RESUMEN
Flavonoids, which contain a benzo-γ-pyrone (C6-C3-C6) skeleton, have been reported to exhibit effective antioxidant ability. This study aimed to compare the antioxidant activities of 7,8-dihydroxyflavone (7,8-DHF) and 7-hydroxyflavone (7-HF) in H2 O2 , lipopolysaccharide (LPS), or tert-butyl hydroperoxide (t-BHP)-induced RAW264.7 cells, respectively. The antioxidant capacities of 7,8-DHF and 7-HF were firstly evaluated by 2,2-azinobis-3-ethyl-benzothiazoline-6-sulphonic acid (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays. Then, reactive oxygen species (ROS), super oxide dismutase (SOD), and malondialdehyde (MDA) productions in H2 O2 , LPS, or t-BHP-induced RAW264.7 cells were tested and compared, respectively. Finally, the antioxidant mechanisms of 7-HF and 7,8-DHF were initially investigated by western blot. Our results showed that 7,8-DHF possessed stronger free-radical scavenging capacity than 7-HF. Both 7,8-DHF and 7-HF suppressed MDA production and ROS accumulation, improved the activity of SOD in H2 O2 , LPS, or t-BHP-induced RAW264.7 cells, respectively. And 7,8-DHF exerted a better antioxidant effect than 7-HF, especially in t-BHP-induced oxidative stress. Mechanically, 7,8-DHF prevented the activation of poly ADP-ribosepolymerase and caspase-3, meanwhile markedly upregulated the expression of HO-1 protein in t-BHP-induced oxidative stress. These results suggested that 7,8-DHF might serve as a potential pharmaceutical drug against oxidative stress injury.
Asunto(s)
Antioxidantes , Flavonas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Antioxidantes/farmacología , Antioxidantes/metabolismo , Caspasa 3/metabolismo , Lipopolisacáridos/toxicidad , Estrés Oxidativo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo , Animales , RatonesRESUMEN
A systemic treatment strategy is urgently demanded to suppress the rapid growth and easy metastasis characteristics of breast cancer. In this work, a chimeric peptide-engineered self-delivery nanomedicine (designated as ChiP-CeR) for photodynamic-triggered breast cancer immunotherapy by macrophage polarization. Among these, ChiP-CeR is composed of the photosensitizer of chlorine e6 (Ce6) and the TLR7/8 agonist of lmiquimod (R837), which is further modified with tumor matrix targeting peptide (Fmoc-K(Fmoc)-PEG8 -CREKA. ChiP-CeR is preferred to actively accumulate at the tumor site via specific recognition of fibronectin, which can eradicate primary tumor growth through photodynamic therapy (PDT). Meanwhile, the destruction of primary tumors would trigger immunogenic cell death (ICD) effects to release high-mobility group box-1(HMGB1) and expose calreticulin (CRT). Moreover, ChiP-CeR can also polarize M2-type tumor-associated macrophages (TAMs) into M1-type TAMs, which can activate T cell antitumor immunity in combination with ICD. Overall, ChiP-CeR possesses superior antitumor effects against primary and lung metastatic tumors, which provide an applicable nanomedicine and a feasible strategy for the systemic management of metastatic breast cancer.
RESUMEN
A series of pleuromutilin analogs containing substituted benzoxazole were designed, synthesised, and assessed for their antibacterial activity both in vivo and in vitro. The MIC of the synthesised derivatives was initially assessed using the broth dilution method against four strains of Staphylococcus aureus (MRSA ATCC 43300, S. aureus ATCC 29213, clinical isolation of S. aureus AD3 and S. aureus 144). Most of the synthesised derivatives displayed prominent in vitro activity (MIC ≤ 0.5 µg/mL). Compounds 50 and 57 exhibited the most effective antibacterial effect against MRSA (MIC = 0.125 µg/mL). Furthermore, the time-kill curves showed that compounds 50 and 57 had a certain inhibitory effect against MRSA in vitro. The in vivo antibacterial activity of compound 50 was evaluated further using a murine thigh model infected with MRSA (-1.24 log10CFU/mL). Compound 50 exhibited superior antibacterial efficacy to tiamulin. It was also found that compound 50 did not display significant inhibitory effect on the proliferation of RAW 264.7 cells. Molecular docking study revealed that compound 50 can effectively bind to the active site of the 50S ribosome (the binding free energy -7.50 kcal/mol).
Asunto(s)
Antibacterianos , Staphylococcus aureus , Animales , Ratones , Simulación del Acoplamiento Molecular , Antibacterianos/farmacología , Benzoxazoles/farmacología , PleuromutilinasRESUMEN
A series of thioether pleuromutilin derivatives containing 1,2,4-triazole on the side chain of C14 were designed and synthesized. The in vitro antibacterial activities experiments of the synthesized derivatives showed that compounds 72 and 73 displayed superior in vitro antibacterial effect against MRSA minimal inhibitory concentration (MIC = 0.0625 µg/mL) than tiamulin (MIC = 0.5 µg/mL). The results of time-kill study and postantibiotic effect study indicated that compound 72 could inhibit the growth of MRSA quickly (-2.16 log10 CFU/mL) and showed certain postantibiotic effect (PAE) time (exposure to 2 × MIC and 4 × MIC for 2 h, the PAE was 1.30 and 1.35 h) against MRSA. Furthermore, the binding mode between compound 72 and 50S ribosome of MRSA was explored by molecular docking and five hydrogen bonds were formed between compound 72 and 50S ribosome.
Asunto(s)
Antibacterianos , Compuestos Policíclicos , Simulación del Acoplamiento Molecular , Antibacterianos/química , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/química , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , PleuromutilinasRESUMEN
A series of pleuromutilin derivatives containing benzimidazole were designed, synthesized, and evaluated for their antibacterial activities against Methicillin-resistant Staphylococcus aureus (MRSA) in this study. The in vitro antibacterial activities of the synthesized derivatives against four strains of S. aureus (MRSA ATCC 43300, S. aureus ATCC 29213, S. aureus 144, and S. aureus AD3) were determined by the broth dilution method. Among these derivatives, compound 58 exhibited superior in vitro antibacterial effect against MRSA (minimal inhibitory concentration [MIC] = 0.0625 µg/mL) than tiamulin (MIC = 0.5 µg/mL). Compound 58 possessed a faster bactericidal kinetic and a longer post-antibiotic effect time against MRSA than tiamulin. Meanwhile, at 8 µg/mL concentration, compound 58 did not display obviously cytotoxic effect on the RAW 264.7 cells. In addition, compound 58 (-2.04 log10 CFU/mL) displayed superior in vivo antibacterial efficacy than tiamulin (-1.02 log10 CFU/mL) in reducing MRSA load in mice thigh infection model. In molecular docking study, compound 58 can successfully attach to the 50S ribosomal active site (the binding free energy is -8.11 kcal/mol). Therefore, compound 58 was a potential antibacterial candidate for combating MRSA infections.
Asunto(s)
Staphylococcus aureus Resistente a Meticilina , Animales , Ratones , Staphylococcus aureus , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Antibacterianos/química , Pruebas de Sensibilidad Microbiana , Bencimidazoles/farmacología , PleuromutilinasRESUMEN
Two series of pleuromutilin derivatives were designed and synthesized as inhibitors against Staphylococcus aureus (S. aureus). 6-chloro-4-amino-1-R-1H-pyrazolo[3,4-d]pyrimidine or 4-(6-chloro-1-R-1H-pyrazolo[3,4-d]pyrimidine-4-yl)amino-phenylthiol were connected to pleuromutilin. A diverse array of substituents was introduced at the N-1 position of the pyrazole ring. The in vitro antibacterial activities of these semisynthetic derivatives were evaluated against two standard strains, Methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300, Staphylococcus aureus (S. aureus), ATCC 29213 and two clinical S. aureus strains (144, AD3) using the broth dilution method. Compounds 12c, 19c and 22c (MIC = 0.25 µg/mL) manifested good in vitro antibacterial ability against MRSA which was similar to that of tiamulin (MIC = 0.5 µg/mL). Among them, compound 22c killed MRSA in a time-dependent manner and performed faster bactericidal kinetics than tiamulin in time-kill curves. In addition, compound 22c exhibited longer PAE than tiamulin, and showed no significant inhibition on the cell viability of RAW 264.7, Caco-2 and 16-HBE cells at high doses (≤8 µg/mL). The neutropenic murine thigh infection model study revealed that compound 22c displayed more effective in vivo bactericidal activity than tiamulin in reducing MRSA load. The molecular docking studies indicated that compound 22c was successfully localized inside the binding pocket of 50S ribosomal, and four hydrogen bonds played important roles in the binding of them.
Asunto(s)
Diterpenos , Staphylococcus aureus Resistente a Meticilina , Compuestos Policíclicos , Infecciones Estafilocócicas , Animales , Ratones , Humanos , Staphylococcus aureus , Simulación del Acoplamiento Molecular , Células CACO-2 , Pruebas de Sensibilidad Microbiana , Antibacterianos/química , Diterpenos/química , Compuestos Policíclicos/farmacología , Pirimidinas/farmacología , Pirimidinas/química , Infecciones Estafilocócicas/tratamiento farmacológico , PleuromutilinasRESUMEN
A series of novel pleuromutilin derivatives containing 4-aminothiophenol moieties have been designed and synthesized as promising antibacterial agents against Methicillin-resistant Staphylococcus aureus (MRSA). The in vitro antibacterial activity of these semisynthetic derivatives against 4 strains of S. aureus (MRSA ATCC 43300, S. aureus ATCC 29213, S. aureus 144 and S. aureus AD3) was evaluated by the broth dilution method. Most of the synthesized derivatives displayed prominent in vitro activity (MIC ≤ 0.5 µg/mL). 12 Compounds possessed superior antibacterial activity against MRSA compared with valnemulin and retapamulin (MIC = 0.0625 µg/mL). Compounds 12, 16a, 16c and 19 exhibited the most effective antibacterial effect against MRSA (MIC = 0.015 µg/mL). Furthermore, the time-kill curves showed compounds 12 and 19 had a certain inhibitory effect against MRSA in vitro. Compounds 12 and 19 possessed longer PAE time (2.74 h and 3.11 h, respectively) than tiamulin (PAE = 2.04 h) against MRSA after exposure at 4 × MIC concentration for 2 h. Compounds 12 and 19 also displayed superior in vivo antibacterial efficacy (-1.20 log10 CFU/mL and -1.21 log10 CFU/mL, respectively) than tiamulin (-0.75 log10 CFU/mL) in reducing MRSA load in the mice thigh infection model. In addition, compound 19 had barely inhibitory effect on RAW 264.7 and 16HBE cells at 8 µg/mL. In molecular docking study, upon docking into the 50S ribosomal subunit, the binding free energy (ΔGb) of compound 12 and 19 was calculated to be -9.02 kcal/mol and -9.89 kcal/mol, respectively.
Asunto(s)
Staphylococcus aureus Resistente a Meticilina , Compuestos de Anilina , Animales , Antibacterianos/química , Diterpenos , Ratones , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Compuestos Policíclicos , Staphylococcus aureus , Compuestos de Sulfhidrilo , PleuromutilinasRESUMEN
A series of pleuromutilin derivatives containing alkylamine and nitrogen heterocycle groups were designed and synthesised under mild conditions. The in vitro antibacterial activity of these semisynthetic derivatives against four strains of Staphylococcus aureus (MRSA ATCC 43300, S.aureus ATCC 29213, S.aureus AD3, and S.aureus 144) were evaluated by the broth dilution method. Compound 13 was found to have excellent antibacterial activity against MRSA (MIC = 0.0625 µg/mL). Furthermore, compound 13 was further studied by the time-killing kinetics and the post-antibiotic effect approach. In the mouse thigh infection model, compound 13 exhibited superior antibacterial efficacy than that of tiamulin. Meanwhile, compound 13 showed a lower inhibitory effect than that of tiamulin on RAW264.7 and 16HBE cells at the concentration of 10 µg/mL. Molecular docking study revealed that compound 13 can effectively bind to the active site of the 50S ribosome (the binding free energy = -9.66 kcal/mol).
Asunto(s)
Diterpenos , Staphylococcus aureus Resistente a Meticilina , Compuestos Policíclicos , Animales , Antibacterianos/química , Antibacterianos/farmacología , Diterpenos/química , Diterpenos/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Nitrógeno/farmacología , Compuestos Policíclicos/farmacología , Staphylococcus aureus , PleuromutilinasRESUMEN
A series of novel pleuromutilin derivatives containing nitrogen groups on the side chain of C14 were synthesized under mild conditions. Most of the synthesized derivatives displayed potent antibacterial activities. Compound 9 was found to be the most active antibacterial derivative against MRSA (MIC = 0.06 µg/mL). Furthermore, the result of time-kill curves showed that compound 9 had a certain inhibitory effect against MRSA in vitro. Moreover, according to a surface plasmon resonance (SPR) study, compound 9 (KD = 1.77 × 10-8 M) showed stronger affinity to the 50S ribosome than tiamulin (KD = 2.50 × 10-8 M). The antibacterial activity of compound 9 was further evaluated in an MRSA-infected murine thigh model. Compared to the negative control group, tiamulin reduced MRSA load (~0.7 log10 CFU/mL), and compound 9 performed a treatment effect (~1.3 log10 CFU/mL). In addition, compound 9 was evaluated in CYP450 inhibition assay and showed only moderate in vitro CYP3A4 inhibition (IC50 = 2.92 µg/mL).
Asunto(s)
Antibacterianos/uso terapéutico , Diterpenos/uso terapéutico , Descubrimiento de Drogas , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Compuestos Policíclicos/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Animales , Humanos , Ratones , Resonancia por Plasmón de Superficie , PleuromutilinasRESUMEN
A series of novel pleuromutilin derivatives were designed and synthesized with 1,2,4-triazole as the linker connected to benzoyl chloride analogues under mild conditions. The in vitro antibacterial activities of the synthesized derivatives against four strains of Staphylococcus aureus (MRSA ATCC 43300, ATCC 29213, AD3 and 144) were tested by the broth dilution method. Most of the synthesized derivatives displayed potent activities, and 22-(3-amino-2-(4-methyl-benzoyl)-1,2,4-triazole-5-yl)-thioacetyl)-22-deoxypleuromutilin (compound 12) was found to be the most active antibacterial derivative against MRSA (MIC = 0.125 µg/mL). Furthermore, the time-kill curves showed compound 12 had a certain inhibitory effect against MRSA in vitro. The in vivo antibacterial activity of compound 12 was further evaluated using MRSA infected murine thigh model. Compound 12 exhibited superior antibacterial efficacy than tiamulin. It was also found that compound 12 had no significant inhibitory effect on the proliferation of RAW264.7 cells. Compound 12 was further evaluated in CYP450 inhibition assay and showed moderate inhibitory effect on CYP3A4 (IC50 = 3.95 µM). Moreover, seven candidate compounds showed different affinities with the 50S ribosome by SPR measurement. Subsequently, binding of compound 12 and 20 to the 50S ribosome was further investigated by molecular modeling. Three strong hydrogen bonds were formed through the interaction of compound 12 and 20 with 50S ribosome. The binding free energy of compound 12 and 20 with the ribosome was calculated to be -10.7 kcal/mol and -11.66 kcal/mol, respectively.
Asunto(s)
Antibacterianos/farmacología , Diterpenos/farmacología , Diseño de Fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Compuestos Policíclicos/farmacología , Subunidades Ribosómicas Grandes Bacterianas/efectos de los fármacos , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Supervivencia Celular/efectos de los fármacos , Diterpenos/síntesis química , Diterpenos/química , Relación Dosis-Respuesta a Droga , Femenino , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/química , Células RAW 264.7 , Relación Estructura-Actividad , PleuromutilinasRESUMEN
A class of pleuromutilin derivatives containing 1, 3, 4-oxadiazole were designed and synthesized as potential antibacterial agents against Methicillin-resistant staphylococcus aureus (MRSA). The ultrasound-assisted reaction was proposed as a green chemistry method to synthesize 1, 3, 4-oxadiazole derivatives (intermediates 85-110). Among these pleuromutilin derivatives, compound 133 was found to be the strongest antibacterial derivative against MRSA (MIC = 0.125 µg/mL). Furthermore, the result of the time-kill curves displayed that compound 133 could inhibit the growth of MRSA in vitro quickly (- 4.36 log10 CFU/mL reduction). Then, compound 133 (- 1.82 log10 CFU/mL) displayed superior in vivo antibacterial efficacy than tiamulin (- 0.82 log10 CFU/mL) in reducing MRSA load in mice thigh model. Besides, compound 133 exhibited low cytotoxicity to RAW 264.7 cells. Molecular docking studies revealed that compound 133 was successfully localized in the binding pocket of 50S ribosomal subunit (ΔGb = -10.50 kcal/mol). The results indicated that these pleuromutilin derivatives containing 1, 3, 4-oxadiazole might be further developed into novel antibiotics against MRSA.
Asunto(s)
Antibacterianos/farmacología , Diterpenos/farmacología , Diseño de Fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Simulación del Acoplamiento Molecular , Oxadiazoles/farmacología , Compuestos Policíclicos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Diterpenos/síntesis química , Diterpenos/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxadiazoles/química , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/química , Relación Estructura-Actividad , PleuromutilinasRESUMEN
Novel series of pleuromutilin analogs containing substituted 1,2,3-triazole moieties were designed, synthesised and assessed for their in vitro antibacterial activity against Methicillin-resistant Staphylococcus aureus (MRSA). Initially, the in vitro antibacterial activities of these derivatives against 4 strains of S. aureus (MRSA ATCC 43300, ATCC 29213, AD3, and 144) were tested by the broth dilution method. Most of the synthesised pleuromutilin analogs displayed potent activities. Among them, compounds 50, 62, and 64 (MIC = 0.5â¼1 µg/mL) showed the most effective antibacterial activity and their anti-MRSA activity were further studied by the time-killing kinetics approach. Binding mode investigations by surface plasmon resonance (SPR) with 50S ribosome revealed that the selected compounds all showed obvious affinity for 50S ribosome (KD = 2.32 × 10-8â¼5.10 × 10-5 M). Subsequently, the binding of compounds 50 and 64 to the 50S ribosome was further investigated by molecular modelling. Compound 50 had a superior docking mode with 50S ribosome, and the binding free energy of compound 50 was calculated to be -12.0 kcal/mol.
Asunto(s)
Antibacterianos/farmacología , Diterpenos/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Simulación del Acoplamiento Molecular , Compuestos Policíclicos/farmacología , Resonancia por Plasmón de Superficie , Antibacterianos/síntesis química , Antibacterianos/química , Química Clic , Diterpenos/síntesis química , Diterpenos/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/química , PleuromutilinasRESUMEN
A novel pleuromutilin derivative, 22-(4-(2-(4-nitrophenyl-piperazin-1-yl)-acetyl)-piperazin-1-yl)-22-deoxypleuromutilin (NPDM), was synthesized in our laboratory and proved excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). In this study, more methods were used to further study its preliminary pharmacological effect. The antibacterial efficacy and toxicity of NPDM were evaluated using tiamulin as the reference drug. The in vitro antibacterial activity study showed that NPDM is a potent bactericidal agent against MRSA that induced time-dependent growth inhibition and a concentration-dependent post-antibiotic effect (PAE). Toxicity determination showed that the cytotoxicity of NPDM was slightly higher than that of tiamulin, but the acute oral toxicity study proved that NPDM was a low-toxic compound. In an in vivo antibacterial effect study, NPDM exhibited a better therapeutic effect than tiamulin against MRSA in a mouse thigh infection model as well as a mouse systemic infection model with neutropenia. The 50% effective dose (ED50) of NPDM in a Galleria mellonella infection model was 50.53 mg/kg. The pharmacokinetic properties of NPDM were also measured, which showed that NPDM was a rapid elimination drug in mice.
Asunto(s)
Antibacterianos/farmacología , Diterpenos/farmacología , Nitrofenoles/farmacología , Piperazina/farmacología , Compuestos Policíclicos/farmacología , Animales , Línea Celular , Insectos/microbiología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana/métodos , Ratas , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , PleuromutilinasRESUMEN
Inhibition of integrin α5ß1 emerges as a novel therapeutic option to block transmission of contractile forces during asthma attack. We designed and synthesized novel inhibitors of integrin α5ß1 by backbone replacement of known αvß1 integrin inhibitors. These integrin α5ß1 inhibitors also retain the nanomolar potency against αvß1 integrin, which shows promise for developing dual integrin α5ß1/αvß1 inhibitor. Introduction of hydrophobic adamantane group significantly boosted the potency as well as selectivity over integrin αvß3. We also demonstrated one of the inhibitors (11) reduced airway hyperresponsiveness in ex vivo mouse tracheal ring assay. Results from this study will help guide further development of integrin α5ß1 inhibitors as potential novel asthma therapeutics.
Asunto(s)
Adamantano/farmacología , Integrina alfa5beta1/antagonistas & inhibidores , Receptores de Vitronectina/antagonistas & inhibidores , Hipersensibilidad Respiratoria/tratamiento farmacológico , Adamantano/química , Animales , Relación Dosis-Respuesta a Droga , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of novel pleuromutilin derivatives containing piperazine ring, 1, 2, 3-triazoles and secondary amines on the side chain of C14 were synthesized under mild conditions via click reaction. The in vitro antibacterial activities of the synthesized derivatives against four strains of Staphylococcus aureus (MRSA ATCC 43300, ATCC 29213 ,144 and AD3) and one strain of Escherichia coli (ATCC 25922) were evaluated by the broth dilution method. Among these derivatives, 22-[2-(4-((4-nitrophenyl piperazine)methyl)-1,2,3-triazol-1-yl)-1-(piperazine-1-yl) ethyl-1-one] deoxy pleuromutilin (compound 59) showed the most prominent in vitro antibacterial effect against MRSA (MIC = 1 µg/mL). Furthermore, compound 59 displayed more rapid bactericidal kinetic than tiamulin time-kill studies and possessed a longer PAE than tiamulin against MRSA in vitro. In addition, in vivo antibacterial activities of compound 59 against MRSA were further evaluated employing thigh infection model. And compound 59 (-8.89 log10 CFU/mL) displayed superior activities than tiamulin. Compound 59 was further evaluated in CYP450 inhibition assay and the results showed that it exhibited low to moderate inhibitory effects on CYP1A2, CYP2E1, CYP2D6 and CYP3A4 enzymes. The PK properties of compound 59 were then measured. The half-life (t1/2), clearance rate (Cl) and the area under the plasma concentration time curve (AUC0â∞) of compound 59 were 0.74 h, 0.29 L/h/kg and 46.28 µg·h/mL, respectively.
Asunto(s)
Antibacterianos/farmacología , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Diterpenos/farmacología , Diseño de Fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Compuestos Policíclicos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Inhibidores Enzimáticos del Citocromo P-450/síntesis química , Inhibidores Enzimáticos del Citocromo P-450/química , Diterpenos/síntesis química , Diterpenos/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Estructura Molecular , Piperazina/química , Piperazina/farmacología , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/química , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacología , PleuromutilinasRESUMEN
Tetracycline (TET) has been widely used in the treatment of Streptococcus suis (S. suis) infection. However, it was found that the efficacy of many antibiotics in S. suis decreased significantly, especially tetracycline. In this study, GML-12 (a novel pleuromutilin derivative) was used in combination with TET against 12 S. suis isolates. In the checkerboard assay, the TET/GML-12 combination exhibited synergistic and additive effects against S. suis isolates (n = 12). In vitro time-killing assays and in vivo therapeutic experiments were used to confirm the synergistic effect of the TET/GML-12 combination against S. suis strains screened based on an FICI ≤ 0.5. In time-killing assays, the TET/GML-12 combination showed a synergistic effect or an additive effect against three isolates with a bacterial reduction of over 2.4-log10 CFU/mL compared with the most active monotherapy. Additionally, the TET/GML-12 combination displayed potent antimicrobial activity against four isolates in a mouse thigh infection model. These results suggest that the TET/GML-12 combination may be a potential therapeutic strategy for S. suis infection.
Asunto(s)
Antibacterianos/administración & dosificación , Diterpenos/administración & dosificación , Compuestos Policíclicos/administración & dosificación , Infecciones Estreptocócicas/tratamiento farmacológico , Streptococcus suis/efectos de los fármacos , Tetraciclina/administración & dosificación , Animales , Antibacterianos/toxicidad , Zoonosis Bacterianas/tratamiento farmacológico , Zoonosis Bacterianas/microbiología , Modelos Animales de Enfermedad , Diterpenos/toxicidad , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Humanos , Técnicas In Vitro , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Neutropenia/tratamiento farmacológico , Neutropenia/microbiología , Compuestos Policíclicos/toxicidad , Infecciones Estreptocócicas/microbiología , Streptococcus suis/aislamiento & purificación , Porcinos , Enfermedades de los Porcinos/tratamiento farmacológico , Enfermedades de los Porcinos/microbiología , PleuromutilinasRESUMEN
In this study, we designed and synthesized a series of pleuromutilin derivatives containing thiazole. The in vitro antimicrobial efficacy of these synthesized compounds was examined by using four strains. Compared with tiamulin (MIC = 0.25 µg/mL), compound 14 exhibited potency in inhibiting MRSA growth (MIC = 0.0625 µg/mL) in these derivatives. Meanwhile, the time-killing kinetics further demonstrated that compound 14 could efficiently inhibit the MRSA growth. After exposure at 4 × MIC, the postantibiotic effect (PAE) of compound 14 was 1.29 h. Additionally, in thigh-infected mice, compound 14 exhibited a more potent antibacterial efficacy (-1.78 ± 0.28 log10 CFU/g) in reducing MRSA load compared to tiamulin (-1.21 ± 0.23 log10 CFU/g). Moreover, the MTT assay on RAW 264.7 cells demonstrated that compound 14 (8 µg/mL) had no significant cytotoxicity. Docking studies indicated the strong affinity of compound 14 toward the 50S ribosomal subunit, with a binding free energy of -9.63 kcal/mol. Taken together, it could be deduced that compound 14 was a promising candidate for treating MRSA infections.
Asunto(s)
Antibacterianos , Diterpenos , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Pleuromutilinas , Compuestos Policíclicos , Infecciones Estafilocócicas , Tiazoles , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/química , Diterpenos/farmacología , Diterpenos/química , Diterpenos/síntesis química , Animales , Ratones , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Tiazoles/farmacología , Tiazoles/química , Tiazoles/síntesis química , Infecciones Estafilocócicas/tratamiento farmacológico , Diseño de Fármacos , Células RAW 264.7RESUMEN
14 novel pleuromutilin derivatives were designed and synthesized as inhibitors against Staphylococcus aureus (S. aureus). The modification was focused on the C22 position of pleuromutilin. We conducted the characterization, in vitro and in vivo biological assessment of the compounds. Compound 18 exhibited the best antibacterial effect against MRSA (MIC = 0.015 µg/mL, MBC = 0.125 µg/mL). Compound 18 was further studied by time-kill kinetic and post-antibiotic effect (PAE) approaches. Besides, most compounds exhibited low cytotoxicity to RAW 264.7 cells. Compound 18 displayed decent bactericidal activity in vivo (-0.51 log10 CFU/mL). Molecular docking study indicated that compound 18 could be located stably at the ribosome (ΔGb = -7.30 kcal/mol). The results revealed that compound 18 might be further developed into a novel antibiotic.
Asunto(s)
Antibacterianos , Diterpenos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Pleuromutilinas , Compuestos Policíclicos , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Diterpenos/farmacología , Diterpenos/química , Ratones , Animales , Estructura Molecular , Células RAW 264.7 , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Diseño de Fármacos , Staphylococcus aureus/efectos de los fármacos , Infecciones Estafilocócicas/tratamiento farmacológicoRESUMEN
Oxidative stress and inflammation responses are closely related to the occurrence and development of many diseases. Therefore, anti-oxidation and anti-inflammation have become hot spots in the treatment of diseases. A series of novel resveratrol derivatives which hybrid with benzoylhydrazines were designed, synthesized and assessed for their in vitro antioxidant and anti-inflammatory activity. Initially, the antioxidant abilities of resveratrol derivatives were investigated by DPPH, ABTS radical scavenging and FRAP assays. RAW 264.7 macrophages are routinely used to evaluate the antioxidant and anti-inflammatory activities of drugs, so we used it to construct cell models of oxidative stress and inflammation. Among all the derivatives, compound 5 exhibited superior ROS- and NO-inhibitory activities. The molecular mechanism detected by Western blotting showed that compound 5 could significantly activate the Nrf2 signaling pathway and up-regulate the expression of HO-1 to resist oxidative stress stimulated by H2O2. At the same time, it could down-regulate the expression of apoptosis-related proteins Caspase3 and PARP, alleviating cells damage and apoptosis. In addition, compound 5 dose-dependently inhibited the activation of NF-κB p65/iNOS and MAPKs signaling pathway.
Asunto(s)
Antioxidantes , Peróxido de Hidrógeno , Ratones , Animales , Humanos , Antioxidantes/uso terapéutico , Resveratrol/farmacología , Resveratrol/uso terapéutico , Peróxido de Hidrógeno/farmacología , FN-kappa B/metabolismo , Células RAW 264.7 , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Inflamación/tratamiento farmacológico , Estrés Oxidativo , Lipopolisacáridos/farmacología , Factor 2 Relacionado con NF-E2/metabolismoRESUMEN
A series of diclofenac hybrid molecules were synthesized and evaluated for their NO-inhibitory ability in LPS-induced RAW 264.7 macrophage cells. Among them, compound 1 showed the highest NO-inhibitory ability (approximately 66%) and no significant cytotoxicity. Compound 1 exhibited superior NF-κB-inhibitory ability compared to diclofenac through the activation of Nrf2/HO-1 signaling pathway in RAW 264.7. 20 mg/kg compound 1 resulted in remarkable colitis improvement in dextran sulfate sodium (DSS)-induced mice model by up-regulating HO-1 and down-regulating phosphorylation level of NF-κB p65. Moreover, 50 mg/kg dose of compound 1 showed a lower ulcerogenic potential compared to diclofenac in rats. The diclofenac-eugenol hybrid (compound 1) may serve as a novel anti-inflammatory agent based on its role in inhibiting the NF-κB signaling pathway and activating HO-1 expression with no toxicity in vitro and in vivo.