beneficial in controlling virulence traits of microbes and hence they may augment the efficacy of antimicrobials. In this study, two analgesics were screened for the inhibition of QS in Chromobacterium violaceum CV026 and their effects on virulence production in Pseudomonas aeruginosa PAO1 strain and clinical isolates of Acinetobacter baumannii were evaluated. The traits investigated were biofilm formation, pyocyanin and rhamnolipid production, twitching, swarming or surface associated motilities, production of protease, phospholipase and gelatinase enzymes and sensitivity to oxidative stress. Relative expression of abaI gene was calculated by performing qRT-PCR. Docking analysis of paracetamol as QSI (quorum sensing inhibitor) of AbaI and AbaR proteins was performed. Paracetamol inhibited QS in CV026, but indomethacin devoids anti-QS activity. Paracetamol inhibited virulence factors of PAO1. It strongly inhibited biofilm formation, and swarming by 66.4% and 57.1%, respectively. While, it moderately to slightly inhibited rhamnolipid, pyocyanin, gelatinase, resistance to oxidative stress, protease and twitching motility by 33.3%, 33.1% 17.5%, 9.1%, 8.7% and 7.7%, respectively. For A. baumannii, paracetamol strongly inhibited biofilm by 39.7-93% and phospholipase enzyme by 8.7-100%, reduced twitching and surface motility by 6.7-82.5% and 7.7-29.4%, respectively, And slightly reduced sensitivity to oxidative stress by 3.3-36.4%. Paracetamol at sub-MIC suppressed the expression of abaI gene by 32% in A. baumannii. Docking studies suggested that paracetamol can bind to AbaR and AbaI proteins and bind more to AbaR, hence it may act by inhibiting AHL signal reception. As a conclusion, paracetamol, beside its analgesic activity, has anti-QS activity and could be used in the eradication of P. aeruginosa and A. baumannii infections in combination with antibiotics.


Assuntos
Acetaminofen , Percepção de Quorum , Acetaminofen/farmacologia , Analgésicos/farmacologia , Antibacterianos/farmacologia , Biofilmes , Chromobacterium , Indometacina/farmacologia , Pseudomonas aeruginosa , Fatores de Virulência
9.
Int J Biol Macromol ; 185: 716-724, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34217742

RESUMO

Chitosan-based hydrogels are a suitable and versatile system for the design of localized and controlled drug delivery systems. In the current study, a hydrogel based on chitosan (CS), Dopamine (DA), and Inulin aldehyde (IA) was fabricated without the further use of catalyst or initiators. The effect of the IA contents as a crosslinking agent on the properties of the prepared hydrogel was studied. The crosslinking reaction between CS and IA was verified by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). Various characteristics of the CS/DA/IA hydrogels were further assessed utilizing swelling experiment, in vitro drug release, in vitro cytotoxicity assay. The drug-loaded hydrogels represented the sustained release of Indomethacin according to the in vitro drug release test in acidic (pH = 4), basic (pH = 10) medium as well as physiological condition (pH = 7). Finally, the CS/DA/IA hydrogels exhibited appropriate cytocompatibility against the L-929 fibroblast cell line according to the direct contact MTT assay.


Assuntos
Quitosana/química , Dopamina/química , Fibroblastos/citologia , Indometacina/farmacologia , Inulina/química , Animais , Varredura Diferencial de Calorimetria , Sistemas de Liberação de Medicamentos , Fibroblastos/efeitos dos fármacos , Hidrogéis , Concentração de Íons de Hidrogênio , Indometacina/química , Camundongos , Microscopia Eletrônica de Varredura , Porosidade , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria
10.
Am J Physiol Regul Integr Comp Physiol ; 321(2): R208-R219, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34161746

RESUMO

Structural and functional changes in the cerebral vasculature occur with advancing age, which may lead to impaired neurovascular coupling (NVC) and cognitive decline. Cyclooxygenase (COX) inhibition abolishes age-related differences in cerebrovascular reactivity, but it is unclear if COX inhibition impacts NVC. The purpose of this study was to examine the influence of aging on NVC before and after COX inhibition. Twenty-three young (age = 25 ± 4 yr) and 21 older (age = 64 ± 5 yr) adults completed two levels of difficulty of the Stroop and n-back tests before and after COX inhibition. Middle cerebral artery blood velocity (MCAv) was measured using transcranial Doppler ultrasound and mean arterial blood pressure (MAP) was measured using a finger cuff. Hemodynamic variables were measured at rest and in response to cognitive challenges. During the Stroop test, older adults demonstrated a greater increase in MCAv (young: 2.2 ± 6.8% vs. older: 5.9 ± 5.8%; P = 0.030) and MAP (young: 2.0 ± 4.9% vs. older: 4.8 ± 4.9%; P = 0.036) compared with young adults. There were no age-related differences during the n-back test. COX inhibition reduced MCAv by 30% in young and 26% in older adults (P < 0.001 for both). During COX inhibition, there were no age-related differences in the percent change in MCAv or MAP in response to the cognitive tests. Our results show that older adults require greater increases in MCAv and MAP during a test of executive function compared with young adults and that any age-related differences in NVC were abolished during COX inhibition. Collectively, this suggests that aging is associated with greater NVC necessary to accomplish a cognitive task.


Assuntos
Circulação Cerebrovascular/efeitos dos fármacos , Cognição , Envelhecimento Cognitivo/psicologia , Inibidores de Ciclo-Oxigenase/farmacologia , Hemodinâmica/efeitos dos fármacos , Indometacina/farmacologia , Artéria Cerebral Média/efeitos dos fármacos , Acoplamento Neurovascular/efeitos dos fármacos , Adolescente , Adulto , Fatores Etários , Idoso , Função Executiva , Feminino , Humanos , Masculino , Memória de Curto Prazo , Pessoa de Meia-Idade , Artéria Cerebral Média/diagnóstico por imagem , Teste de Stroop , Fatores de Tempo , Adulto Jovem
11.
Food Chem Toxicol ; 154: 112354, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34146620

RESUMO

Preparations of the fungus Cordyceps sinensis and bovine colostrum are considered nutraceuticals due to their anti-inflammatory, repair and gut alimentation properties in mammalian models. To reduce the reliance on rodents in routine experimentation, we gauged the capacity of nutraceuticals to alleviate gastric damage in an insect surrogate, Galleria mellonella. Larvae were reared on standard or supplemented diets - 10% (w/w) colostrum, 10% (w/w) C. sinensis, or 5% + 5% each - prior to receiving an oral dose of the NSAID indomethacin (30 mg/kg) or challenged with the bacterial pathogen Campylobacter jejuni (1-3 x106) via two inoculation routes. Insects reared on a cordyceps-supplemented diet proved most resistant to indomethacin-induced gut leakiness, and displayed stable health indices after C. jejuni challenge (~77% survival). Insects reared on a colostrum-supplemented diet also showed recalcitrance in the gut, but were more sensitive to C. jejuni when injected directly into the body cavity (50% survival). The nutraceutical blend yielded improved health outcomes when compared to the standard diet, but was not as effective as either nutraceutical alone. Our findings represent clear evidence that insects were more resistant to known chemical and microbial agitators when reared on nutraceutical-supplemented diets - toxicological endpoints that are shared with vertebrate studies.


Assuntos
Infecções por Campylobacter/dietoterapia , Suplementos Nutricionais , Trato Gastrointestinal/efeitos dos fármacos , Mariposas/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Animais , Campylobacter jejuni/efeitos dos fármacos , Bovinos , Colostro , Cordyceps , Indometacina/farmacologia , Larva/efeitos dos fármacos , Permeabilidade
12.
Biomed Pharmacother ; 139: 111678, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33964802

RESUMO

In this study we present design and synthesis of nineteen new nitric oxide-releasing indomethacin derivatives with 1,3-thiazolidine-4-one scaffold (NO-IND-TZDs) (6a-s), as a new safer and efficient multi-targets strategy for inflammatory diseases. The chemical structure of all synthesized derivatives (intermediaries and finals) was proved by NMR and mass spectroscopic analysis. In order to study the selectivity of NO-IND-TZDs for COX isoenzymes (COX-1 and COX-2) a molecular docking study was performed using AutoDock 4.2.6 software. Based on docking results, COX-2 inhibitors were designed and 6o appears as the most selective derivative which showed an improved selective index compared with indomethacin (IND) and diclofenac (DCF), used as reference drugs. The biological evaluation of 6a-s, using in vitro assays has included the anti-inflammatory and antioxidant effects as well as the nitric oxide (NO) release. Referring to the anti-inflammatory effects, the most active compound was 6i, which was more active than IND and aspirin (ASP) in term of denaturation effect, on bovine serum albumin (BSA), as indirect assay to predict the anti-inflammatory effect. An appreciable anti-inflammatory effect, in reference with IND and ASP, was also showed by 6k, 6c, 6q, 6o, 6j, 6d. The antioxidant assay revealed the compound 6n as the most active, being 100 times more active than IND. The compound 6n showed also the most increase capacity to release NO, which means is safer in terms of gastro-intestinal side effects. The ADME-Tox study revealed also that the NO-IND-TZDs are generally proper for oral administration, having optimal physico-chemical and ADME properties. We can conclude that the compounds 6i and 6n are promising agents and could be included in further investigations to study in more detail their pharmaco-toxicological profile.


Assuntos
Indometacina/análogos & derivados , Indometacina/farmacologia , Doadores de Óxido Nítrico/farmacologia , Tiazolidinas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Aspirina/farmacologia , Simulação por Computador , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Diclofenaco/farmacologia , Desenho de Fármacos , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Humanos , Indometacina/química , Espectroscopia de Ressonância Magnética , Simulação de Acoplamento Molecular , Doadores de Óxido Nítrico/química , Doadores de Óxido Nítrico/toxicidade , Soroalbumina Bovina/química , Relação Estrutura-Atividade
13.
Anticancer Res ; 41(5): 2287-2296, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952454

RESUMO

BACKGROUND/AIM: Indoleamine 2,3-dioxygenase (IDO) is regarded as an important molecular target for cancer immune therapy. This study aimed to examine the IDO1 inhibitory activity of newly synthesized indomethacin derivatives to develop an IDO1 inhibitor. MATERIALS AND METHODS: The inhibitory effects of indole-containing compounds against recombinant human IDO1 (rhIDO1) were evaluated. RESULTS: While some drugs including those with an indole scaffold could inhibit rhIDO1, simple indole compounds were inactive. A total of 27 indomethacin derivatives, including 18 newly synthesized derivatives, were evaluated. Numerous derivatives showed enhanced IDO1 inhibitory activity. The functional group at the 3-position had a strong effect on IDO1 inhibitory activity. The IDO1 inhibitory activity was not directly correlated with tumor cell cytotoxicity. CONCLUSION: We report the finding of novel IDO1 inhibitors and the structure-activity relationship based on indomethacin derivatives. Our findings will be beneficial for the development of IDO1 inhibitors for cancer immune therapy.


Assuntos
Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indometacina/farmacologia , Relação Estrutura-Atividade , Biocatálise/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indometacina/química , Espectroscopia de Ressonância Magnética/métodos , Estrutura Molecular
14.
Int J Biol Macromol ; 183: 718-726, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-33930447

RESUMO

This work demonstrates a facile pathway to develop a biopolymer based amphiphilic macromolecule through reversible addition-fragmentation chain transfer (RAFT) polymerization, using dextran (a biopolymer) as starting material. Also, a new hydrophobic monomer [2-methyl-acrylic acid 1-benzyl-1H-[1,2,3] triazol-4-ylmethyl ester (MABTE)] has been synthesized using methacrylic acid via "click" approach. The resultant copolymer displays controlled radical polymerization characteristics: narrow polydispersity (Ð) and controlled molecular weight as obtained through advanced polymer chromatography (APC) analysis. In aqueous solution, the copolymer can proficiently be self-assembled to provide micellar structure, which has been evidenced from field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM) analyses. The in-vitro cytotoxicity study illustrates the nontoxic nature of the copolymer up to 100 µg/mL polymer concentration. The copolymer has been found to be worthy as an efficient carrier for the sustained release of hydrophobic drug: Indomethacin (IND).


Assuntos
Materiais Biocompatíveis/síntese química , Dextranos/química , Indometacina/farmacologia , Materiais Biocompatíveis/química , Química Click , Preparações de Ação Retardada , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Indometacina/química , Metacrilatos/química , Micelas , Peso Molecular , Polimerização
15.
Viruses ; 13(4)2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810356

RESUMO

The 2019 coronavirus infectious disease (COVID-19) is caused by infection with the new severe acute respiratory syndrome coronavirus (SARS-CoV-2). Currently, the treatment options for COVID-19 are limited. The purpose of the experiments presented here was to investigate the effectiveness of ketotifen, naproxen and indomethacin, alone or in combination, in reducing SARS-CoV-2 replication. In addition, the cytotoxicity of the drugs was evaluated. The findings showed that the combination of ketotifen with indomethacin (SJP-002C) or naproxen both reduce viral yield. Compared to ketotifen alone (60% inhibition at EC50), an increase in percentage inhibition of SARS-CoV-2 to 79%, 83% and 93% was found when co-administered with 25, 50 and 100 µM indomethacin, respectively. Compared to ketotifen alone, an increase in percentage inhibition of SARS-CoV-2 to 68%, 68% and 92% was found when co-administered with 25, 50 and 100 µM naproxen, respectively. For both drug combinations the observations suggest an additive or synergistic effect, compared to administering the drugs alone. No cytotoxic effects were observed for the administered dosages of ketotifen, naproxen, and indomethacin. Further research is warranted to investigate the efficacy of the combination of ketotifen with indomethacin (SJP-002C) or naproxen in the treatment of SARS-CoV-2 infection in humans.


Assuntos
Antivirais/farmacologia , COVID-19/virologia , Indometacina/farmacologia , Cetotifeno/farmacologia , Naproxeno/farmacologia , SARS-CoV-2/efeitos dos fármacos , COVID-19/tratamento farmacológico , Efeito Citopatogênico Viral/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , SARS-CoV-2/genética , SARS-CoV-2/fisiologia
16.
Molecules ; 26(4)2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33672078

RESUMO

The development of controlled drug delivery systems based on bio-renewable materials is an emerging strategy. In this work, a controlled drug delivery system based on mesoporous oxidized cellulose beads (OCBs) was successfully developed by a facile and green method. The introduction of the carboxyl groups mediated by the TEMPO(2,2,6,6-tetramethylpiperidine-1-oxyradical)/NaClO/NaClO2 system presents the pH-responsive ability to cellulose beads, which can retain the drug in beads at pH = 1.2 and release at pH = 7.0. The release rate can be controlled by simply adjusting the degree of oxidation to achieve drug release at different locations and periods. A higher degree of oxidation corresponds to a faster release rate, which is attributed to a higher degree of re-swelling and higher hydrophilicity of OCBs. The zero-order release kinetics of the model drugs from the OCBs suggested a constant drug release rate, which is conducive to maintaining blood drug concentration, reducing side effects and administration frequency. At the same time, the effects of different model drugs and different drug-loading solvents on the release behavior and the physical state of the drugs loaded in the beads were studied. In summary, the pH-responsive oxidized cellulose beads with good biocompatibility, low cost, and adjustable release rate have shown great potential in the field of controlled drug release.


Assuntos
Celulose Oxidada/química , Óxidos N-Cíclicos/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Trato Gastrointestinal/fisiologia , Varredura Diferencial de Calorimetria , Liberação Controlada de Fármacos , Fenofibrato/farmacologia , Concentração de Íons de Hidrogênio , Indometacina/farmacologia , Cinética , Pós , Difração de Raios X
17.
J Ethnopharmacol ; 274: 114028, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-33775807

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Osteoarthritis (OA), a degenerative joint disease, is characterized by cartilage erosion and matrix degradation. Solanum xanthocarpum Schrad. & Wendl. fruits (SXF) and leaves have long been used as folk remedy in the treatment of pain in rheumatism. AIM OF THE STUDY: This study was aimed to investigate the phytochemical components and protective benefits of SXF on in vitro chondrocytes proliferation, and in vivo suppression of collagenase-induced OA. MATERIALS AND METHODS: Phytochemical components in ethanolic SXF extract were evaluated using gas chromatography-mass spectrometry (GC-MS). Effect of SXF on in vitro cell proliferation of primary chondrocytes was determined by cell proliferation assay and cell cycle analysis by flow cytometry. OA was induced in the right knees of rats through intra-articular injection of collagenase type-II. To evaluate in vivo preventive function of SXF, body weight, blood ALP, histopathological changes in the knee joint, proteoglycan, and collagen content were determined. The mRNA expression of COL-2, MMP-3 and COX-2 genes through qRT-PCR was studied. Antioxidant activities, total phenolics and flavonoid contents of SXF were also examined. RESULTS: GC-MS analysis revealed that SXF constitutes 28 phytochemicals including flavonoids (3-methoxy apigenin, quercetin, luteolin), tannin (quinic acid), terpenes (oleanolic acid, lupeol, psi.psi carotene), phytosterols (campesterol, stigmasterol, ß-sitosterol), and ascorbic acid. In vitro studies demonstrated that SXF enhanced the cell proliferation in a dose-dependent manner and has no cytotoxic effect on primary chondrocytes. In vivo study suggests that SXF protects the cartilage destruction induced by collagenase. The histological study revealed that SXF restored the synthesis of collagen and proteoglycan, vital factors for cartilage restoration, and reduced the arthritic score. An up-regulation in COL-2 expression and suppression of MMP-3 and COX-2 were detected by qRT-PCR analysis. Thus, in vivo study suggests the protective effects of SXF on cartilage destruction induced by collagenase. CONCLUSIONS: Our results imply that SXF benefits and ameliorates OA by enhancing the chondrocytes proliferation and preventing the articular cartilage damage through the restoration of their structural molecules, arthritic score reduction, suppression of MMP-3 and COX-2 expression level and up regulation of COL-2 genes expression. These results suggest that SXF could be a promising alternative treatment candidate for osteoarthritis.


Assuntos
Cartilagem Articular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Solanum/química , Administração Oral , Fosfatase Alcalina/sangue , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Peso Corporal/efeitos dos fármacos , Cartilagem Articular/lesões , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo II/metabolismo , Colagenases/toxicidade , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Flavonoides/análise , Sequestradores de Radicais Livres/administração & dosagem , Sequestradores de Radicais Livres/farmacologia , Frutas/química , Indometacina/farmacologia , Metaloproteinase 3 da Matriz/metabolismo , Osteoartrite/induzido quimicamente , Fenóis/análise , Extratos Vegetais/administração & dosagem , Cultura Primária de Células , Substâncias Protetoras/administração & dosagem , Proteoglicanas/metabolismo , Ratos Sprague-Dawley
18.
Bull Exp Biol Med ; 170(4): 440-443, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33725241

RESUMO

The anti-inflammatory effect of the ester derivative of indomethacin (IML) in doses of 6.25, 12.5, and 25 mg/kg was studied in rats with modeled rheumatoid arthritis (adjuvant arthritis) and compared to the effects of the reference drug indomethacin in a dose of 1 mg/kg. IML in doses of 12.5 and 25 mg/kg reduced joint inflammation and promoted recovery of the microstructure of the synovial membrane and articular cartilage better than indomethacin. IML produced no ulcerogenic effect, while indomethacin concentration in the stomach wall after administration of IML was 1.8-3.4 times lower than after administration of the reference drug (p<0.05).


Assuntos
Artrite Experimental/tratamento farmacológico , Indometacina/farmacologia , Indometacina/uso terapêutico , Inflamação/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Experimental/metabolismo , Inflamação/metabolismo , Masculino , Ratos , Ratos Wistar , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo
19.
PLoS One ; 16(1): e0245995, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33507971

RESUMO

Non-steroidal anti-inflammatory drugs (NSAIDs) induce small intestinal damage. It has been reported that rebamipide, a mucoprotective drug, exerts a protective effect against NSAID-induced small intestinal damage; however, the underlying mechanism remains unknown. In this study, we investigated the significance of the small intestinal microbiota in the protective effect of rebamipide against indomethacin-induced small intestinal damage in mice. A comprehensive analysis of the 16S rRNA gene sequencing revealed an alteration in the composition of the small intestinal microbiota at the species level, modulated by the administration of rebamipide and omeprazole. The transplantation of the small intestinal microbiota of the mice treated with rebamipide suppressed the indomethacin-induced small intestinal damage. Omeprazole, a proton pump inhibitor, exacerbated the indomethacin-induced small intestinal damage, which was accompanied by the alteration of the small intestinal microbiota. We found that the transplantation of the small intestinal microbiota of the rebamipide-treated mice ameliorated indomethacin-induced small intestinal damage and the omeprazole-induced exacerbation of the damage. These results suggest that rebamipide exerts a protective effect against NSAID-induced small intestinal damage via the modulation of the small intestinal microbiota, and that its ameliorating effect extends also to the exacerbation of NSAID-induced small intestinal damage by proton pump inhibitors.


Assuntos
Alanina/análogos & derivados , Antiulcerosos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Indometacina/farmacologia , Intestino Delgado/efeitos dos fármacos , Inibidores da Bomba de Prótons/farmacologia , Quinolonas/uso terapêutico , Alanina/uso terapêutico , Animais , Mucosa Intestinal/efeitos dos fármacos , Masculino , Camundongos
20.
Life Sci ; 265: 118742, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33181176

RESUMO

Rheumatoid arthritis is an autoimmune inflammatory disease with progressive degradation of cartilage and joints. Additionally, gastric ulcer affects many patients who make prolonged use of non-steroidal anti-inflammatory drugs widely used in the symptomatic treatment of rheumatoid arthritis. Nerolidol, a natural sesquiterpene, has several biological activities including anti-inflammatory and antiulcerogenic action. This study aims to develop and characterize a nerolidol ß-cyclodextrin inclusion complex and to evaluate its activity in an experimental arthritis model. Inclusion complex was prepared by the lyophilization method and characterized by NMR, term analysis, XRD and SEM. Neutrophil migration assays and histopathological analysis were performed on zymosan-induced arthritis model using Swiss mice. And the gastroprotective effect was evaluated in two models of gastric ulcers: induced by ethanol and indomethacin. Inclusion complex showed no cytotoxicity and free nerolidol at a dose of 100 mg/kg (p.o.) in the arthritis model reduced neutrophil migration in 56% in relation to vehicle, and this inhibition was more expressive in the inclusion complex (67%) at the same dose. Histopathological analysis of the joint tissue confirmed the reduction of inflammatory signs. In the ethanol-induced gastric ulcer model, free nerolidol reduced the relative ulcer area more expressively (4.64%) than the inclusion complex (21.3%). However, in the indomethacin induction model, the inclusion complex showed better results in gastric protection compared to free nerolidol. The action of nerolidol complexed in beta-cyclodextrin in reducing arthritis inflammation combined with its gastroprotective action make it a potential new drug.


Assuntos
Artrite/tratamento farmacológico , Sesquiterpenos/farmacologia , beta-Ciclodextrinas/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antiulcerosos/farmacologia , Artrite Experimental/tratamento farmacológico , Linhagem Celular , Mucosa Gástrica/metabolismo , Indometacina/farmacologia , Masculino , Camundongos , Extratos Vegetais/farmacologia , Estômago/patologia , Úlcera Gástrica/induzido quimicamente
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