RESUMO
Bacterial cystitis, a commonly occurring urinary tract infection (UTI), is renowned for its extensive prevalence and tendency to recur. Despite the extensive utilization of levofloxacin as a conventional therapeutic approach for bacterial cystitis, its effectiveness is impeded by adverse toxic effects, drug resistance concerns, and its influence on the gut microbiota. This study introduces Lev@PADM, a hydrogel with antibacterial properties that demonstrates efficacy in the treatment of bacterial cystitis. Lev@PADM is produced by combining levofloxacin with decellularized porcine acellular dermal matrix hydrogel and exhibits remarkable biocompatibility. Lev@PADM demonstrates excellent stability as a hydrogel at body temperature, enabling direct administration to the site of infection through intravesical injection. This localized delivery route circumvents the systemic circulation of levofloxacin, resulting in a swift and substantial elevation of the antimicrobial agent's concentration specifically at the site of infection. The in vivo experimental findings provide evidence that Lev@PADM effectively prolongs the duration of levofloxacin's action, impedes the retention and invasion of E.coli in the urinary tract, diminishes the infiltration of innate immune cells into infected tissues, and simultaneously preserves the composition of the intestinal microbiota. These results indicate that, in comparison to the exclusive administration of levofloxacin, Lev@PADM offers notable benefits in terms of preserving the integrity of the bladder epithelial barrier and suppressing the recurrence of urinary tract infections.
Assuntos
Derme Acelular , Cistite , Infecções Urinárias , Suínos , Animais , Levofloxacino , HidrogéisRESUMO
α-Glucosidase, which is involved in the hydrolysis of carbohydrates to glucose and directly mediates blood glucose elevation, is a crucial therapeutic target for type 2 diabetes. In this work, 2,5-disubstituted furan derivatives containing 1,3-thiazole-2-amino or 1,3-thiazole-2-thiol moiety (III-01 â¼ III-30) were synthesized and screened for their inhibitory activity against α-glucosidase. α-Glucosidase inhibition assay demonstrated that all compounds had IC50 in the range of 0.645-94.033 µM and more potent than standard inhibitor acarbose (IC50 = 452.243 ± 54.142 µM). The most promising inhibitors of the two series were compound III-10 (IC50 = 4.120 ± 0.764 µM) and III-24 (IC50 = 0.645 ± 0.052 µM), respectively. Kinetic study and molecular docking simulation revealed that compound III-10 (Ki = 2.04 ± 0.72 µM) is a competitive inhibitor and III-24 (Ki = 0.44 ± 0.53 µM) is a noncompetitive inhibitor against α-glucosidase. Significantly, these two compounds showed nontoxicity towards HEK293, RAW264.7 and HepG2 cells, suggesting that compounds may be considered as a class of potential candidates for further developing novel antidiabetic drugs.
Assuntos
Diabetes Mellitus Tipo 2 , Inibidores de Glicosídeo Hidrolases , Humanos , alfa-Glucosidases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Células HEK293 , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/farmacologia , Furanos/químicaRESUMO
α-Glucosidase inhibitors (AGIs) are oral antidiabetic drugs, preferably used in treating type 2 diabetes mellitus, that delay the absorption of carbohydrates from the gastrointestinal system. In this work, 2,5-disubstituted furan derivatives containing imidazole, triazole or tetrazole moiety (III-01 â¼ III-45) were synthesized and characterized by elemental analysis, HRMS, 1H NMR, 13C NMR and single crystal X-ray. Their inhibitory activity against α-glucosidase was screened. The most promising inhibitors were compound III-11 (IC50 = 6.0 ± 1.1 µM), III-16 (IC50 = 2.2 ± 0.2 µM) and III-39 (IC50 = 4.6 ± 1.9 µM), respectively. Kinetic study revealed that compounds III-11 and III-39 were uncompetitive inhibitors against α-glucosidase. Meanwhile, III-16 (Ki = 5.1 ± 0.7 µM) was a competitive inhibitor. Furthermore, molecular docking studies indicated that the existence of the azole group played a critically important role in hydrogen bond interaction with α-glucosidase. Significantly, in vivo toxicity towards HEK293 cells, RAW264.7 cells and HepG2 cells suggested that compounds III-11 and III-39 possessed non-toxicity, that could be considered as potential candidates for further development of novel antidiabetic drugs.
Assuntos
Diabetes Mellitus Tipo 2 , Inibidores de Glicosídeo Hidrolases , Humanos , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Relação Estrutura-Atividade , alfa-Glucosidases/metabolismo , Simulação de Acoplamento Molecular , Triazóis/farmacologia , Triazóis/química , Células HEK293 , Hipoglicemiantes/farmacologia , Imidazóis/farmacologia , Tetrazóis , Estrutura Molecular , CinéticaRESUMO
Gut microbial ß-glucuronidases have drawn much attention due to their role as a potential therapeutic target to alleviate some drugs or their metabolites-induced gastrointestinal toxicity. In this study, fifteen 5-phenyl-2-furan derivatives containing 1,3-thiazole moiety (1-15) were synthesized and evaluated for their inhibitory effects against Escherichia coli ß-glucuronidase (EcGUS). Twelve of them showed satisfactory inhibition against EcGUS with IC50 values ranging from 0.25 µM to 2.13 µM with compound 12 exhibited the best inhibition. Inhibition kinetics studies indicated that compound 12 (Ki = 0.14 ± 0.01 µM) was an uncompetitive inhibitor for EcGUS and molecular docking simulation further predicted the binding model and capability of compound 12 with EcGUS. A preliminary structure-inhibitory activity relationship study revealed that the heterocyclic backbone and bromine substitution of benzene may be essential for inhibition against EcGUS. The compounds have the potential to be applied in drug-induced gastrointestinal toxicity and the findings would help researchers to design and develop more effective 5-phenyl-2-furan type EcGUS inhibitors.
Assuntos
Descoberta de Drogas , Escherichia coli/enzimologia , Furanos/farmacologia , Glucuronidase/antagonistas & inibidores , Glicoproteínas/farmacologia , Tiazóis/farmacologia , Relação Dose-Resposta a Droga , Furanos/síntese química , Furanos/química , Glucuronidase/metabolismo , Glicoproteínas/síntese química , Glicoproteínas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
Gut microbial ß-glucuronidases have the ability to deconjugate glucuronides of some drugs, thus have been considered as an important drug target to alleviate the drug metabolites-induced gastrointestinal toxicity. In this study, thiazolidin-2-cyanamide derivatives containing 5-phenyl-2-furan moiety (1-13) were evaluated for inhibitory activity against Escherichia coli ß-glucuronidase (EcGUS). All of them showed more potent inhibition than a commonly used positive control, d-saccharic acid 1,4-lactone, with the IC50 values ranging from 1.2 µM to 23.1 µM. Inhibition kinetics studies indicated that compound 1-3 were competitive type inhibitors for EcGUS. Molecular docking studies were performed and predicted the potential molecular determinants for their potent inhibitory effects towards EcGUS. Structure-inhibitory activity relationship study revealed that chloro substitution on the phenyl moiety was essential for EcGUS inhibition, which would help researchers to design and develop more effective thiazolidin-2-cyanamide type inhibitors against EcGUS.
Assuntos
Cianamida/farmacologia , Escherichia coli/enzimologia , Glucuronidase/antagonistas & inibidores , Glicoproteínas/farmacologia , Tiazolidinas/farmacologia , Cianamida/química , Relação Dose-Resposta a Droga , Glucuronidase/metabolismo , Glicoproteínas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiazolidinas/químicaRESUMO
Tetrahydroquinoline and tetrahydroisoquinoline derivatives containing 2-phenyl-5-furan moiety were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. The bioassay results showed that title compounds showed good inhibitory activity against PDE4B and blockade of LPS (lipopolysaccharide) induced TNF-α release, which also exhibited considerable in vivo activity in animal models of asthma/COPD (chronic obstructive pulmonary disease) and sepsis induced by LPS. The bioactivity of compounds containing tetrahydroquinoline (series 4) was higher than that of tetrahydroisoquinoline derivatives (series 3). Compound 4â¯m with 4-methoxybenzene moiety exhibited the best potential selective activity against PDE4B. The primary structure-activity relationship study and docking results showed that the tetrahydroquinoline moiety of compound 4â¯m played a key role to form hydrogen bonds and π-π stacking interaction with PDE4B protein while the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4B. Based on LPS induced sepsis model for the measurement of TNF-α inhibition in Swiss Albino mice and neutrophilia inhibition for asthma and COPD in Sprague Dawley rats with the potential molecules, compound 4â¯m would be great promise as a hit inhibitor in the future study.
Assuntos
Inibidores da Fosfodiesterase 4/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacologia , Animais , Domínio Catalítico , Camundongos , Inibidores da Fosfodiesterase 4/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
In this study, a series of pyrazole derivatives containing 4-phenyl-2-oxazole moiety were designed and synthesized in a concise way, some of which exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNF-α release. Compound 4c displayed the strongest inhibition activity (IC50=1.6±0.4µM) and good selectivity against PDE4B. Meanwhile, compound 4c showed good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary structure-activity relationship study showed the 3,5-dimethylpyrazole residue was essential for the bioactivity, and the substituted group R1 at the benzene ring also affected the activity. Docking results showed that compound 4c played a key role to form integral hydrogen bonds and a π-π stacking interaction, using hydrazide scaffold (CONN) and pyrazole ring respectively, with PDE4B protein. While the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4B. Compound 4c would be great promise as a lead compound for further study based on the preliminary structure-activity relationship and molecular modeling studies.
Assuntos
Oxazóis/química , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Pirazóis/química , Animais , Asma/tratamento farmacológico , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Modelos Animais de Doenças , Desenho de Fármacos , Feminino , Concentração Inibidora 50 , Masculino , Camundongos , Simulação de Acoplamento Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/uso terapêutico , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-AtividadeRESUMO
Metamerism phenomenon is an important problem in spectral reflectance reconstruction and color reproduction. In this paper, a 3-primary color CCD camera is used to acquire spectral information in CIE standard illuminant D65 and a nonlinear composite model is established, including principal component analysis and neural network method (PCA-NET) to modify the Matrix R Method based on the Metameric Black theory. The standard Munsell color card is used in spectral reflectance reconstruction experiment and the results are evaluated and discussed. The experimental results verified that the PCA-NET algorithm can accurately fit the nonlinear relationship between the output signal of the camera and the principal component coefficients; and it can be used in the R matrix algorithm instead of the linear algorithm; the new method can serve as a promising technique for building a spectral image database whihc is better than the original Matrix R Method. In the fixed illumination environment, the mean RMS of the test set is 0.76 improved, and the mean STD of the test set is 0.85 improved, which can effectively improve the accuracy of spectral reflectance reconstruction. The modified matrix R method has the advantages of higher accuracy and easy implementation, and it can be used in the field of color reproduction and spectral reflectance reconstruction.
Assuntos
Cor , Análise de Componente Principal , Algoritmos , IluminaçãoRESUMO
A series of pyrazole and triazole derivatives containing 5-phenyl-2-furan functionality were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. The bioassay results showed that title compounds exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNFα release. Meanwhile, the activity of compounds containing 1,2,4-triazole (series II) was higher than that of pyrazole-attached derivatives (series I). The primary structure-activity relationship study and docking results showed that the 1,2,4-triazole moiety of compound IIk played a key role to form integral hydrogen bonds and π-π stacking interaction with PDE4B protein while the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4. Compound IIk would be great promise as a hit compound for further study based on the preliminary structure-activity relationship and molecular modeling studies.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Pirazóis/farmacologia , Triazóis/farmacologia , Relação Dose-Resposta a Droga , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossínteseAssuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Piridinas/farmacologia , Tiofenos/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/química , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/químicaRESUMO
Background emergence of multidrug-resistant (MDR) bacterial strains is a public health concern that threatens global and regional security. Efflux pump-overexpressing MDR strains from clinical isolates are the best subjects for studying the mechanisms of MDR caused by bacterial efflux pumps. A Klebsiella pneumoniae strain overexpressing the OqxB-only efflux pump was screened from a clinical strain library to explore reverse OqxB-mediated bacterial resistance strategies. We identified non-repetitive clinical isolated K. pneumoniae strains using a matrix-assisted laser desorption/ionization time-of-flight (TOF) mass spectrometry clinical TOF-II (Clin-TOF-II) and susceptibility test screening against levofloxacin and ciprofloxacin. And the polymorphism analysis was conducted using pulsed-field gel electrophoresis. Efflux pump function of resistant strains is obtained by combined drug sensitivity test of phenylalanine-arginine beta-naphthylamide (PaßN, an efflux pump inhibitor) and detection with ethidium bromide as an indicator. The quantitative reverse transcription PCR was performed to assess whether the oqxB gene was overexpressed in K. pneumoniae isolates. Additional analyses assessed whether the oqxB gene was overexpressed in K. pneumoniae isolates and gene knockout and complementation strains were constructed. The binding mode of PaßN with OqxB was determined using molecular docking modeling. Among the clinical quinolone-resistant K. pneumoniae strains, one mediates resistance almost exclusively through the overexpression of the resistance-nodulation-division efflux pump, OqxB. Crystal structure of OqxB has been reported recently by N. Bharatham, P. Bhowmik, M. Aoki, U. Okada et al. (Nat Commun 12:5400, 2021, https://doi.org/10.1038/s41467-021-25679-0). The discovery of this strain will contribute to a better understanding of the role of the OqxB transporter in K. pneumoniae and builds on the foundation for addressing the threat posed by quinolone resistance.IMPORTANCEThe emergence of antimicrobial resistance is a growing and significant health concern, particularly in the context of K. pneumoniae infections. The upregulation of efflux pump systems is a key factor that contributes to this resistance. Our results indicated that the K. pneumoniae strain GN 172867 exhibited a higher oqxB gene expression compared to the reference strain ATCC 43816. Deletion of oqxB led a decrease in the minimum inhibitory concentration of levofloxacin. Complementation with oqxB rescued antibiotic resistance in the oqxB mutant strain. We demonstrated that the overexpression of the OqxB efflux pump plays an important role in quinolone resistance. The discovery of strain GN 172867 will contribute to a better understanding of the role of the OqxB transporter in K. pneumoniae and promotes further study of antimicrobial resistance.
RESUMO
P-glycoprotein (P-gp) is one of the drug efflux transporters that triggers multidrug resistance (MDR) in cells. Herein, by utilizing the strategies of active skeleton splicing and structural optimization on the lead compound 5 m, a total of 50 novel 2,5-disubstituted furan derivatives were designed, synthesized, and screened for P-gp inhibitory activity. The structure-activity relationship analysis enabled the identification of an important pharmacophore N-phenylbenzamide, which resulted in the discovery of a promising drug lead compound â ¢-8. â ¢-8 possesses broad-spectrum reversal activity and low toxicity in MCF-7/ADR cells. Western blot and Rh123 accumulation assay demonstrated that â ¢-8 displayed the reversal activity by inhibiting P-gp efflux. Molecular docking analysis indicated a potent affinity of â ¢-8 to P-gp by forming H-bond interactions with residues Asn 721 and Met 986. â ¢-8 was determined to be a highly effective and safe P-gp inhibitor in an MCF-7/ADR xenograft mouse model.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Resistência a Múltiplos Medicamentos , Animais , Humanos , Camundongos , Subfamília B de Transportador de Cassetes de Ligação de ATP , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Furanos/farmacologia , Células MCF-7 , Simulação de Acoplamento Molecular , Glicoproteínas/química , Glicoproteínas/metabolismoRESUMO
In this paper, the 2,5-disubstituted furan derivatives containing 1,3,4-thiadiazole were synthesized and screened for their inhibitory activity against α-glucosidase and ß-glucuronidases to obtain potent α-glucosidase inhibitor 9 (IC50 = 0.186 µM) and E. coli ß-glucuronidase inhibitor 26 (IC50 = 0.082 µM), respectively. The mechanisms of the compounds were studied. The kinetic study revealed that compound 9 is a competitive inhibitor against α-glucosidase (Ki = 0.05 ± 0.003 µM) and molecular docking simulation showed several key interactions between 9 and the target including hydrogen bond and p-π stacking interaction. Derivative 26 (Ki = 0.06 ± 0.005 µM) displayed uncompetitive inhibition behavior against EcGUS. Furthermore, the result of docking revealed the furan ring of 26 may be a key moiety in obstructing the active domain of EcGUS. In addition, compound 15 exhibited significant inhibitory activity against these two enzymes, with potential therapeutic effects against diabetes and against CPT-11-induced diarrhea. At the same time, their low toxicity against normal liver tissue LO2 cells lays the foundation for in vivo studies and the development of bifunctional drug.
Assuntos
Escherichia coli/enzimologia , Furanos/química , Glicoproteínas/química , Inibidores de Glicosídeo Hidrolases/química , Tiadiazóis/química , Sítios de Ligação , Domínio Catalítico , Linhagem Celular , Sobrevivência Celular , Proteínas de Escherichia coli/antagonistas & inibidores , Proteínas de Escherichia coli/metabolismo , Furanos/farmacologia , Glucuronidase/antagonistas & inibidores , Glucuronidase/metabolismo , Glicoproteínas/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Cinética , Simulação de Acoplamento Molecular , Relação Estrutura-AtividadeRESUMO
P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a phenomenon in which cells become resistant to structurally and mechanistically unrelated drugs resulting in low intracellular drug concentrations. It is one of the noteworthy problems in malignant tumor clinical therapeutics. So P-gp protein is one of the ideal targets to solve MDR. Based on the lead compound 5m obtained from our previous work, a series of furan derivatives featuring alkyl-substituted phenols and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline were designed and synthesized as reversal agents against P-gp in this paper. Compound 16 containing isopropoxy possessed good potency against P-gp mediated MDR in MCF-7/ADR (IC50 (doxorubicin) = 0.73 µM, RF = 69.6 with 5 µM 16 treated). Western blot results and Rh123 accumulation assays showed that 16 effectively inhibited P-gp efflux function but not its expression. The preliminary structure-activity relationship and docking studies demonstrated that compound 16 would be a potential P-gp inhibitor. Most worthy of mention is that compound 16 has achieved satisfactory results in combination with a variety of anti-tumor drugs, such as doxorubicin, paclitaxel, and vincristine. This study forwards a hopeful P-gp inhibitor for withstanding malignant tumor cell with multidrug resistance setting the basis for further studies.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacologia , Furanos/metabolismo , Furanos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Paclitaxel/farmacologia , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/metabolismo , Tetra-Hidroisoquinolinas/farmacologiaRESUMO
Multidrug resistance (MDR) is a tendency in which cells become resistant to structurally and mechanistically unrelated drugs, which is mediated by P-glycoprotein (P-gp). It is one of the noteworthy problems in cancer therapy. As one of the most important drugs in cancer therapy, doxorubicin has not good effectiveness if used independently. So targeting the P-gp protein is one of the key points to solve the MDR. Three series of furan derivatives containing tetrahydroquinoline or tetrahydroisoquinoline were designed and synthesized as P-gp inhibitors in this paper. Compound 5m containing 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline possessed good potency against P-gp (EC50â¯=â¯0.89⯱â¯0.11⯵M). The preliminary structure-activity relationship and docking studies demonstrated that compound 5m would be great promise as a lead compound for further study. Most worthy of mention is drug combination of doxorubicin and 5m displayed antiproliferative effect of about 97.8%. This study provides highlighted P-gp inhibitor for withstanding malignant tumor cell with multidrug resistance especially doxorubicin resistance setting the basis for further studies.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antibióticos Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Furanos/síntese química , Furanos/química , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/químicaRESUMO
A pair of chemical isomeric structures of novel N-tert-butylphenyl thenoylhydrazide compounds I and II were designed and synthesized. Their structures were characterized by MS, IR, (1)H NMR, elemental analysis and X-ray single crystal diffraction. The regioselectivity of the Meerwein arylation reaction and the electrophilic substitution reaction of N-tert-butyl hydrazine were studied by density functional theory (DFT) quantum chemical method. The larvicidal tests revealed that some compounds I had excellent larvicidal activity against Culex pipiens pallens. As the candidates of insect growth regulators (IGRs), the larval growth inhibition and regulation against Culex pipiens pallens were examined for some compounds, especially I1 and I7. Compounds I1 and I7 were further indicated as an ecdysteroid agonist by reporter gene assay on the Spodoptera frugiperda cell line (Sf9 cells). Finally, a molecular docking study of compound I7 was conducted, which was not only beneficial to understand the structure-activity relationship, but also useful for development of new IGRs for the control of mosquitos.
Assuntos
Hidrazinas/química , Inseticidas/química , Hormônios Juvenis/química , Larva/efeitos dos fármacos , Animais , Culex/efeitos dos fármacos , Culex/patogenicidade , Humanos , Hidrazinas/síntese química , Hidrazinas/farmacologia , Inseticidas/síntese química , Inseticidas/farmacologia , Hormônios Juvenis/síntese química , Hormônios Juvenis/farmacologia , Espectroscopia de Ressonância Magnética , Simulação de Acoplamento Molecular , Spodoptera/efeitos dos fármacos , Spodoptera/patogenicidade , Relação Estrutura-AtividadeRESUMO
A series of 2,5-disubstituted-1,3,4-thiadiazoles were synthesized using Lawesson's reagent by an efficient approach under microwave irradiation in good yields. Their structures were characterized by MS, IR, (1)H NMR, (13)C NMR, and elemental analysis. Their in vitro and in vivo fungicidal activities revealed that the title compounds exhibited considerable activity against five selected fungi, especially to Phytophthora infestans. In order to illustrate the mechanism of title compounds against P. infestans, scanning electron micrographs (SEM) and transmission electron micrographs (TEM) were applied. The morphological and ultrastructural studies demonstrated that compound I18 led to swelling of hyphae, thickening and proliferating multilayer cell walls, excessive septation and accumulation of dense bodies. The bioassay results indicated compound I18 might act on cell wall biosynthesis, and blocked the nutrition transportation and led to cells senescence and death. Meanwhile, compound I18 had broad fungicidal activity against other twenty different kinds of fungi. These results suggested that title compounds were eligible to be development candidates and compound I18 as a promising lead compound was worthy to be further discovery, especially against P. infestans.