RESUMEN
Several facets of the host response to tuberculosis have been tapped for clinical investigation, especially targeting angiogenesis mediated by VEGF signaling from infected macrophages. Herein, we rationalized combining the antiangiogenic effects of VEGFR-2 blockade with direct antitubercular InhA inhibition in single hybrid dual inhibitors as advantageous alternatives to the multidrug regimens. Inspired by expanded triclosans, the ether ligation of triclosan was replaced by rationalized linkers to assemble the VEGFR-2 inhibitors thematic scaffold. Accordingly, new series of 3-(p-chlorophenyl)-1-phenylpyrazole derivatives tethered to substituted ureas and their isosteres were synthesized, evaluated against Mycobacterium tuberculosis virulent cell line H37Rv, and assessed for their InhA inhibitory activities. The urea derivatives 8d and 8g exhibited the most promising antitubercular activity (MIC = 6.25 µg/mL) surpassing triclosan (MIC = 20 µg/mL) with potential InhA inhibition, thus identified as the study hits. Interestingly, both compounds inhibited VEGFR-2 at nanomolar IC50 (15.27 and 24.12 nM, respectively). Docking and molecular dynamics simulations presumed that 8d and 8g could bind to their molecular targets InhA and VEGFR-2 posing essential stable interactions shared by the reference inhibitors triclosan and sorafenib. Finally, practical LogP, Lipinski's parameters and in silico ADMET calculations highlighted their drug-likeness as novel leads in the arsenal against TB.
Asunto(s)
Mycobacterium tuberculosis , Triclosán , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Relación Estructura-Actividad , Triclosán/farmacología , Antituberculosos/farmacología , Pirazoles/farmacología , Simulación del Acoplamiento Molecular , Proteínas Bacterianas/metabolismoRESUMEN
BACKGROUND: The liver serves as a metabolic hub within the human body, playing a crucial role in various essential functions, such as detoxification, nutrient metabolism, and hormone regulation. Therefore, protecting the liver against endogenous and exogenous insults has become a primary focus in medical research. Consequently, the potential hepatoprotective properties of multiple 4-phenyltetrahydroquinolines inspired us to thoroughly study the influence of four specially designed and synthesized derivatives on carbon tetrachloride (CCl4)-induced liver injury in rats. METHODS AND RESULTS: Seventy-seven Wistar albino male rats weighing 140 ± 18 g were divided into eleven groups to investigate both the toxicity profile and the hepatoprotective potential of 4-phenyltetrahydroquinolines. An in-vivo hepatotoxicity model was conducted using CCl4 (1 ml/kg body weight, a 1:1 v/v mixture with corn oil, i.p.) every 72 h for 14 days. The concurrent treatment of rats with our newly synthesized compounds (each at a dose of 25 mg/kg body weight, suspended in 0.5% CMC, p.o.) every 24 h effectively lowered transaminases, preserved liver tissue integrity, and mitigated oxidative stress and inflammation. Moreover, the histopathological examination of liver tissues revealed a significant reduction in liver fibrosis, which was further supported by the immunohistochemical analysis of α-SMA. Additionally, the expression of the apoptotic genes BAX and BCL2 was monitored using real-time PCR, which showed a significant decrease in liver apoptosis. Further investigations unveiled the ability of the compounds to significantly decrease the expression of autophagy-related proteins, Beclin-1 and LC3B, consequently inhibiting autophagy. Finally, our computer-assisted simulation dockingonfirmed the obtained experimental activities. CONCLUSION: Our findings suggest that derivatives of 4-phenyltetrahydroquinoline demonstrate hepatoprotective properties in CCl4-induced liver damage and fibrosis in rats. The potential mechanism of action may be due to the inhibition of autophagy in liver cells.
Asunto(s)
Autofagia , Tetracloruro de Carbono , Enfermedad Hepática Inducida por Sustancias y Drogas , Quinolinas , Ratas Wistar , Animales , Autofagia/efectos de los fármacos , Masculino , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Ratas , Quinolinas/farmacología , Estrés Oxidativo/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Sustancias Protectoras/farmacología , Apoptosis/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
A structure-guided modelling approach using COX-2 as a template was used to investigate the effect of replacing the chloro atom located at the chlorophenyl ring of amide-linked bipyrazole moieties, aiming at attaining better anti-inflammatory effect with a good safety profile. Bromo, fluoro, nitro, and methyl groups were revealed to be ideal candidates. Consequently, new bipyrazole derivatives were synthesised. The in vitro inhibitory COX-1/COX-2 activity of the synthesised compounds exhibited promising selectivity. The fluoro and methyl derivatives were the most active candidates. The in vivo formalin-induced paw edoema model confirmed the anti-inflammatory activity of the synthesised compounds. All the tested derivatives had a good ulcerogenic safety profile except for the methyl substituted compound. In silico molecular dynamics simulations of the fluoro and methyl poses complexed with COX-2 for 50 ns indicated stable binding to COX-2. Generally, our approach delivers a fruitful matrix for the development of further amide-linked bipyrazole anti-inflammatory candidates.
Asunto(s)
Amidas , Edema , Amidas/farmacología , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/química , Edema/inducido químicamente , Edema/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Promising inhibitory activities of the parasite multiplication were obtained upon evaluation of in vivo antimalarial activities of new pyrazolylpyrazoline derivatives against Plasmodium berghei infected mice. Further evaluation of 5b and 6a against chloroquine-resistant strain (RKL9) of P. falciparum showed higher potency than chloroquine. In vitro antileishmanial activity testing against Leishmania aethiopica promastigote and amastigote forms indicated that 5b, 6a and 7b possessed promising activity compared to miltefosine and amphotericin B deoxycholate. Moreover, antileishmanial activity reversal of the active compounds via folic and folinic acids showed comparable results to the positive control trimethoprim, indicating an antifolate mechanism via targeting leishmanial DHFR and PTR1. The compounds were non-toxic at 125, 250 and 500 mg/kg. In addition, docking of the most active compound against putative malarial target Pf-DHFR-TS and leishmanial PTR1 rationalised the observed activities. Molecular dynamics simulations confirmed a stable and high potential binding of 7a against leishmanial PTR1.
Asunto(s)
Antimaláricos , Antiprotozoarios , Antagonistas del Ácido Fólico , Leishmania , Animales , Cloroquina , Ratones , Simulación de Dinámica Molecular , Plasmodium berghei , Plasmodium falciparumRESUMEN
The present study reports the synthesis of new purine bioisosteres comprising a pyrazolo[3,4-d]pyrimidine scaffold linked to mono-, di-, and trimethoxy benzylidene moieties through hydrazine linkages. First, in silico docking experiments of the synthesized compounds against Bax, Bcl-2, Caspase-3, Ki67, p21, and p53 were performed in a trial to rationalize the observed cytotoxic activity for the tested compounds. The anticancer activity of these compounds was evaluated in vitro against Caco-2, A549, HT1080, and Hela cell lines. Results revealed that two (5 and 7) of the three synthesized compounds (5, 6, and 7) showed high cytotoxic activity against all tested cell lines with IC50 values in the micro molar concentration. Our in vitro results show that there is no significant apoptotic effect for the treatment with the experimental compounds on the viability of cells against A549 cells. Ki67 expression was found to decrease significantly following the treatment of cells with the most promising candidate: drug 7. The overall results indicate that these pyrazolopyrimidine derivatives possess anticancer activity at varying doses. The suggested mechanism of action involves the inhibition of the proliferation of cancer cells.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos de Bencilideno/síntesis química , Biomarcadores de Tumor/metabolismo , Neoplasias/metabolismo , Pirazoles/química , Pirimidinas/química , Células A549 , Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos de Bencilideno/química , Compuestos de Bencilideno/farmacología , Biomarcadores de Tumor/química , Células CACO-2 , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HeLa , Humanos , Concentración 50 Inhibidora , Antígeno Ki-67/química , Antígeno Ki-67/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Neoplasias/tratamiento farmacológicoRESUMEN
New tetrahydro-1H-pyrazolo[3,4-b]quinoline derivatives were designed, synthesized and characterized as dual anticholinestrase and cyclooxygenase-2 inhibitors. The in vitro and in vivo anti-cholinesterase evaluation exhibited promising activities with lower hepatotoxicity for many candidates compared to tacrine as a reference. Furthermore, their anti-inflammatory activity using in vitro (COX-1/COX-2) inhibitory assay demonstrated superior activity to celecoxib with higher selectivity indices for some compounds. In addition, some candidates showed extended anti-inflammatory activity by inhibiting COX-2 protein induction. Besides, in silico docking experiments of the active compounds against hAChE rationalized the observed in vitro AChE inhibitory activity. In conclusion, this work provides an extension of the chemical space of tetrahydro-1H-pyrazolo[3,4-b]quinoline chemotype for the anticholinestrase and anti-inflammatory activity. This would aid to minimize the possible neuroinflammation linked to the pathogenesis of Alzheimer's disease.
Asunto(s)
Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Pirazoles/química , Pirazoles/farmacología , Quinolinas/química , Quinolinas/farmacología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Anuros , Inhibidores de la Colinesterasa/síntesis química , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/síntesis química , Diseño de Fármacos , Humanos , Hígado/efectos de los fármacos , Simulación del Acoplamiento Molecular , Pirazoles/síntesis química , Quinolinas/síntesis químicaRESUMEN
Based on a structure-guided approach, aryl sulfonyl hydrazones conjugated with 1,3-diaryl pyrazoles were designed to target metallo-ß-lactamases (MBLs), using Klebsiella pneumoniaeNDM-1 as a model. The in vitro MBLs inhibition showed remarkable inhibition constant for most of the designed compounds at a low micromolar range (1.5-16.4 µM) against NDM-1, IMP-1 and AIM-1 MBLs. Furthermore, all compounds showed promising antibacterial activity against (K+, K1-K9) resistant clinical isolates of K. pneumoniae and were able to re-sensitize resistant K. pneumoniae (K5) strain towards meropenem and cefalexin. Besides, in vivo toxicity testing exhibited that the most active compound was non-toxic and well tolerated by the experimental animals orally up to 350 mg/kg and up to 125 mg/kg parenterally. The docking experiments on NDM-1 and IMP-1 rationalized the observed in vitro MBLs inhibition activity. Generally, this work presents a fruitful matrix to extend the chemical space for MBLs inhibition. This aids in tackling drug-resistance issues in antibacterial treatment.
Asunto(s)
Antibacterianos/farmacología , Hidrazonas/farmacología , Klebsiella pneumoniae/efectos de los fármacos , Pirazoles/farmacología , Inhibidores de beta-Lactamasas/farmacología , beta-Lactamasas/metabolismo , Antibacterianos/síntesis química , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Farmacorresistencia Bacteriana/efectos de los fármacos , Hidrazonas/síntesis química , Hidrazonas/química , Klebsiella pneumoniae/enzimología , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Pirazoles/química , Relación Estructura-Actividad , Inhibidores de beta-Lactamasas/síntesis química , Inhibidores de beta-Lactamasas/químicaRESUMEN
In search of potent acetyl cholinesterase inhibitors with low hepatotoxicity for the treatment of Alzheimer's disease, introduction of a chloro substitution to tacrine and some of its analogs has proven to be beneficial in maintaining or potentiating the cholinesterase inhibitory activity. Furthermore, it was found to be able to reduce the hepatotoxicity of the synthesized compounds, which is the main target of the study. Accordingly, a series of new 4-(chlorophenyl)tetrahydroquinoline derivatives, was synthesized and characterized. The synthesized compounds were evaluated for their in vitro and in vivo anti-cholinesterase activity using tacrine as a reference standard. Furthermore, they were investigated for their hepatotoxicity compared to tacrine. The obtained biological results revealed that all synthesized compounds displayed equivalent or significantly higher anti-cholinesterase activity and lower hepatotoxicity in comparison to tacrine. In addition, in silico drug-likeness of the synthesized compounds were predicted and their practical logP were assessed indicating that all synthesized compounds can be considered as promising hits/leads. Furthermore, docking study of the compound showing the highest in vitro anticholinesterase activity was performed and its binding mode was compared to that of tacrine.
Asunto(s)
Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Tacrina/farmacología , Enfermedad de Alzheimer/metabolismo , Animales , Anuros , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Halogenación , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Simulación del Acoplamiento Molecular , Estructura Molecular , Ratas , Relación Estructura-Actividad , Tacrina/síntesis química , Tacrina/químicaRESUMEN
Four series of new bipyrazoles comprising the N-phenylpyrazole scaffold linked to polysubstituted pyrazoles or to antipyrine moiety through different amide linkages were synthesized. The synthesized compounds were evaluated for their anti-inflammatory and analgesic activities. In vitro COX-1/COX-2 inhibition study revealed that compound 16b possessed the lowest IC50 value against both COX-1 and COX-2. Moreover, the effect of the most promising compounds on inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) protein expression in lipopolysaccharide (LPS)-activated rat monocytes was also investigated. The results revealed that some of the synthesized compounds showed anti-inflammatory and/or analgesic activity with less ulcerogenic potential than the reference drug diclofenac sodium and are well tolerated by experimental animals. Moreover, they significantly inhibited iNOS and COX-2 protein expression induced by LPS stimulation. Compounds 16b and 18 were proved to display anti-inflammatory activity superior to diclofenac sodium and analgesic activity equivalent to it with minimal ulcerogenic potential.
Asunto(s)
Amidas/química , Analgésicos/farmacología , Antiinflamatorios/farmacología , Pirazoles/química , Evaluación Preclínica de Medicamentos , Análisis Espectral/métodosRESUMEN
The liver is responsible for critical functions such as metabolism, secretion, storage, detoxification, and the excretion of various compounds. However, there is currently no approved drug treatment for liver fibrosis. Hence, this study aimed to explore the potential hepatoprotective effects of chlorinated and nonchlorinated 4-phenyl-tetrahydroquinoline derivatives. Originally developed as tacrine analogs with reduced hepatotoxicity, these compounds not only lacked hepatotoxicity but also displayed a remarkable hepatoprotective effect. Treatment with these derivatives notably prevented the chemically induced elevation of hepatic indicators associated with liver injury. Additionally, the compounds restored the activities of defense antioxidant enzymes as well as levels of inflammatory markers (TNF-α and IL-6), apoptotic proteins (Bax and Bcl2), and fibrogenic mediators (α-SMA and TGF-ß) to normal levels. Histopathologic analysis confirmed the hepatoprotective activity of tetrahydroquinolines. Furthermore, computer-assisted simulation docking results were highly consistent with those of the observed in vivo activities. In conclusion, the designed tacrine analogs exhibited a hepatoprotective role in acute liver damage, possibly through their antioxidative, anti-inflammatory, and antifibrotic effects.
RESUMEN
The synthesis of nanoparticles using environmentally friendly methods for applications in fields such as food packaging and biomedicine has been gaining increasing attention. Organic-inorganic nanostructures offer opportunities to create innovative materials suitable for use in optoelectronics and biological applications. In this study, we focused on producing nanocomposite films by blending carboxymethyl cellulose (CMC) and chitosan (CS) polymers in equal proportions (50/50 wt %) and adding silver nanoparticles (Ag NPs) through a solution casting process. Our objective was to examine how the introduction of Ag NPs influenced the structural, optical, mechanical, electrical, and antibacterial properties of the virgin CMC/CS composites. XRD patterns of the prepared samples indicated the presence of crystalline Ag phases within the CMC/CS blend. FT-IR spectroscopy showed the primary vibrational peaks associated with CMC and CS, which exhibited reduced intensity after the addition of Ag NPs. The UV absorption of the nanocomposites exhibited a gradual increase and a shift toward longer wavelengths. The electrical properties are enhanced with higher concentrations of Ag NPs. An increase in the content of Ag NPs resulted in a corresponding enhancement of antibacterial activity against both Staphylococcus aureus and Escherichia coli. The CMC/CS-Ag-doped films demonstrated significant enhancements in Young's modulus (Y), tensile stress (σt), and elongation at break (εB). These findings suggest that these nanocomposite films hold promise for potential applications in optoelectronics and biological fields.
RESUMEN
Liver Fibrosis can be life-threatening if left untreated as it may lead to serious, incurable complications. The common therapeutic approach is to reverse the fibrosis while the intervention is still applicable. Celecoxib was shown to exhibit some antifibrotic properties in the induced fibrotic liver in rats. The present study aimed to investigate the possible antifibrotic properties in CCl4-induced liver fibrosis in male Sprague-Dawley rats compared to celecoxib of three novel methoxylated pyrazolo[3,4-d]pyrimidines. The three newly synthesized compounds were proved to be safe candidates. They showed a therapeutic effect against severe CCl4-induced fibrosis but at different degrees. The three compounds were able to partially reverse hepatic architectural distortion and reduce the fibrotic severity by showing antioxidant properties reducing MDA with increasing GSH and SOD levels, remodeling the extracellular matrix proteins and liver enzymes balance, and reducing the level of proinflammatory (TNF-α and IL-6) and profibrogenic (TGF-ß) cytokines. The results revealed that the dimethoxy-analog exhibited the greatest activity in all the previously mentioned parameters compared to celecoxib and the other two analogs which could be attributed to the different methoxylation patterns of the derivatives. Collectively, the dimethoxy-derivative could be considered a safe promising antifibrotic candidate.
RESUMEN
Papain-Like Protease (PLpro) is a key protein for SARS-CoV-2 viral replication which is the cause of the emerging COVID-19 pandemic. Targeting PLpro can suppress viral replication and provide treatment options for COVID-19. Due to the dynamic nature of its binding site loop, PLpro multiple conformations were generated through a long-range 1 micro-second molecular dynamics (MD) simulation. Clustering the MD trajectory enabled us to extract representative structures for the conformational space generated. Adding to the MD representative structures, X-ray structures were involved in an ensemble docking approach to screen the FDA approved drugs for a drug repositioning endeavor. Guided by our recent benchmarking study of SARS-CoV-2 PLpro, FRED docking software was selected for such a virtual screening task. The results highlighted potential consensus binders to many of the MD clusters as well as the newly introduced X-ray structure of PLpro complexed with a small molecule. For instance, three drugs Benserazide, Dobutamine and Masoprocol showed a superior consensus enrichment against the PLpro conformations. Further MD simulations for these drugs complexed with PLpro suggested the superior stability and binding of dobutamine and masoprocol inside the binding site compared to Benserazide. Generally, this approach can facilitate identifying drugs for repositioning via targeting multiple conformations of a crucial target for the rapidly emerging COVID-19 pandemic.
Asunto(s)
Proteasas 3C de Coronavirus , Inhibidores de Cisteína Proteinasa/química , Reposicionamiento de Medicamentos , Simulación de Dinámica Molecular , SARS-CoV-2/enzimología , Sitios de Unión , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/química , Cristalografía por Rayos X , Estabilidad de Enzimas , HumanosRESUMEN
Matrix metalloproteinase-9 (MMP-9) and monoamine oxidase-A (MAO-A) are central signaling nodes in CRC and promotors of distant metastasis associated with high mortality rates. Novel series of quinoxaline-based dual MMP-9/MAO-A inhibitors were synthesized to suppress CRC progression. The design rationale combines the thematic pharmacophoric features of MMP-9 and MAO-A inhibitors in hybrid scaffolds. All derivatives were initially screened via MTT assay for cytotoxic effects on normal colonocytes to assess their safety profiles, then evaluated for their anticancer potential on HCT116 cells overexpressing MMP-9 and MAO-A. The most promising derivatives 8, 16, 17, 19, and 28 exhibited single digit nanomolar IC50 against HCT116 cells within their safe doses (EC100) on normal colonocytes. They suppressed HCT116 cell migration by 73.32, 61.29, 21.27, 28.82, and 27.48%, respectively as detected by wound healing assay. Enzymatic assays revealed that the selected derivatives were superior to the reference MMP-9 and MAO-A inhibitors (quercetin and clorgyline, respectively). The nanomolar dual MMP-9/MAO-A inhibitor 19 was identified as the most potent and balanced dual inhibitor among the evaluated series with considerable selectivity against MAO-A over MAO-B. Besides, qRT-PCR analysis was conducted to explore the hit compounds' potential to downregulate hypoxia-inducing factor (HIF-1α) in HCT116 cells being correlated with MAO-A mediated CRC migration and invasion. The five above-mentioned compounds significantly downregulated HIF-1α by more than 5 folds. Docking simulations predicted their possible binding modes with MMP-9 and MAO-A and highlighted their essential structural features. Finally, they recorded drug-like in silico physicochemical parameters and ADMET profiles.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Diseño de Fármacos , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Quinoxalinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Metaloproteinasa 9 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz/química , Estructura Molecular , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/química , Quinoxalinas/síntesis química , Quinoxalinas/química , Relación Estructura-ActividadRESUMEN
This study reports the synthesis of two series of new purine bioisosteres comprising a pyrazolo[3,4-d]pyrimidine scaffold linked to piperazine moiety through different amide linkages. The newly synthesized compounds were evaluated for anticancer activity against four cell lines (MDA-MB-231, MCF-7, SF-268, B16F-10) and cyclooxygenase (COX-2) protein expression inhibition in lipopolysaccharide (LPS)-activated rat monocytes. The results revealed that most of the synthesized compounds showed moderate-to-high cytotoxic activity against at least one cell line, with compound 10b being the most active against all used cell lines (IC50 values 5.5-11 µg/ml) comparable to cisplatin. In addition, six of these compounds (7b, 10a-d, and 12c) demonstrated inhibition of LPS-induced COX-2 protein expression at low concentration (25 µg/ml) as compared to the control non-stimulated cells and showed a COX-2 selectivity index range comparable to diclofenac sodium. The overall results indicate that many of these pyrazolopyrimidine derivatives possess in vitro anti-inflammatory and anticancer activities at varying doses, and the most active compounds will be subjected to in vivo pharmacological evaluation.
Asunto(s)
Antiinflamatorios/síntesis química , Antineoplásicos/síntesis química , Inhibidores de la Ciclooxigenasa/síntesis química , Pirazoles/química , Pirazoles/síntesis química , Pirimidinas/química , Pirimidinas/síntesis química , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 1/química , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/química , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Diclofenaco/farmacología , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Lipopolisacáridos/farmacología , Células MCF-7 , Monocitos/citología , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Pirazoles/metabolismo , Pirazoles/farmacología , Pirimidinas/metabolismo , Pirimidinas/farmacología , RatasRESUMEN
There has been considerable interest in azole-containing compounds as promising antiinflammatory agents. Designed compounds with five-membered nitrogen-containing nuclei have demonstrated good anti-inflammatory activity, indicating their potential for the treatment of this highly irritating condition. Pyrazoles, have attracted much more attention than other azoles, however, reports on other azoles demonstrated that they were as effective as pyrazoles. This review describes the different classes of azoles designed as cyclooxygenase inhibitors and the effect of different structural modifications on their activity.
Asunto(s)
Azoles/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Antiinflamatorios/química , Antiinflamatorios/farmacología , Azoles/química , Inhibidores de la Ciclooxigenasa/químicaRESUMEN
This work describes the synthesis of new series of compounds derived from methyl pyridyl- 2,4-dioxobutanoates that contain pyridine ring attached to substituted bioactive heterocyclic moieties in order to investigate their preliminary in vitro antibacterial and antifungal activities. The results revealed that most of the tested compounds exhibited significant activity against P. aeruginosa. and E. coli. They also displayed considerable activity against S. aureus and B. subtilis. On the other hand, the compounds displayed moderate antifungal activity.
Asunto(s)
Antibacterianos/síntesis química , Antifúngicos/síntesis química , Butiratos/síntesis química , Piridinas/síntesis química , Antibacterianos/farmacología , Antifúngicos/farmacología , Bacillus subtilis/efectos de los fármacos , Bacillus subtilis/crecimiento & desarrollo , Butiratos/farmacología , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/crecimiento & desarrollo , Piridinas/farmacología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrolloRESUMEN
A series of substituted pyridinylpyrazole (or isoxazole) derivatives were synthesized and evaluated for their anti-inflammatory (AI) activity using formalin-induced paw edema bioassays. Their inhibitory activities of cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) were also determined. The analgesic activity of the same compounds was evaluated using rat-tail withdrawal technique. Their antipyretic activity was also evaluated. The results revealed that compounds 4a,b, 6a, 8a, 14c and 15a exhibited significant AI and analgesic activities. Compounds 5a, 6a and 8a displayed good antipyretic activity. Compounds 14c and 15a showed good COX-2 inhibitory activity and weak inhibition of COX-1. Additionally, the most active compounds were shown to have a large safety margin (ALD50 >300-400 mg / Kg) and minimal ulcerogenic potentialities when administered orally at a dose of 300 mg/Kg. Docking studies for 14c and 15a with COX-2 showed good binding profile. Antimicrobial evaluation proved that most of the compounds exhibited distinctive activity against the gram negative bacteria, P. aeruginosa and E coli.
Asunto(s)
Analgésicos/farmacología , Antibacterianos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Antipiréticos/farmacología , Diseño de Fármacos , Isoxazoles/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Analgésicos/administración & dosificación , Analgésicos/síntesis química , Animales , Antibacterianos/administración & dosificación , Antibacterianos/síntesis química , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/síntesis química , Antipiréticos/administración & dosificación , Antipiréticos/síntesis química , Ciclooxigenasa 2/metabolismo , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Edema/tratamiento farmacológico , Escherichia coli/efectos de los fármacos , Formaldehído , Isoxazoles/síntesis química , Isoxazoles/química , Masculino , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Pseudomonas aeruginosa/efectos de los fármacos , Pirazoles/síntesis química , Pirazoles/química , Piridinas/síntesis química , Piridinas/química , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Structure-affinity relationships for the binding of 3-[2-(N,N,N-trimethylammonium)ethoxy]pyridine (AXPQ) at alpha7 nACh receptors were investigated due to its close structural similarity to a known alpha7 antagonist.