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1.
Molecules ; 26(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652837

RESUMO

In search of anti-inflammatory compounds, novel scaffolds containing isonicotinoyl motif were synthesized via an efficient strategy. The compounds were screened for their in vitro anti-inflammatory activity. Remarkably high activities were observed for isonicotinates 5-6 and 8a-8b. The compound 5 exhibits an exceptional IC50 value (1.42 ± 0.1 µg/mL) with 95.9% inhibition at 25 µg/mL, which is eight folds better than the standard drug ibuprofen (11.2 ± 1.9 µg/mL). To gain an insight into the mode of action of anti-inflammatory compounds, molecular docking studies were also performed. Decisively, further development and fine tuning of these isonicotinates based scaffolds for the treatment of various aberrations is still a wide-open field of research.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Inflamação/tratamento farmacológico , Ácidos Isonicotínicos/síntese química , Espécies Reativas de Oxigênio/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Humanos , Ibuprofeno/química , Ácidos Isonicotínicos/química , Ácidos Isonicotínicos/farmacologia , Simulação de Acoplamento Molecular , Espécies Reativas de Oxigênio/química , Relação Estrutura-Atividade
2.
Int J Mol Sci ; 21(24)2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33348757

RESUMO

The long-term use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in treatment of different chronic inflammatory disorders is strongly restricted by their serious gastrointestinal adverse effects. Therefore, there is still an urgent need to search for new, safe, and efficient anti-inflammatory agents. Previously, we have reported the Mannich base-type derivatives of pyrrolo[3,4-d]pyridazinone which strongly inhibit cyclooxygenase, have better affinity to COX-2 isoenzyme and exert promising anti-oxidant activity. These findings encouraged us to perform further optimization of that structure. Herein, we present the design, synthesis, molecular docking, spectroscopic, and biological studies of novel pyrrolo[3,4-d]pyridazinone derivatives bearing 4-aryl-1-(1-oxoethyl)piperazine pharmacophore 5a,b-6a,b. The new compounds were obtained via convenient, efficient, one-pot synthesis. According to in vitro evaluations, novel molecules exert no cytotoxicity and act as selective COX-2 inhibitors. These findings stay in good correlation with molecular modeling results, which additionally showed that investigated compounds take a position in the active site of COX-2 very similar to Meloxicam. Moreover, all derivatives reduce the increased level of reactive oxygen and nitrogen species and prevent DNA strand breaks caused by oxidative stress. Finally, performed spectroscopic and molecular docking studies demonstrated that new compound interactions with bovine serum albumin (BSA) are moderate, formation of complexes is in one-to-one ratio, and binding site II (subdomain IIIA) is favorable.


Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Bases de Mannich/química , Oxidiazóis/química , Piridazinas/farmacologia , Pirróis/farmacologia , Antioxidantes/síntese química , Domínio Catalítico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Feminino , Fibroblastos/metabolismo , Humanos , Concentração Inibidora 50 , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/química , Pirróis/síntese química , Pirróis/química , Soroalbumina Bovina/química , Relação Estrutura-Atividade
3.
Int J Nanomedicine ; 15: 5345-5360, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801693

RESUMO

Background: Soft corals have been endorsed as a plentiful source of bioactive compounds with promising anti-inflammatory activities; therefore, exploring their potential as source of anti-inflammatory metabolites has stimulated a growing research interest. Purpose: To investigate the anti-inflammatory potential of the soft coral, Nephthea sp., in its bulk and silver nanostructure. Metabolomics analysis of Nephthea sp., followed by molecular docking studies, was also conducted in order to explore and predict the secondary metabolites that might provide its inhibitory actions on inflammation. Materials and Methods: The petroleum ether and ethyl acetate fractions were used to synthesize silver nanoparticles. The prepared silver nanoparticles were characterized through UV-vis spectrophotometric, transmission electron microscopy (TEM) and Fourier-transform infrared spectroscopy (FTIR) analyses. Testing for the anti-inflammatory activity was performed against COX-1 and COX-2. Furthermore, liquid chromatography-mass spectrometry (LC-MS) based metabolomics analysis and molecular docking were also applied. Results: A variety of secondary metabolites were identified, among them, sesquiterpenes were found to prevail. The petroleum ether and acetone fractions of Nephthea sp. showed the highest COX-2 inhibitory activities, possibly attributable to their substantial contents of terpenoids. Additionally, the green synthesized silver nanoparticles of both the petroleum ether and ethyl acetate fractions of Nephthea sp. demonstrated higher anti-COX-2 properties. Conclusion: The obtained results showed the effectiveness of non-targeted metabolomics technique in metabolic profiling of Nephthea sp., helping the search for new bioactive metabolites in future chemical studies on this soft coral. The interesting anti-inflammatory potential of the tested extracts and their nanoparticles could also be relevant to the development of new, effective anti-inflammatory agents.


Assuntos
Antozoários/metabolismo , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Nanopartículas Metálicas/química , Prata/química , Alcanos/química , Animais , Antozoários/química , Anti-Inflamatórios/síntese química , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Química Verde , Humanos , Metabolômica , Simulação de Acoplamento Molecular , Metabolismo Secundário , Sesquiterpenos/análise , Espectrometria de Massas por Ionização por Electrospray , Espectroscopia de Infravermelho com Transformada de Fourier
4.
Adv Exp Med Biol ; 1195: 137-148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468468

RESUMO

In the present work a series of N'-arylidene-2-(benzamido)-3-(naphthalen-2-yl)acrylohydrazides were synthesized by refluxing the intermediate 2-(benzamido)-3-(naphthalen-2-yl)acrylohydrazide with various substituted benzaldehyde in the presence of glacial acetic acid. The intermediate 2-(benzamido)-3-(naphthalen-2-yl)acrylohydrazide 2 was prepared by stirring 4-((naphthalen-2-yl)methylene)-2-phenyloxazol-5(4H)-one with hydrazine hydrate in the presence of absolute ethanol. The chemical structures of the compounds were established by IR, 1H NMR and mass spectral data. All the compounds were evaluated for anti-inflammatory (in vivo, in vitro) activity and performed docking against COX-2. The compounds 3a, 3c and 3o showed good inhibition of COX-2 in in vitro studies (0.75 µM, 0.5 µM and 0.7 µM as IC50, respectively). The compounds 3c, 3e and 3f were found to be more active than standard drug phenylbutazone at equidose. Molecular docking studies showed that compound 3 m exhibited good binding affinity against COX-2 with docking score 9.328 kcal/mol, when compared to the standard celecoxib.


Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Hidrazonas/síntese química , Hidrazonas/farmacologia , Simulação de Acoplamento Molecular , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Hidrazonas/química , Hidrazonas/uso terapêutico , Estrutura Molecular , Relação Estrutura-Atividade
5.
Life Sci ; 251: 117631, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32251635

RESUMO

Initially, the selective COX-2 inhibitors were developed as safer alternatives to the conventional NSAIDs, but later on, most of them were withdrawn from the market due to the risk of heart attack and stroke. Celecoxib, the first selective COX-2 inhibitor, was approved by the Food and Drug Administration (FDA) in December 1998 and was taken back from the market in 2004. Since then, many coxibs have been discontinued one by one due to adverse cardiovascular events. United States (US), Australian and European authorities related to Therapeutic Goods Administration (TGA) implemented the requirements to carry the "Black box" warning on the labels of COX-2 drugs highlighting the risks of serious cardiovascular events. These facts encouraged the researchers to explore them well and find out the biochemical basis behind the cardiotoxicity. From the last few decades, the molecular mechanisms behind the coxibs have regained the attention, especially the specific structural features of the selective COX-2 inhibitors that are associated with cardiotoxicity. This review discusses the key structural features of the selective COX-2 inhibitors and underlying mechanisms that are responsible for the cardiotoxicity. This report also unfolds different strategies that have been reported in the last 10 years to combat the problem of selective COX-2 inhibitors mediated cardiotoxicity.


Assuntos
Cardiotoxicidade/etiologia , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Cardiotoxicidade/fisiopatologia , Cardiotoxicidade/prevenção & controle , Celecoxib/administração & dosagem , Celecoxib/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/química , Rotulagem de Medicamentos , Humanos
6.
Eur J Med Chem ; 193: 112217, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32182488

RESUMO

Because of the complex etiology in neuroinflammatory process, the design of multifunctional agents is a potent strategy to cure neuroinflammatory diseases including AD and PD. Herein, based on the combination principles, 23 of N-salicyloyl tryptamine derivatives as multifunctional agents were designed and their new application for anti-neuroinflammation was disclosed. In cyclooxygenase assay, two compounds 3 and 16 displayed extremely preferable COX-2 inhibition than N-salicyloyl tryptamine. In LPS-induced C6 and BV2 cell models, some compounds decreased the production of proinflammatory mediators NO, PGE2, TNF-α, iNOS, COX-2 and ROS, while increased the production of IL-10. Among them, compound 3 and 16 showed approximately six-fold better inhibition on nitric oxide production than N-salicyloyl tryptamine in C6. Besides, compounds 3, 13 and 16 attenuated the activation of BV2 and C6 cells. More importantly, in vivo, compounds 3 and 16 reduced GFAP and Iba-1 levels in the hippocampus, and displayed neuroprotection in Nissl staining. Besides, both compounds 3 and 16 had high safety (LD50 > 1000 mg/kg). Longer plasma half-life of compounds 3 and 16 than melatonin supported combination strategy. All these results demonstrated that N-salicyloyl tryptamine derivatives are potential anti-neuroinflammation agents for the treatment of neurodegenerative disorder.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Triptaminas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Compostos de Bifenilo/antagonistas & inibidores , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Picratos/antagonistas & inibidores , Relação Estrutura-Atividade , Triptaminas/síntese química , Triptaminas/química
7.
J Enzyme Inhib Med Chem ; 35(1): 744-758, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32183576

RESUMO

A series of 24 compounds was synthesised based on a 2-cyclopentyloxyanisole scaffold 3-14 and their in vitro antitumor activity was evaluated. Compounds 4a, 4b, 6b, 7b, 13, and 14 had the most potent antitumor activity (IC50 range: 5.13-17.95 µM), compared to those of the reference drugs celecoxib, afatinib, and doxorubicin. The most active derivatives 4a, 4b, 7b, and 13 were evaluated for their inhibitory activity against COX-2, PDE4B, and TNF-α. Compounds 4a and 13 potently inhibited TNF-α (IC50 values: 2.01 and 6.72 µM, respectively) compared with celecoxib (IC50=6.44 µM). Compounds 4b and 13 potently inhibited COX-2 (IC50 values: 1.08 and 1.88 µM, respectively) comparable to that of celecoxib (IC50=0.68 µM). Compounds 4a, 7b, and 13 inhibited PDE4B (IC50 values: 5.62, 5.65, and 3.98 µM, respectively) compared with the reference drug roflumilast (IC50=1.55 µM). The molecular docking of compounds 4b and 13 with the COX-2 and PDE4B binding pockets was studied.HighlightsAntitumor activity of new synthesized cyclopentyloxyanisole scaffold was evaluated.The powerful antitumor 4a, 4b, 6b, 7b & 13 were assessed as COX-2, PDE4B & TNF-α inhibitors.Compounds 4a, 7b, and 13 exhibited COX-2, PDE4B, and TNF-α inhibition.Compounds 4b and 13 showed strong interactions at the COX-2 and PDE4B binding pockets.


Assuntos
Anisóis/farmacologia , Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Simulação de Acoplamento Molecular , Inibidores da Fosfodiesterase 4/farmacologia , Anisóis/síntese química , Anisóis/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores
8.
Fitoterapia ; 141: 104470, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31917300

RESUMO

Phytochemical investigations on Physalis. alkekengi L. var. franchetii, a widespread traditional Chinese medicine, led to the isolation and identification of three new sesquiterpenoids physalisitins A-C (1-3). Their structures were elucidated by NMR and HRESIMS analysis, and their absolute configurations were determined by quantum chemical NMR and ECD calculations, as well as by comparing their optical rotation values with those known analogues. All of the isolated compounds were evaluated for their cyclooxygenase-2 (COX-2) inhibitory activity. Compounds 1-3 dose-dependently inhibited the COX-2 enzyme with IC50 values of 3.22 ± 0.25, 6.35 ± 0.84, and 11.13 ± 1.47 µM, respectively.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Physalis/química , Sesquiterpenos/farmacologia , Bioensaio , Inibidores de Ciclo-Oxigenase 2/química , Modelos Moleculares , Estrutura Molecular , Plantas Medicinais/química , Sesquiterpenos/química
9.
Arch Pharm (Weinheim) ; 353(3): e1900293, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31917485

RESUMO

A new series of 1,4-diarylazetidin-2-one derivatives (ß-lactams) were designed and synthesized to evaluate their biological activities as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 inhibition studies showed that all compounds were selective inhibitors of the COX-2 isozyme with IC50 values in the 0.05-0.11 µM range, and COX-2 selectivity indexes in the range of 170-703.7. Among the synthesized ß-lactams, 3-methoxy-4-(4-(methylsulfonyl)phenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (4j) possessing trimethoxy groups at the N-1 phenyl ring exhibited the highest COX-2 inhibitory selectivity and potency, even more potent than the reference drug celecoxib. The analgesic activity of the synthesized compounds was also determined using the formalin test. Compound 4f displayed the best analgesic activity among the synthesized molecules. Molecular modeling studies indicated that the methylsulfonyl pharmacophore group can be inserted into the secondary pocket of the COX-2 active site for interactions with Arg513 . The structure-activity data acquired indicate that the ß-lactam ring moiety constitutes a suitable scaffold to design new 1,4-diarylazetidin-2-ones with selective COX-2 inhibitory activity.


Assuntos
Analgésicos/farmacologia , Azetidinas/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Dor/tratamento farmacológico , beta-Lactamas/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Azetidinas/síntese química , Azetidinas/química , Gatos , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , beta-Lactamas/síntese química , beta-Lactamas/química
10.
Mol Pharm ; 17(1): 251-261, 2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31816246

RESUMO

Inducible isozyme cyclooxygenase-2 (COX-2) is upregulated under acute and chronic inflammatory conditions, including cancer, wherein it promotes angiogenesis, tissue invasion, and resistance to apoptosis. Due to its high expression in various cancers, COX-2 has become an important biomarker for molecular imaging and therapy of cancer. Recently, our group applied in situ click chemistry for the identification of the highly potent and selective COX-2 inhibitor triacoxib. In this study, we present the radiosynthesis in vitro and in vivo radiopharmacological validation of [18F]triacoxib, a novel radiotracer for PET imaging of COX-2. Radiosynthesis of [18F]triacoxib was accomplished using copper-mediated late-stage radiofluorination chemistry. The radiosynthesis, including radio-HPLC purification, of [18F]triacoxib was accomplished within 90 min in decay-corrected radiochemical yields of 72% (n = 7) at molar activities exceeding 90 GBq/µmol. Cellular uptake and inhibition studies with [18F]triacoxib were carried out in COX-2 expressing HCA-7 cells. Cellular uptake of [18F]triacoxib in HCA-7 cells reached 25% radioactivity/mg protein after 60 min. Cellular uptake was reduced by 63% upon pretreatment with 0.1 mM celecoxib, and 90% of the radiotracer remained intact in vivo after 60 min p.i. in mice. [18F]Triacoxib was further evaluated in HCA-7 tumor-bearing mice using dynamic PET imaging, radiometabolite analysis, autoradiography, and immunohistochemistry. PET imaging revealed a favorable baseline radiotracer uptake in HCA-7 tumors (SUV60min = 0.76 ± 0.02 (n = 4)), which could be blocked by 20% through i.p. pretreatment with 2 mg of celecoxib. Autoradiography and immunohistochemistry experiments further the confirmed blocking of COX-2 in vivo. [18F]Triacoxib, whose nonradioactive analogue was identified through in situ click chemistry, is a novel radiotracer for PET imaging of COX-2 in cancer. Despite a substantial amount of nonspecific uptake in vivo, [18F]triacoxib displayed specific binding to COX-2 in vivo and reinforced the feasibility of optimal structure selection by in situ click chemistry. It remains to be elucidated how this novel radiotracer would perform in first-in-human studies to detect COX-2 with PET.


Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Neoplasias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Animais , Celecoxib/farmacologia , Linhagem Celular Tumoral , Química Click , Inibidores de Ciclo-Oxigenase 2/síntese química , Radioisótopos de Flúor/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Distribuição Tecidual , Transplante Heterólogo
12.
Drug Des Devel Ther ; 13: 4007-4020, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819372

RESUMO

Purpose: The aim of this work was to study the influence of solidification of meloxicam (Mel) containing nanosuspension (nanoMel) on the physical stability and drug bioavailability of the products. The nanoMel sample had poly(vinyl alcohol) (PVA) as a protective polymer, but no surfactant as a further stabilizing agent because the final aim was to produce surfactant-free solid phase products as well. Methods: The solidified samples produced by fluidization and lyophilization (fluidMel, lyoMel) were examined for particle size, crystallinity, and in vitro release of Mel compared to similar parameters of nanoMel. The products were subjected to an animal experiment using per oral administration to verify their bioavailability. Results: Mel containing (1%) nanoMel sample was produced by wet milling process using an optimized amount of PVA (0.5%) which resulted in 130 nm as mean particle size and a significant reduction in the degree of crystallinity (13.43%) of Mel. The fluidization technique using microcrystalline cellulose (MCC) as carrier resulted in a quick conversion and no significant change in the critical product parameters. The process of lyophilization required a longer operation time, which resulted in the amorphization of the crystalline carrier (trehalose) and the recrystallization of Mel increased its particle size and crystallinity. The fluidMel and lyoMel samples had nearly five-fold higher relative bioavailability than nanoMel application by oral administration. The correlation between in vitro and in vivo studies showed that the fixed Mel nanoparticles on the surface of solid carriers (MCC, trehalose) in both the artificial gastric juice and the stomach of the animals rapidly reached saturation concentration leading to faster dissolution and rapid absorption. Conclusion: The solidification of the nanosuspension not only increased the stability of the Mel nanoparticles but also allowed the preparation of surfactant-free compositions with excellent bioavailability which may be an important consideration for certain groups of patients to achieve rapid analgesia.


Assuntos
Analgesia , Anti-Inflamatórios não Esteroides/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Meloxicam/uso terapêutico , Nanopartículas/química , Dor/tratamento farmacológico , Administração Oral , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Disponibilidade Biológica , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Humanos , Meloxicam/administração & dosagem , Meloxicam/química , Tamanho da Partícula , Álcool de Polivinil/química , Propriedades de Superfície , Suspensões/química
13.
Biomolecules ; 9(11)2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-31766252

RESUMO

A series of 5-oxo-5H-furo[3,2-g]chromene-6-carbaldehydes and their hydrazone derivatives were evaluated as potential multi-target-directed ligands in vitro against cholinesterases, ß-secretase, cyclooxygenase-2, and lipoxygenase-15 (LOX-15), as well as for free radical-scavenging activities. The most active compounds against LOX-15 were also evaluated for activity against the human lipoxygenase-5 (LOX-5). Kinetic studies against AChE, BChE, and ß-secretase (BACE-1) were performed on 2-(3-fluorophenyl)- (3b) and 2-(4-chlorophenyl)-6-[(4-trifluoromethylphenyl)hydrazonomethyl]furo[3,2-h]chromen-5-one (3e) complemented with molecular docking (in silico) to determine plausible protein-ligand interactions on a molecular level. The docking studies revealed hydrogen and/or halogen bonding interactions between the strong electron-withdrawing fluorine atoms of the trifluoromethyl group with several residues of the enzyme targets, which are probably responsible for the observed increased biological activity of these hydrazone derivatives. The two compounds were found to moderately inhibit COX-2 and lipoxygenases (LOX-5 and LOX-15). Compounds 3b and 3e were also evaluated for cytotoxicity against the breast cancer MCF-7 cell line and Hek293-T cells.


Assuntos
Secretases da Proteína Precursora do Amiloide , Araquidonato 5-Lipoxigenase , Inibidores da Colinesterase , Colinesterases , Inibidores de Ciclo-Oxigenase 2 , Ciclo-Oxigenase 2 , Inibidores de Lipoxigenase , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Araquidonato 5-Lipoxigenase/química , Araquidonato 5-Lipoxigenase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Colinesterases/química , Colinesterases/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/química , Células HEK293 , Humanos , Ligantes , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Células MCF-7 , Simulação de Acoplamento Molecular
14.
J Chem Inf Model ; 59(11): 4720-4728, 2019 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-31613620

RESUMO

When both the difference between two quantities and their individual values can be measured or computationally predicted, multiple quantities can be determined from the measurements or predictions of select individual quantities and select pairwise differences. These measurements and predictions form a network connecting the quantities through their differences. Here, I analyze the optimization of such networks, where the trace (A-optimal), the largest eigenvalue (E-optimal), or the determinant (D-optimal) of the covariance matrix associated with the estimated quantities are minimized with respect to the allocation of the measurement (or computational) cost to different measurements (or predictions). My statistical analysis of the performance of such optimal measurement networks-based on large sets of simulated data-suggests that they substantially accelerate the determination of the quantities and that they may be useful in applications such as the computational prediction of binding free energies of candidate drug molecules.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Descoberta de Drogas , Termodinâmica , Algoritmos , Química Computacional/métodos , Inibidores de Ciclo-Oxigenase 2/química , Descoberta de Drogas/métodos , Humanos , Ligação Proteica
15.
Molecules ; 24(20)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31652609

RESUMO

Non-invasive imaging of cyclooxygenase-2 (COX-2) by radiolabeled ligands is attractive for the diagnosis of cancer, and novel highly affine leads with optimized pharmacokinetic profile are of great interest for future developments. Recent findings have shown that methylsulfonyl-substituted (dihydro)pyrrolo[3,2,1-hi]indoles represent highly potent and selective COX-2 inhibitors but possess unsuitable pharmacokinetic properties for radiotracer applications. Based on these results, we herein present the development and evaluation of a second series of sulfonamide-substituted (dihydro)pyrrolo[3,2,1-hi]indoles and their conversion into the respective more hydrophilic N-propionamide-substituted analogs. In comparison to the methylsulfonyl-substituted leads, COX inhibition potency and selectivity was retained in the sulfonamide-substituted compounds; however, the high lipophilicity might hinder their future use. The N-propionamide-substituted analogs showed a significantly decreased lipophilicity and, as expected, lower or no COX-inhibition potency. Hence, the N-(sulfonyl)propionamides can be regarded as potential prodrugs, which represents a potential approach for more sophisticated radiotracer developments.


Assuntos
Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Indóis/síntese química , Indóis/farmacologia , Sulfonamidas/química , Amidas/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/química , Desenho de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Indóis/química , Neoplasias/diagnóstico por imagem , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade
16.
Biomolecules ; 9(11)2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31661893

RESUMO

The cyclooxygenase-2 (COX-2) enzyme is considered to be an important target for developing novel anti-inflammatory agents. Selective COX-2 inhibitors offer the advantage of lower adverse effects that are commonly associated with non-selective COX inhibitors. In this work, a novel series of methyl 3-(substituted benzoyl)-7-substituted-2-phenylindolizine-1-carboxylates was synthesized and evaluated for COX-2 inhibitory activity. Compound 4e was identified as the most active compound of the series with an IC50 of 6.71 M, which is comparable to the IC50 of indomethacin, a marketed non-steroidal anti-inflammatory drug (NSAID). Molecular modeling and crystallographic studies were conducted to further characterize the compounds and gain better understanding of the binding interactions between the compounds and the residues at the active site of the COX-2 enzyme. The pharmacokinetic properties and potential toxic effects were predicted for all the synthesized compounds, which indicated good drug-like properties. Thus, these synthesized compounds can be considered as potential lead compounds for developing effective anti-inflammatory therapeutic agents.


Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Indolizinas/química , Indolizinas/farmacologia , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/toxicidade , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/toxicidade , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacologia , Inibidores das Enzimas do Citocromo P-450/toxicidade , Humanos , Indolizinas/metabolismo , Indolizinas/toxicidade , Simulação de Acoplamento Molecular , Conformação Proteica , Relação Estrutura-Atividade
17.
Bioorg Chem ; 92: 103301, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31563696

RESUMO

A group of tetrazole bearing compounds were synthesized and evaluated for their in vitro cyclooxygenase (COX) isozymes (COX-1/COX-2) inhibitory activity, in vitro anti-inflammatory activity through measuring levels of expression of IL-6 and TNF-α and antimicrobial activity. Cyclization of pyridine derivative 5b was confirmed using 2D NMR such as NOESY and HMBC experiments. Within the synthesized compounds, compound 7c was identified as effective and selective COX-2 inhibitors (COX-2 IC50 = 0.23 uM; COX-2 selectivity index = 16.91). Moreover 7c was the most effective derivative on TNF-α (37.6 pg/ml). While, the most active compound on IL-6 was isoxazole derivative 6 (42.8 pg/ml). Dual inhibitory activity on both IL-6 and TNF-α was exhibited by compounds 2 and 3 (IL-6 = 47.5 and 82.7 pg/ml, respectively) and (TNF-α = 31.7 and 33.8 pg/ml, sequentially). Additionally, compound 7a, showed broad spectrum antimicrobial activity against Gram positive cocci, Gram positive rods and yeast fungus (inhibition zone = 20 and 19 mm). None of the test compounds exhibited activity against Gram negative rods. Compounds 3 and 7c exhibited good antifungal activity at MIC equal to 64.5 µg/ml. While compound 6 showed antibacterial activities against Micrococcus lysodicticus and Bacillus subtilis at MIC = 32.25 and 64.5 µg/ml, respectively. Computational analysis was used to predict molecular properties and bioactivity of the target compounds. To confirm the mode of action of the synthesized compounds as anti-inflammatory agents, molecular docking was done. Appreciable binding interactions were observed for compound 7c containing COX-2 pharmacophore (SO2NH2), with binding energy -10.6652 Kcal/mol, forming two hydrogen bonding interactions with His90 and Tyr355 amino acids. It was fully fitted within COX-2 active site having the highest COX-2 selectivity index between all the test compounds (S.I. = 16.91).


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Tetrazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Saccharomyces cerevisiae/efeitos dos fármacos , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
18.
Org Lett ; 21(21): 8523-8527, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31556302

RESUMO

(±)-Lucidumone (1), an enantiomeric meroterpenoid possessing an unprecedented skeleton comprising a fused 6/5/6/6/5 polycyclic system, was isolated from Ganoderma lucidum and structurally identified. The absolute configuration of (-)-1 was assigned by single-crystal X-ray crystallography. A plausible biosynthetic pathway for 1 is proposed. A chemical biology approach reveals that (-)-1 selectively inhibits COX-2 by directly binding with an amino acid residue of Tyr385, representing a new structure scaffold of COX-2 inhibitors.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Ganoderma/química , Terpenos/farmacologia , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/química , Modelos Moleculares , Conformação Proteica , Terpenos/química
19.
Assay Drug Dev Technol ; 17(6): 285-291, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31532713

RESUMO

In silico molecular docking is an efficient technique for drug design that predicts the optimized orientation of the ligand against a specific drug target. This is a cost-effective and time-saving technique that requires limited manpower. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed drugs in various prescriptions. The drawbacks with NSAIDs in its long-term usage are gastric irritation, bleeding, and perforation. Prodrug approach is a commonly used method to overcome these side effects. In this study, the reported prodrugs of mefenamic acid were utilized to validate the molecular docking simulation process by comparing obtained in silico results with the reported in vivo results. The molecules were evaluated for their binding affinity against human cyclooxygenase-2 enzyme as well as their pharmacokinetics profile is predicted on the basis of Lipinski's and Veber rule. The in silico result showed high degree similarity with experimental results. This confirms the efficiency and reliability of the molecular docking technique for identification of potential lead compounds.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Ácido Mefenâmico/farmacologia , Simulação de Acoplamento Molecular , Pró-Fármacos/farmacologia , Sítios de Ligação/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/química , Humanos , Ligantes , Ácido Mefenâmico/química , Estrutura Molecular , Pró-Fármacos/química
20.
Eur J Med Chem ; 183: 111693, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31539778

RESUMO

Novel heterocyclic oxadiazoles viz. 2-subsituted-5-(4-pyridyl)-1,3,4-oxadiazoles, 2-subsituted-5-(3-pyridyl)-1,3,4-oxadiazoles and 2-subsituted-5-(phenyl or 4-chlorophenyl-1,3,4-oxadiazoles) were designed and synthesized as potential anticancer agents. In this investigation, all compounds were evaluated for their COX-1 and COX-2 inhibitory activity in vitro as new therapeutic approaches assumed cytotoxic effect associated with selective COX-2 inhibition. Results showed that most of the derivatives demonstrated inhibition towards both isoforms of COX comparable to the standard reference drugs indomethacin, diclofenac sodium and celecoxib. Then, nine selected compounds (IIId, VIb, VIIc, IX, XI, XIIa, XIVa, XVIb and XVIIIb) were subjected to cytotoxic screening against UO-31 renal cancer cell line using MTT assay. Compounds IIId, IX and XIIa displayed promising behavior by showing good anticancer activity. Moreover, kinase inhibitory assay against the tyrosine kinase EGFR was performed for the three compounds showing the highest cytotoxic activity. The tested compounds were potent against EGFR with the highest activity being observed for compound IX showing nearly double the potency of the reference drug Erlotinib. Moreover, molecular docking and molecular dynamics were performed for IIId, IX and XIIa against EGFR, in an attempt to elucidate a model for their binding at the molecular level, simulate and understand the possible binding interactions underlying the association between these small molecules and the kinase enzyme ATP binding pocket essential amino acids. Finally, in silico pharmacokinetic profile predication was investigated for IIId, IX and XIIIa using SWISS/ADME to identify the most promising small-molecule cytotoxic agent on the basis of displaying the best drug-like properties. Results indicated that compound IX has a potential to serve as a lead compound for developing novel anticancer therapeutic agents.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Desenho de Fármacos , Oxidiazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
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