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1.
Drug Dev Res ; 85(5): e22231, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38956926

RESUMO

The close association between inflammation and cancer inspired the synthesis of a series of 1,3,4-oxadiazole derivatives (compounds H4-A-F) of 6-methoxynaphtalene. The chemical structures of the new compounds were validated utilizing Fourier-transform infrared, proton nuclear magnetic resonance, and carbon-13 nuclear magnetic resonance spectroscopic techniques and CHN analysis. Computer-aided drug design methods were used to predict the compounds biological target, ADMET properties, toxicity, and to evaluate the molecular similarities between the design compounds and erlotinib, a standard epidermal growth factor receptor (EGFR) inhibitor. The antiproliferative effects of the new compounds were evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, cell cycle analysis, apoptosis detection by microscopy, quantitative reverse transcription-polymerase chain reaction, and immunoblotting, and EGFR enzyme inhibition assay. In silico analysis of the new oxadiazole derivatives indicated that these compounds target EGFR, and that compounds H4-A, H4-B, H4-C, and H4-E show similar molecular properties to erlotinib. Additionally, the results indicated that none of the synthesized compounds are carcinogenic, and that compounds H4-A, H4-C, and H4-F are nontoxic. Compound H4-A showed the best-fit score against EGFR pharmacophore model, however, the in vitro studies indicated that compound H4-C was the most cytotoxic. Compound H4-C caused cytotoxicity in HCT-116 colorectal cancer cells by inducing both apoptosis and necrosis. Furthermore, compounds H4-D, H4-C, and H4-B had potent inhibitory effect on EGFR tyrosine kinase that was comparable to erlotinib. The findings of this inquiry offer a basis for further investigation into the differences between the synthesized compounds and erlotinib. However, additional testing will be needed to assess all of these differences and to identify the most promising compound for further research.


Assuntos
Antineoplásicos , Receptores ErbB , Simulação de Acoplamento Molecular , Naproxeno , Oxidiazóis , Receptores ErbB/antagonistas & inibidores , Humanos , Oxidiazóis/farmacologia , Oxidiazóis/química , Oxidiazóis/síntese química , Naproxeno/farmacologia , Naproxeno/análogos & derivados , Naproxeno/química , Naproxeno/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Proliferação de Células/efeitos dos fármacos
2.
Molecules ; 26(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34443379

RESUMO

Herein, we review the recent progress in the synthesis of representative nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen and naproxen. Although these drugs were discovered over 50 years ago, novel practical and asymmetric approaches are still being developed for their synthesis. In addition, this endeavor has enabled access to more potent and selective derivatives from the key frameworks of ibuprofen and naproxen. The development of a synthetic route to ibuprofen and naproxen over the last 10 years is summarized, including developing methodologies, finding novel synthetic routes, and applying continuous-flow chemistry.


Assuntos
Ibuprofeno/síntese química , Naproxeno/síntese química , Eletroquímica , Humanos , Hidrogenação , Ibuprofeno/química , Naproxeno/química , Oxirredução , Estereoisomerismo
3.
Molecules ; 26(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071240

RESUMO

The synthesis of naproxen-containing diaryliodonium salts has been realized from naproxen methyl ester and ArI(OH)OTs activated by trimethylsilyl trifluoromethanesulfonate (TMSOTf) in a solvent mixture comprising dichloromethane and 2,2,2-trifluoroethanol (TFE). Those iodonium salts have been successfully used in the functionalization of an aromatic ring of naproxen methyl ester, including fluorination, iodination, alkynylation, arylation, thiophenolation, and amination and esterification reactions. Moreover, further hydrolysis of the obtained 5-iodo-naproxen methyl ester afforded 5-iodo-naproxen.


Assuntos
Ésteres/química , Naproxeno/síntese química , Sais/química , Catálise , Química Farmacêutica/métodos , Esterificação , Flúor/química , Halogenação , Hidrólise , Iodo/química , Lipase/metabolismo , Espectroscopia de Ressonância Magnética , Fenóis/química , Solventes , Estereoisomerismo , Trifluoretanol/química , Difração de Raios X
4.
AAPS PharmSciTech ; 22(3): 85, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33650023

RESUMO

In this study, an attempt was made to produce Liqui-Tablets for the first time. This was carried out through the compaction of naproxen Liqui-Pellets. The incentive to convert the novel Liqui-Pellet into Liqui-Tablet was due to the array of inherent advantages of the popular and preferred tablet dosage form. The study showed that naproxen Liqui-Tablet could be successfully produced and the rapid drug release rate (100% drug release ~ 20 min) could be achieved under pH 1.2, where naproxen is insoluble. It was observed that the different pH of the dissolution medium affected the trend of drug release from formulations with varying amounts of liquid vehicle. The order of the fastest drug-releasing formulations was different depending on the pH used. The presence of Neusilin US2 showed considerable enhancement in the drug release rate as well as improving Liqui-Tablet robustness and hardness. Furthermore, images from X-ray micro-tomography displayed a uniform distribution of components in the Liqui-Tablet. The accelerated stability studies showed acceptable stability in terms of dissolution profile.


Assuntos
Composição de Medicamentos/métodos , Naproxeno/administração & dosagem , Naproxeno/síntese química , Tecnologia Farmacêutica/métodos , Administração Oral , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacocinética , Formas de Dosagem , Liberação Controlada de Fármacos , Excipientes/administração & dosagem , Excipientes/síntese química , Excipientes/farmacocinética , Naproxeno/farmacocinética , Comprimidos
5.
Molecules ; 25(15)2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-32731527

RESUMO

A flexible two-step, one-pot procedure was developed to synthesize 2-aryl propionic acids including the anti-inflammatory drugs naproxen and flurbiprofen. Optimal results were obtained in the presence of the novel ligand neoisopinocampheyldiphenylphosphine (NISPCPP) (9) which enabled the efficient sequential palladium-catalyzed Heck coupling of aryl bromides with ethylene and hydroxycarbonylation of the resulting styrenes to 2-aryl propionic acids. This cascade transformation leads with high regioselectivity to the desired products in good yields and avoids the need for additional purification steps.


Assuntos
Flurbiprofeno , Naproxeno , Paládio/química , Catálise , Flurbiprofeno/síntese química , Flurbiprofeno/química , Naproxeno/síntese química , Naproxeno/química
6.
Daru ; 28(2): 567-579, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32757155

RESUMO

AIM: Liqui-Pellet is potentially an emerging next-generation oral pill, which has shown promising results with unique advantages as well as displaying potential for commercial feasibility. Since Liqui-Pellet technology is still in its infancy, it is important to explore the parameters that can affect its performance, particularly the drug release rate. Therefore, the aim of this study is to investigate thoroughly the effect of Avicel PH101 (carrier) and Aerosil 300 (coating material) ratio (R-value) in Liqui-Pellet. METHODS: Key parameter for Liqui-Pellet formulation in this study was the ratio of carrier and coating material. Tests were carried out to assess the physicochemical properties of different formulations. This involved looking into particle size, robustness, flowability, solid-state and drug release profile. The morphology of Liqui-Pellet was investigated by SEM. RESULTS: It is found that R-value does not have a major effect on the success of Liqui-Pellet production. However, R-value does seem to have an effect on Liqui-Pellet size at a certain water content level and a slight effect on the drug release rate. A decrease in Avicel PH101 concentration and an increase in Aerosil 300 concentration in Liqui-Pellet formulations can reduce Liqui-Pellet size and slightly increase drug release rate by 9% after 2 h. The data shows Liqui-Pellet is resistant to friability, able to achieve exceptional flow property and have smooth surfaces, which is critical for applying coatings technology. Such properties are ideal in terms of commercial manufacturing. The XRPD and DSC both show the reduction in formulation crystallinity, which is expected in Liqui-Pellet formulation as a result of solubility of the drug in the co-solvent used in the preparation of Liqui-Pellets. CONCLUSION: Overall it seems that R-value can affect Liqui-Pellet drug release rate and size but not on the production success rate.


Assuntos
Celulose/química , Naproxeno/síntese química , Dióxido de Silício/química , Varredura Diferencial de Calorimetria , Composição de Medicamentos , Implantes de Medicamento , Microscopia Eletrônica de Varredura , Naproxeno/química , Tamanho da Partícula , Difração de Pó , Solubilidade , Difração de Raios X
7.
Bioorg Chem ; 100: 103892, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32388433

RESUMO

A new series of 1,2,4-triazole-5-thione Mannich derivatives containing a naproxen moiety (1a-o) was designed and synthesized to create naproxen analogs, with the aim of developing novel anti-inflammatory/analgesic agents with improved safety profiles. Target compounds were synthesized using classical Mannich reaction (i.e. one-pot three component condensation reaction), by reacting triazole molecule (1), formaldehyde, and diverse secondary amines in ethanol. The synthesized compounds were investigated using FT-IR, 1H NMR, 13C NMR and mass spectroscopies, as well as elemental analysis. Compounds were then evaluated for their potential antinociceptive and anti-inflammatory activities using some validated invivo methods. Data obtained from acetic acid induced-writhing and carrageenan-induced paw edema tests revealed that all compounds induced peripherally-mediated antinociceptive activities, as well as notable anti-inflammatory effects. The results of hot-plate and tail-clip tests indicated that compounds 1a, 1b, 1c, 1d, 1g, and 1j have also centrally-mediated antinociceptive activities in addition to their peripherally-mediated effects. Molecular docking studies were performed to investigate the putative binding modes of the interactions between all compounds and COX-1/COX-2 enzymes using AutoDock Vina software. Docking of the compounds into the COX-2 active site produced binding interactions that are essential for COX-2 inhibitory activity. None of the compounds in the serial, except for 1m and 1j, induced significant gastrointestinal irritation. Overall, the results indicated that triazol Mannich bases bearing a naproxen moiety potentially represent a novel class of antinociceptive and anti-inflammatory agent with an improved gastric safety profile.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Edema/tratamento farmacológico , Naproxeno/uso terapêutico , Dor/tratamento farmacológico , Triazóis/uso terapêutico , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Ciclo-Oxigenase 2/metabolismo , Desenho de Fármacos , Edema/metabolismo , Humanos , Masculino , Bases de Mannich , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Naproxeno/análogos & derivados , Naproxeno/síntese química , Dor/metabolismo , Triazóis/síntese química , Triazóis/química
8.
Macromol Biosci ; 20(7): e2000002, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32421256

RESUMO

Recent studies have demonstrated in vivo synergistic immunosuppressive and anti-inflammatory capacity of dexamethasone (Dx) and naproxen (NAP) in collagen-induced arthritis (CIA) rats. However, the molecular basis of this synergistic effect is barely understood. The low solubility of these drugs and their adverse effects hamper their efficacy on the treatment of inflammatory processes making nanoparticulated systems promising candidates to overcome these drawbacks. The aim of this work is the preparation of polymeric nanoparticles (NPs) that combine NAP and Dx in different concentrations, and the evaluation of the expression of key genes related to autoimmune diseases like CIA. To do so, self-assembled polymeric NPs that incorporate covalently-linked NAP and physically entrapped Dx are designed to have hydrodynamic properties that, according to bibliography, may improve retention and colocalization of both drugs at inflammation sites. The rapid uptake of NPs by macrophages is demonstrated using coumarine-6-loaded NPs. Dx is efficiently encapsulated and in vitro biological studies demonstrate that the Dx-loaded NAP-bearing NPs are noncytotoxic and reduce lipopolysaccharide-induced NO released levels at any of the tested concentrations. Moreover, at the molecular level, a significant synergistic reduction of Il12b transcript gene expression when combining Dx and NAP is demonstrated.


Assuntos
Dexametasona/farmacologia , Macrófagos/metabolismo , Nanopartículas/química , Naproxeno/farmacologia , Polímeros/química , Inibidores da Angiogênese/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Morte Celular/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Hidrodinâmica , Interações Hidrofóbicas e Hidrofílicas , Subunidade p40 da Interleucina-12 , Macrófagos/efeitos dos fármacos , Camundongos , Peso Molecular , Nanopartículas/toxicidade , Nanopartículas/ultraestrutura , Naproxeno/síntese química , Naproxeno/química , Óxido Nítrico/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Células RAW 264.7
9.
Angew Chem Int Ed Engl ; 59(7): 2875-2880, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-31793137

RESUMO

We have demonstrated that small, modular, tetrameric peptides featuring the Lewis-basic residue ß-dimethylaminoalanine (Dmaa) are capable of atroposelectively coupling naphthols and ester-bearing quinones to yield non-C2 -symmetric BINOL-type scaffolds with good yields and enantioselectivity. The study culminates in the asymmetric synthesis of backbone-substituted scaffolds similar to 3,3'-disubstituted BINOLs, such as (R)-TRIP, with good (94:6 e.r.) to excellent (>99.9:0.1 e.r.) enantioselectivity after recrystallization, and a diastereoselective net arylation of the minimally modified nonsteroidal anti-inflammatory drug (NSAID) naproxen.


Assuntos
Anti-Inflamatórios/síntese química , Naftóis/síntese química , Naproxeno/síntese química , Peptídeos/química , Anti-Inflamatórios/química , Catálise , Estrutura Molecular , Naftóis/química , Naproxeno/química , Estereoisomerismo
10.
J Am Chem Soc ; 141(34): 13610-13618, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31373809

RESUMO

Hydrogen sulfide (H2S) is an important signaling molecule that provides protective activities in a variety of physiological and pathological processes. Among the different types of H2S donor compounds, thioamides have attracted attention due to prior conjugation to nonsteroidal anti-inflammatory drugs (NSAIDs) to access H2S-NSAID hybrids with significantly reduced toxicity, but the mechanism of H2S release from thioamides remains unclear. Herein, we reported the synthesis and evaluation of a class of thioamide-derived sulfenyl thiocarbamates (SulfenylTCMs) that function as a new class of H2S donors. These compounds are efficiently activated by cellular thiols to release carbonyl sulfide (COS), which is quickly converted to H2S by carbonic anhydrase (CA). In addition, through mechanistic investigations, we establish that COS-independent H2S release pathways are also operative. In contrast to the parent thioamide-based donors, the SulfenylTCMs exhibit excellent H2S releasing efficiencies of up to 90% and operate through mechanistically well-defined pathways. In addition, we demonstrate that the sulfenyl thiocarbamate group is readily attached to common NSAIDs, such as naproxen, to generate YZ-597 as an efficient H2S-NSAID hybrid, which we demonstrate releases H2S in cellular environments. Taken together, this new class of H2S donor motifs provides an important platform for new donor development.


Assuntos
Sulfeto de Hidrogênio/administração & dosagem , Compostos de Sulfidrila/metabolismo , Óxidos de Enxofre/administração & dosagem , Tiocarbamatos/síntese química , Tiocarbamatos/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Anidrases Carbônicas/metabolismo , Ciclização , Células HeLa , Humanos , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/metabolismo , Naproxeno/análogos & derivados , Naproxeno/síntese química , Naproxeno/farmacologia , Óxidos de Enxofre/química , Óxidos de Enxofre/metabolismo , Tiocarbamatos/química
11.
Drug Des Devel Ther ; 13: 1773-1790, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213767

RESUMO

Background and aim: Naproxen is a member of the Nonsteroidal anti-inflammatory drugs (NSAIDs). This work aimed to synthesize a safe NSAID agent based on a peptide derivative. Methods: The structure of compounds 5-20 was established on the basis of spectral data. Frontier molecular orbitals and chemical reactivity were discussed to clarify inter- and intramolecular interactions among tested compounds. We applied competitive molecular docking using polynomial logarithms to identify the most accurate algorithm for pharmacological activity prediction for the tested compounds. The docking protocol with the lowest RMSD was selected for analyzing binding affinity. Results: Docking results illustrated that the binding interaction increased after introduction of an acidic fragment to the parent compound. These compounds were selected for additional study against adsorption, distribution, metabolism, excretion, and toxicity (ADMET) in silico. The compounds tested had good oral bioavailability without any carcinogenesis effect; no marked health effects were observed via rodent toxicity. Compounds passed through docking and ADMET profiles for them (5-16) were examined as anti-inflammatory and analgesic agents. Compounds 8 and 16 showed higher anti-inflammatory potency than the reference drug and tested compounds. Compounds 8, 10, and 14 exhibited the highest analgesic potency compared to the other tested compounds. Conclusion: The tested compounds have shown negligible ulcerogenic effects, and may be considered safer drugs than naproxen for treating inflammatory conditions.


Assuntos
Aminoácidos/química , Analgésicos/síntese química , Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Simulação de Acoplamento Molecular , Naproxeno/análogos & derivados , Naproxeno/farmacologia , Aminoácidos/farmacologia , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/química , Carragenina , Edema/induzido quimicamente , Edema/tratamento farmacológico , Estrutura Molecular , Naproxeno/síntese química , Naproxeno/química , Ratos , Ratos Wistar
12.
Biomed Pharmacother ; 116: 109024, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31150990

RESUMO

This work aimed to design and synthesize a safe nonsteroidal anti-inflammatory drug NSAIDs agent based on Naproxen scaffold. The structure of compounds 6-21 established on the basis of different spectral data. Anti-inflammatory and analgesic profile were examined for synthesizing compounds. The compounds 6 and 17 have shown a higher anti-inflammatory potency than Naproxen. The compounds 16, 19 and 21 have exhibited the highest analgesic potency compared to other tested compounds. The synthesized compounds have shown negligible ulcerogenic effect and may be considered as safer drugs than naproxen for treating inflammatory conditions. The molecular docking against COX-2 was performed, it verified that compound 6, 17 show stronger interactions with COX-2. This may result in a better inhibitory effect on COX-2. The best generated QSAR model shows correlation between BCUT_SMR_3 and vsurf_Wp6 with biological activity. ADMET in silico showed that these compounds are a good oral bioavailability without observed carcinogenesis affect.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Desenho de Fármacos , Simulação de Acoplamento Molecular , Naproxeno/síntese química , Naproxeno/farmacologia , Relação Quantitativa Estrutura-Atividade , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/química , Ligantes , Naproxeno/química , Naproxeno/farmacocinética , Ratos
13.
Bioorg Chem ; 85: 577-584, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30878890

RESUMO

A series of novel naproxen analogues containing 3-aryl-1,2,4-oxadiazoles moiety (4b-g) and their reaction intermediates aryl carboximidamides moiety (3b-g) was synthesized and evaluated in vitro as dual COXs/15-LOX inhibitors. Compounds 3b-g exhibited superior inhibitory activity than celecoxib as COX-2 inhibitors. Compounds 3b-d and 3g were the most potent COX-2 inhibitors with IC50 range of 6.4 - 8.13 nM and higher selectivity indexes (3b, SI = 26.19; 3c, SI = 13.73; 3d, SI = 29.27; 3g, SI = 18.00) comparing to celecoxib (IC50 = 42.60 nM, SI = 8.05). Regarding 15-LOX inhibitory activity, compounds belonging to aryl carboximidamide backbone 3b-e and 3g were the most potent with IC50 range of 1.77-4.91 nM comparing to meclofenamate sodium (IC50 = 5.64 µM). Data revealed that The levels of NO released by aryl carboximidamides 3b-g were more higher than 3-aryl-1,2,4-oxadiazole derivatives 4b-g, which correlated well with their COX-2 inhibitory activities.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Lipoxigenase/farmacologia , Naproxeno/análogos & derivados , Naproxeno/farmacologia , Oxidiazóis/farmacologia , Animais , Bovinos , Celecoxib/farmacologia , Inibidores de Ciclo-Oxigenase 2/síntese química , Desenho de Fármacos , Humanos , Inibidores de Lipoxigenase/síntese química , Linfócitos/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Naproxeno/síntese química , Doadores de Óxido Nítrico/síntese química , Doadores de Óxido Nítrico/farmacologia , Oxidiazóis/síntese química , Glycine max/enzimologia
14.
J Mater Chem B ; 7(3): 469-476, 2019 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-32254734

RESUMO

Herein, we report supramolecular hydrogelators made of forky peptides and nonsteroidal anti-inflammatory drugs (NSAID). Two zinc ions (ZIs)-responsive short peptide dendrons (E3FID and E3FNP) modified by NSAID (indometacinand naproxen) were designed and synthesized successfully. These novel small molecule hydrogelators can self-assemble in water to form stable supramolecular nanofibers/hydrogels. The formation of these supramolecular hydrogels can be triggered by zinc ions, which are highly concentrated in prostate tissue. The anticancer drug docetaxel (DTX) was employed as chemotherapeutic and loaded into the hydrogels to construct a novel drug delivery system for prostate cancer therapy. This approach is anticipated realizing the sustained release of antitumour drugs into the prostate and cancer associated pain relief, simultaneously. The E3FID hydrogel and E3FNP hydrogel have excellent biocompatibility and viscoelastic properties as a promising drug delivery materials. The result of drugs release in vitro indicated that DTX was released slowly following a non-Fickian diffusion mechanism. In addition, the results of the in vitro cytotoxicity assay demonstrated that these DTX-loaded hydrogels exhibited dose-dependent cytotoxicity to both DU-145 cells and PC-3 cells, in particular, the drug-loaded hydrogel of E3FID had better anticancer efficacy. As a drug delivery strategy, the system realizes better anticancer efficacy, excellent sustained-release and relief of cancer pain, simultaneously, the most important being that the DDS facilitates local delivery of drug to the prostate.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Hidrogéis/farmacologia , Peptídeos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrogéis/síntese química , Hidrogéis/química , Indometacina/síntese química , Indometacina/química , Indometacina/farmacologia , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/química , Substâncias Macromoleculares/farmacologia , Masculino , Naproxeno/síntese química , Naproxeno/química , Naproxeno/farmacologia , Tamanho da Partícula , Peptídeos/síntese química , Peptídeos/química , Neoplasias da Próstata/patologia , Reologia , Propriedades de Superfície
15.
Bioorg Chem ; 83: 29-46, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30339862

RESUMO

Current study is based on the biology-oriented drug synthesis (BIODS) of S-naproxen (NSAID) derivatives and the evaluation of their urease inhibitory potential. In this regard, a variety of S-naproxen derivatives 2-39 including hydrazide 1, Schiff bases 2-21, aroyl substituted hydrazides 22-24, sulfohydrazides 25-34, 2-mercapto oxadiazole 35, phenacyl substituted 2-mercapto oxadiazoles 36-39 were synthesized under the umbrella of BIODS by simple chemical transformation of its pharmacophoric carboxylic group. Compounds 1-39 were evaluated for in vitro urease inhibitory activity and most of them showed good to moderate inhibitory potential in the range of IC50 = 14.01 ±â€¯0.23-76.43 ±â€¯0.8 µM as compared to standard acetohydroxamic acid (IC50 = 27.0 ±â€¯0.5 µM). Limited structure-activity relationship (SAR) was established in order to rationalize the participation of varying groups (R) in the inhibitory potential of compounds. Molecular docking study on all active compounds was also carried out to decipher the interactions detail of the ligand with the receptors of active site of enzyme.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores Enzimáticos/farmacologia , Naproxeno/farmacologia , Urease/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Naproxeno/síntese química , Naproxeno/química , Relação Estrutura-Atividade , Urease/metabolismo
16.
Spectrochim Acta A Mol Biomol Spectrosc ; 207: 132-142, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30223247

RESUMO

The conformational study on the new S­nitrosothiols esters (SNO-ESTERS): para-substituted (X = H, OMe, Cl and NO2) S­nitrosothiol derivatives 2­methyl­2­(sulfanyl)propyl phenylacetates (R1), 2­(4­isobutylphenyl)propanoate (ibuprofen, R2), and 2­(4­isobutylphenyl)propanoate of 2­methyl­2­(nitrososulfanyl)propyl (naproxen, R3) was performed using infrared spectroscopy (IR) in solvents with increasing polarity (CCl4, CH3Cl, and CH3CN), and theoretical calculations, to determine the preferential conformer and the potential of these compounds to release nitric oxide (NO). S­Nitrosothiols were synthesized by esterification reactions, using chlorides of the corresponding carboxylic acids, with good yields (~60%). IR results showed that these compounds presented only one conformation, and the experimental data were supported by the theoretical results obtained by density functional theory (DFT) calculations using the 6311+G (2df, 2p) basis set. The calculations revealed that all S­nitrosothiols presented one preferential anticlinal (ac) geometric conformation, which agrees with the data obtained experimentally in CCl4. These conformers are stabilized by intramolecular hydrogen bonds. Examination of the geometry with regard to the RSNO group revealed that these compounds are preferentially in the trans (anti) conformation. The calculation of the orbital interactions using the Natural Bond Orbital (NBO) method showed that the nO(NO) → σ(SN)∗ hyper-conjugative interaction increases the SN bond length. The strong nS → π(NO)∗ interaction and electronic delocalization induces a partial π character to the SN bond. The weak σSN bond indicates strong delocalization of the electron pair in O (NO) by the nO(NO) → σ(SN)∗ interaction, thereby increasing the capacity of NO release from SNO-ESTERS.


Assuntos
Ibuprofeno/análogos & derivados , Naproxeno/análogos & derivados , Doadores de Óxido Nítrico/química , S-Nitrosotióis/química , Elétrons , Esterificação , Ibuprofeno/síntese química , Modelos Moleculares , Conformação Molecular , Naproxeno/síntese química , Doadores de Óxido Nítrico/síntese química , Teoria Quântica , S-Nitrosotióis/síntese química , Espectrofotometria Infravermelho , Eletricidade Estática
17.
Chemosphere ; 218: 818-826, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30508800

RESUMO

This research advances the knowledge of the pharmaceutical removal interactions by biochar in synthetic and real urine through the use of reference adsorbents and adsorbate probes. Earlier work has combined biochar and urine for pharmaceutical removal, however, the interactions that influence adsorption are unknown. In this study, bamboo biochar and softwood biochar were chosen as the representative materials and the model pharmaceuticals were naproxen and paracetamol. To further investigate the physical-chemical interactions, two nonpolar adsorbates, para-xylene and dimethylnaphthalene, were tested. Graphite and anion exchange resin, were used to isolate van der Waals and electrostatic interactions, respectively. Experimental kinetic and equilibrium data were fit to multiple adsorption models where the pseudo-second order and Freundlich exhibited the best fit, respectively. The Freundlich and Langmuir parameters had similar trends showing that softwood had the highest adsorption capacity. The model parameters indicated higher selectivity for nonpolar para-xylene and dimethylnaphthalene by graphite and polar paracetamol and naproxen by softwood biochar. The decreasing trend of importance of key interactions for pharmaceutical sorption to biochar are: van der Waals > hydrogen bonding > electrostatic interactions. No statistically significant difference was found between urine age (fresh vs. hydrolyzed) and pharmaceutical removal; however, the urine matrix (synthetic vs. synthetic with metabolites vs. real urine) did show a statistically significant difference on pharmaceutical removal where synthetic urine had comparatively greater adsorption. As constituents (i.e., metabolites) were added to urine matrices, reduced adsorption of pharmaceuticals was observed, indicating that adsorption processes should be tested in real urine for accuracy.


Assuntos
Carvão Vegetal/química , Preparações Farmacêuticas/isolamento & purificação , Urina/química , Acetaminofen/química , Acetaminofen/isolamento & purificação , Acetaminofen/urina , Adsorção , Cinética , Naproxeno/síntese química , Naproxeno/isolamento & purificação , Naproxeno/urina , Preparações Farmacêuticas/química , Preparações Farmacêuticas/urina , Poluentes Químicos da Água/análise
18.
Eur J Med Chem ; 158: 134-143, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30216848

RESUMO

A new series of non-carboxylic naproxen analogues, bearing a variety of ring systems, such as oxadiazoles 3a-c and 6a-c, cycloalkanes 4a-d, cyclic imides 5a-c, and triazoles 7-9 and 10a-c, was synthesized. In addition, in vitro antitumor activity and cyclooxygenase isozymes (COX-1/COX-2) inhibition assay of the target compounds 3-10 was studied. The results of the antitumor activity assays indicated that compounds 4b, 6c, 10b, and 10c exhibited the greatest antitumor activities against the tested cell lines MCF-7, MDA-231, HeLa, and HCT-116, with an IC50 range of 4.83-14.49 µM. By comparison, the reference drugs doxorubicin, afatinib, and celecoxib yielded IC50 values of 3.18-26.79, 6.20-11.40, and 22.79-42.74 µM, respectively. Furthermore, in vitro COX-1/COX-2 inhibition testing showed that the compounds 4b, 6c, 10b, and 10c exhibited effective COX-2 inhibition, with IC50 values of 0.40-1.20 µM, and selectivity index (SI) values of >62.50-20.83, using celecoxib as a reference drug (IC50 = 0.11 µM; COX-2 SI: >227.20). Compounds 6c and 10c, which were potent COX-2 inhibitors, were docked into the COX-2 binding site, where these compounds exhibited strong interactions.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Naproxeno/análogos & derivados , Naproxeno/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Naproxeno/síntese química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Relação Estrutura-Atividade
19.
IET Nanobiotechnol ; 12(6): 814-821, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30104456

RESUMO

Small molecule-based amphiphiles self-assemble into nanostructures (micelles) in aqueous medium which are currently being explored as novel drug delivery systems. Here, naproxen-polyethylene glycol (N-PEG), a small molecule-derived amphiphile, has been synthesised, characterised and evaluated as hydrophobic drug carrier. 1H, 13C Nuclear magnetic resonance (NMR), mass spectrometry (MS) and Fourier-transform infrared spectroscopy (FTIR) confirmed the formation of N-PEG and dynamic light scattering (DLS) revealed the formation of nano-sized structures of ∼228 nm. Transmission electron microscope (TEM) analysis showed aggregation behaviour of the structures with average size of ∼230 nm. Biodegradability aspect of the micellar-structured N-PEG was demonstrated by lipase-mediated degradation studies using DLS and TEM. High encapsulation efficiency followed by release in a sustained manner of a well-known anticancer drug, doxorubicin, demonstrated the feasibility of the new drug delivery system. These results advocate the promising potential of N-PEG micelles as efficient drug delivery system for specific delivery to cancerous cells in vitro and in vivo.


Assuntos
Portadores de Fármacos/síntese química , Portadores de Fármacos/farmacocinética , Nanoconchas/química , Naproxeno/química , Polietilenoglicóis/química , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Sistemas de Liberação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Liberação Controlada de Fármacos , Células HEK293 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Espectroscopia de Ressonância Magnética , Micelas , Nanoestruturas/química , Naproxeno/síntese química , Naproxeno/farmacocinética , Tamanho da Partícula , Polietilenoglicóis/síntese química , Polietilenoglicóis/farmacocinética , Espectroscopia de Infravermelho com Transformada de Fourier
20.
Biomed Pharmacother ; 101: 553-562, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29514128

RESUMO

The aim of this work was to design, synthesize and characterize the potential anti-nociceptive and anti-inflammatory activities of a new series of bioisosteres and hybrids from known non-steroidal anti-inflammatory drugs (NSAIDs). The compounds 4-(acetylamino)phenyl (2S)-2-(6-methoxy-2-naphthyl)propanoate (GUF-1) and 4-(acetylamino)phenyl 2-(R,S)-(4-isobutylphenyl)propanoate (GUF-2) were synthesized as hybrids (also known as heterodimers); whereas those named 2-(R,S)-(4-isobutylphenyl)-N-1H-tetrazol-5-ylpropanamide (GUF-3), (2S)-2-(6-methoxy-2-naphthyl)-N-1H-tetrazol-5-ylpropanamide (GUF-4), [2-(R,S)-N-hydroxy-2-[4-(2-methylpropyl)phenyl]propanamide] (GUF-5), and (2S)-N-hydroxy-2-(6-methoxy-2-naphthyl)propanamide (GUF-6) were synthesized as bioisosteres of the NSAIDs paracetamol, ibuprofen, and naproxen, respectively. All these compounds were characterized by spectroscopic and spectrometric analysis. Antinociceptive activity of GUF-1 to GUF-6 was evaluated using the formalin test in rats. Pharmacological responses of GUF-1, GUF-2 (hybrids), and GUF-5 (bioisostere) demonstrated significant antinociceptive effects; thus these compounds were assayed in an inflammation test like carrageenan-induced paw oedema in rats. Complete molecular docking of cyclooxygenase and the GUF-1 and GUF-2 hybrids showed high docking scores, compared to the reference drugs. Our data demonstrate that compounds GUF-1, GUF-2, and GUF-5 possesses antinociceptive and antiinflammatory activities resembling and improving those known for the traditional NSAIDs, paracetamol, naproxen and ibuprofen.


Assuntos
Acetaminofen/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Ibuprofeno/síntese química , Simulação de Acoplamento Molecular/métodos , Naproxeno/síntese química , Medição da Dor/efeitos dos fármacos , Acetaminofen/metabolismo , Acetaminofen/farmacologia , Animais , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Sítios de Ligação/fisiologia , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Ibuprofeno/metabolismo , Ibuprofeno/farmacologia , Imageamento Tridimensional/métodos , Naproxeno/metabolismo , Naproxeno/farmacologia , Medição da Dor/métodos , Ratos , Ratos Wistar
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