Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 31
Filtrar
Más filtros










Base de datos
Intervalo de año de publicación
1.
Eur J Med Chem ; 216: 113322, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33652353

RESUMEN

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.

2.
Eur J Med Chem ; 216: 113336, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33725657

RESUMEN

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.

3.
Eur J Med Chem ; 207: 112795, 2020 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-33002845

RESUMEN

In this present study, a series of 5-phenyl-2-furan and 4-phenyl-2-oxazole derivatives were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. In vitro results showed that the synthesized compounds exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNF-α release. Among the designed compounds, Compound 5j exhibited lower IC50 value (1.4 µM) against PDE4 than parent rolipram (2.0 µM) in in vitro enzyme assay, which also displayed good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. Docking results suggested that introduction of methoxy group at para-position of phenyl ring, demonstrated good interaction with metal binding pocket domain of PDE4B, which was helpful to enhance inhibitory activity.

4.
J Enzyme Inhib Med Chem ; 35(1): 1736-1742, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32928007

RESUMEN

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.

5.
Bioorg Med Chem Lett ; 29(22): 126720, 2019 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-31610942

RESUMEN

Currently, it is in urgent need to develop novel selective PDE4 inhibitors with novel structural scaffolds to overcome the adverse effects and improve the efficacy. Novel 1-phenyl-3,4-dihydroisoquinoline amide derivatives were developed as potential PDE4 inhibitors based on the structure-based drug design and fragment identification strategy. A SARs analysis was performed in substituents attached in the C-3 side chain phenyl ring, indicating that the attachment of methoxy group or halogen atom substitution at the ortho-position of the phenyl ring was helpful to enhance both inhibitory activity toward PDE4B and selectivity. Compound 15 with excellent selectivity, exhibited the most potent inhibition in vitro and in vivo, which is a promising lead for development of a new class of selective PDE4 inhibitors.


Asunto(s)
Amidas/farmacología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Descubrimiento de Drogas , Isoquinolinas/farmacología , Inhibidores de Fosfodiesterasa 4/farmacología , Amidas/síntesis química , Amidas/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/química , Modelos Moleculares , Estructura Molecular , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/química , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismo
6.
J Agric Food Chem ; 67(43): 11867-11876, 2019 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-31584805

RESUMEN

Bacterial leaf blight (BLB) caused by Xanthomonas oryzae pv oryzae (Xoo) is considered as the most destructive disease of rice. The use of bactericides is among the most widely used traditional methods to control this destructive disease. The excessive and repeated use of the same bactericides is also becoming the reason behind the development of bactericide resistance. The widely used method for finding the new antimicrobial agents often involves the bacterial virulence factors as a target without affecting bacterial growth. Type III secretion system (T3SS) is a protein appendage and is considered as having essential virulence factors in most Gram-negative bacteria. Due to the conserved construct, T3SS has been regarded as an important mark for the blooming of novel antimicrobial drugs. Toward the search of new T3SS inhibitors, an alternative series of 1,3-thiazole derivatives were designed and synthesized. Their structures were characterized and confirmed by 1H NMR, 13C NMR, MS, and elemental analysis. All the title compounds inhibited the promoter activity of hpa1 gene significantly. Eight of them showed better inhibition than our previous T3SS inhibitor TS006 (o-coumaric acid, OCA). The treatment of Xoo with eight compounds significantly attenuated HR without affecting bacterial growth. The mRNA levels of some representative genes (hrp/hrc genes) were reduced up to different extents. In vivo bioassay results showed that eight T3SS inhibitors could reduce bacterial leaf blight and bacterial leaf streak symptoms on rice, significantly.


Asunto(s)
Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Furanos/farmacología , Oryza/microbiología , Enfermedades de las Plantas/microbiología , Sistemas de Secreción Tipo III/antagonistas & inhibidores , Xanthomonas/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Furanos/química , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Sistemas de Secreción Tipo III/genética , Sistemas de Secreción Tipo III/metabolismo , Xanthomonas/genética , Xanthomonas/metabolismo
7.
Front Microbiol ; 10: 1874, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31481941

RESUMEN

Xanthomonas oryzae pv. oryzae (Xoo) is a gram-negative pathogen which causes leaf blight disease. Known traditional bactericides are not much more effective in inhibiting this bacteria than before. Selecting the virulence factor of the bacteria as the target without affecting their growth has been considered as a novel method for developing new anti-microbial drugs. Type III secretion systems (T3SS) are one of the important and highly conserved virulence factors in most gram-negative pathogens, which has been considered as an effective target to develop new anti-microbial drugs. In order to discover potential anti-microbial drugs against Xoo pathogens, a series of ethyl 2-nitro-3-arylacrylates compounds were screened. Among them, the compounds I-9, I-12, and I-13 could highly inhibit the promoter activity of a harpin gene hpa1, which were used to further check for the influence on bacterial growth and on the hypersensitive response (HR) caused by Xoo bacteria on non-host plants. The results showed that above compounds could reduce HR without affecting bacterial growth and survival. Moreover, qRT-PCR analysis indicated that treatment with the three inhibitors (I-9, I-12, and I-13) could suppress the expression of the Xoo T3SS in different extent. The mRNA levels of representative genes in the hrp cluster, including the key regulatory genes hrpG and hrpX, were decreased. Last but not least, in vivo test ensured that the above compounds reduced the disease symptoms of Xoo on the rice and Xcc on the Chinese radish.

8.
Pestic Biochem Physiol ; 160: 87-94, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31519261

RESUMEN

Xanthomonas oryzae pv. oryzae (Xoo) infection directly leads to a severe disease known as leaf blight, which is a major cause of yield loss of rice. Use of traditional bactericides has resulted in severe resistance in pathogenic bacteria. A new approach screening compounds that target the virulence factors rather than killing bacterial pathogens is imperative. In gram-negative bacteria, the type III secretion system (T3SS) is a conserved and significant virulence factor considered as a target for drug development. Therefore, we designed and synthesized a new series of 5-phenyl-2-furan carboxylic acid derivatives stitched with 2-mercapto-1,3,4-thiadiazole. Bioassays revealed that the title candidates attenuated the hypersensitive response through suppressing the promoter activity of a harpin gene hpa1 without affecting bacterial growth. Quantitative real time polymerase chain reaction (qRT-PCR) analysis demonstrated reduced the expression of several genes associated with T3SS, when title compounds were applied. Additionally, hrp gene cluster members, including hrpG and hrpX, had reduced mRNA levels. In vivo greenhouse tests showed that candidate compounds could alleviate the effects of Xoo infection in rice (Oryza sativa) and possess better protective activity against rice bacterial leaf blight than bismerthiazol and thiodiazole copper. All tested compounds were safe to rice. This work suggests there are new safe options for Xoo control in rice from these 1,3,4-thiadiazole derivatives.


Asunto(s)
Tiadiazoles/síntesis química , Tiadiazoles/farmacología , Sistemas de Secreción Tipo III/efectos de los fármacos , Xanthomonas/efectos de los fármacos , Antibacterianos/farmacología , Oryza/microbiología
9.
Org Biomol Chem ; 17(34): 7854-7857, 2019 08 28.
Artículo en Inglés | MEDLINE | ID: mdl-31408075

RESUMEN

A copper-catalyzed DTBP oxidative dual C-H sulfurization has been developed for the direct thiocarbamation of imidazopyridines using a combination of elemental sulfur and formamides as carbamothioyl surrogates. NBS (bromo succinimide) was found to promote the thiocarbamation in good yields. This dual C-H sulfurization strategy enables access to a wide range of carbamothioyl imidazoheterocycles without the use of highly toxic phosgene.

10.
Bioorg Med Chem ; 27(19): 115048, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31439387

RESUMEN

Pyrazole constitutes an important heterocyclic family covering a broad range of synthetic as well as natural products that exhibit numerous chemical, biological, agrochemical and pharmacological properties. In order to explore compounds with good fungicidal activity, a series of new pyrazole derivatives containing 5-phenyl-2-furan were designed and synthesized. In vitro and in vivo fungicidal activities were evaluated and the compound ethyl-1-(5-phenylfuran-2-carbonyl)-5-propyl-1H-pyrazole-3-carboxylate (I8) displayed significant fungicidal activity against various fungi, especially against P. infestans. The structures of the novel pyrazole derivatives were confirmed by 1H NMR, 13C NMR, MS, elemental analysis and X-ray single crystal diffraction. Further study showed that compound I8 might act on the synthesis of cell walls from morphological and ultrastructural studies by SEM and TEM. The results also revealed that compound I8 could block the nutritional transportation leading to cells senescence and death. These results suggested that the novel pyrazole derivatives proved to be promising lead compounds.


Asunto(s)
Antifúngicos/farmacología , Hongos/efectos de los fármacos , Furanos/farmacología , Pirazoles/farmacología , Antifúngicos/síntesis química , Pared Celular/efectos de los fármacos , Furanos/síntesis química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirazoles/síntesis química , Relación Estructura-Actividad
11.
Bioorg Med Chem ; 27(18): 4048-4058, 2019 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-31350154

RESUMEN

Currently, entry inhibitors contribute immensely in developing a new generation of anti-influenza virus drugs. Our earlier studies have identified that 3-O-ß-chacotriosyl ursolic acid (1) could inhibit H5N1 pseudovirus by targeting hemagglutinin (HA). In the present study, a series of C-28 modified pentacyclic triterpene saponins via conjugation with a series of amide derivatives were synthesized and their antiviral activities against influenza A/Duck/Guangdong/99 virus (H5N1) in MDCK cells were evaluated. The SARs analysis of these compounds revealed that introduction of certain amide structures at the 17-COOH of ursolic acid could significantly enhance both their antiviral activity and selective index. This study indicated that the attachment of the methoxy group or Cl atom to the phenyl ring at the ortho- or para-position was crucial to improve inhibitory activity. Mechanism studies demonstrated that these title triterpenoids could bind tightly to the viral envelope HA to block the attachment of viruses to host cells, which was consistent with docking studies.


Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Triterpenos/uso terapéutico , Antineoplásicos Fitogénicos/farmacología , Humanos , Relación Estructura-Actividad , Triterpenos/farmacología
12.
Bioorg Med Chem ; 27(15): 3364-3371, 2019 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-31204227

RESUMEN

Targeting virulence factors of bacterial without affecting their growth and survival, has been an initiative strategy for the development of novel anti-microbial agents. The type III secretion system (T3SS), one of essential and highly conserved virulence factors in most Gram-negative pathogenic bacteria, has been regarded as an effective target that developed new anti-microbial drugs. Xanthomonas oryzae pv. oryzae (Xoo) is one of the most important bacterial pathogens on rice, which causes leaf blight disease. To discover potential anti-virulence agents against the pathogens, a new series of 1,3-thiazolidine-2-thione derivatives containing 5-phenyl-2-furan were designed and synthesized. Their structures were characterized by 1H NMR, 13C NMR, MS, and elemental analysis. All the title compounds inhibited the promoter activity of a harpin gene hpa1, significantly, that were further checked for the impact on bacterial growth. The results indicated that treatment of Xoo with the title compound III-7 did not affect bacterial growth or survival. Moreover, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis showed that the expression of the Xoo T3SS was suppressed by treatment with the inhibitor. The mRNA levels of representative genes in the hrp (hypersensitive response and pathogenicity) cluster, as well as the regulatory genes hrpG and hrpX, were reduced. Finally, the in vivo test demonstrated that the compounds could reduce the disease symptoms of Xoo on the rice cultivar (Oryza sativa) IR24.


Asunto(s)
Antibacterianos/farmacología , Tiazolidinas/farmacología , Tionas/farmacología , Sistemas de Secreción Tipo III/antagonistas & inhibidores , Xanthomonas/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Tiazolidinas/síntesis química , Tiazolidinas/química , Tionas/síntesis química , Tionas/química , Sistemas de Secreción Tipo III/genética , Sistemas de Secreción Tipo III/metabolismo , Xanthomonas/crecimiento & desarrollo , Xanthomonas/metabolismo
13.
Int J Mol Sci ; 20(4)2019 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-30813400

RESUMEN

The initiative strategy for the development of novel anti-microbial agents usually uses the virulence factors of bacteria as a target, without affecting their growth and survival. The type III secretion system (T3SS), one of the essential virulence factors in most Gram-negative pathogenic bacteria because of its highly conserved construct, has been regarded as an effective target that developed new anti-microbial drugs. Xanthomonas oryzae pv. oryzae (Xoo) causes leaf blight diseases and is one of the most important pathogens on rice. To find potential anti-virulence agents against this pathogen, a number of natural compounds were screened for their effects on the T3SS of Xoo. Three of 34 compounds significantly inhibited the promoter activity of the harpin gene, hpa1, and were further checked for their impact on bacterial growth and on the hypersensitive response (HR) caused by Xoo on non-host tobacco plants. The results indicated that treatment of Xoo with CZ-1, CZ-4 and CZ-9 resulted in an obviously attenuated HR without affecting bacterial growth and survival. Moreover, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis showed that the expression of the Xoo T3SS was suppressed by treatment with the three inhibitors. The mRNA levels of representative genes in the hypersensitive response and pathogenicity (hrp) cluster, as well as the regulatory genes hrpG and hrpX, were reduced. Finally, the in vivo test demonstrated that the compounds could reduce the disease symptoms of Xoo on the rice cultivar (Oryza sativa) IR24.


Asunto(s)
Oryza/microbiología , Bibliotecas de Moléculas Pequeñas/farmacología , Sistemas de Secreción Tipo III/metabolismo , Xanthomonas/metabolismo , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Genes de Plantas , Oryza/efectos de los fármacos , Oryza/genética , Enfermedades de las Plantas/microbiología , Regiones Promotoras Genéticas , Bibliotecas de Moléculas Pequeñas/análisis , Bibliotecas de Moléculas Pequeñas/química , Tabaco/microbiología , Xanthomonas/efectos de los fármacos , Xanthomonas/crecimiento & desarrollo
14.
Bioorg Med Chem Lett ; 28(19): 3271-3275, 2018 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-30131242

RESUMEN

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 4 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 4 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 4 m would be great promise as a hit inhibitor in the future study.


Asunto(s)
Inhibidores de Fosfodiesterasa 4/farmacología , Quinolinas/química , Quinolinas/farmacología , Tetrahidroisoquinolinas/química , Tetrahidroisoquinolinas/farmacología , Animales , Dominio Catalítico , Ratones , Inhibidores de Fosfodiesterasa 4/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
15.
Bioorg Med Chem Lett ; 28(19): 3276-3280, 2018 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-30131240

RESUMEN

A series of 3,5-dimethylpyrazole derivatives containing 5-phenyl-2-furan moiety were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. Bioassay results showed that the title compounds exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNFα release. Among the designed compounds, compound If showed the best inhibitory activity against PDE4B with the IC50 value of 1.7 µM, which also showed good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary structure-activity relationship (SAR) study and docking results suggested that introduction of the substituent groups to the phenyl ring at the para-position, especially methoxy group, was helpful to enhance inhibitory activity against PDE4B.


Asunto(s)
Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Animales , Asma/tratamiento farmacológico , Líquido del Lavado Bronquioalveolar , Concentración 50 Inhibidora , Ratones , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Pirazoles/uso terapéutico , Ratas , Ratas Sprague-Dawley , Sepsis/tratamiento farmacológico , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismo
16.
Pestic Biochem Physiol ; 149: 89-97, 2018 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30033022

RESUMEN

Targeting virulence factors of bacterial without affecting their growth and survival, has been an initiative strategy for the development of novel anti-microbial agents. The type III secretion system (T3SS), one of essential and highly conserved virulence factors in most Gram-negative pathogenic bacteria, has been regarded as an effective target that developed new anti-microbial drugs. Xanthomonas oryzae pv. oryzae (Xoo) is one of the most Important bacterial pathogens on rice, which causes leaf blight disease. To discover potential anti-virulence agents against the pathogens, a new series of thiazolidin-2-cyanamide derivatives containing 5-phenyl-2-furan were designed and synthesized. Their structures were characterized by 1H NMR, 13C NMR, MS, and elemental analysis. All the title compounds inhibited the promoter activity of a harpin gene hpa1, significantly, that were further checked for the impact on bacterial growth and on the hypersensitive response (HR) caused by Xoo on non-host tobacco plants. The results indicated that treatment of Xoo with the title compounds II-2, II-3 and II-4 resulted in significantly attenuated HR without affecting bacterial growth or survival. Moreover, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis showed that the expression of the Xoo T3SS was suppressed by treatment with the three inhibitors. The mRNA levels of representative genes in the hrp (hypersensitive response and pathogenicity) cluster, as well as the regulatory genes hrpG and hrpX, were reduced. Finally, the in vivo test demonstrated that the compounds could reduce the disease symptoms of Xoo on the rice cultivar (Oryza sativa) IR24.


Asunto(s)
Antibacterianos/farmacología , Cianamida/farmacología , Oryza/microbiología , Tiazolidinas/farmacología , Sistemas de Secreción Tipo III/efectos de los fármacos , Xanthomonas/efectos de los fármacos , Antibacterianos/química , Espectroscopía de Resonancia Magnética con Carbono-13 , Genes Bacterianos , Genes Reguladores , Regiones Promotoras Genéticas , Espectroscopía de Protones por Resonancia Magnética , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Espectrometría de Masa por Ionización de Electrospray , Virulencia/genética , Xanthomonas/genética , Xanthomonas/crecimiento & desarrollo , Xanthomonas/patogenicidad
17.
Eur J Med Chem ; 151: 546-556, 2018 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-29656198

RESUMEN

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 (EC50 = 0.89 ±â€¯0.11 µM). 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.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Antibióticos Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Furanos/farmacología , Tetrahidroisoquinolinas/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Neoplasias de la Mama/metabolismo , Proliferación Celular/efectos de los fármacos , Femenino , Furanos/síntesis química , Furanos/química , Humanos , Células MCF-7 , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/química
18.
Bioorg Med Chem ; 25(20): 5709-5717, 2017 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-28888661

RESUMEN

Improvement of subtype selectivity of an inhibitor's binding activity using the conformational restriction approach has become an effective strategy in drug discovery. In this study, we applied this approach to PDE4 inhibitors and designed a series of novel oxazolidinone-fused 1,2,3,4-tetrahydroisoquinoline derivatives as conformationally restricted analogues of rolipram. The bioassay results demonstrated the oxazolidinone-fused tetrahydroisoquinoline derivatives exhibited moderate to good inhibitory activity against PDE4B and high selectivity for PDE4B/PDE4D. Among these derivatives, compound 12 showed both the strongest inhibition activity (IC50=0.60µM) as well as good selectivity against PDE4B and good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary SAR study showed that restricting the conformation of the catechol moiety in rolipram with the scaffold of oxazolidinone-fused tetrahydroisoquinoline could lead to an increase in selectivity for PDE4B over PDE4D, which was consistent with the observed docking simulation.


Asunto(s)
Diseño de Fármacos , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/farmacología , Animales , Asma/tratamiento farmacológico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Modelos Animales de Enfermedad , Humanos , Concentración 50 Inhibidora , Conformación Molecular , Simulación del Acoplamiento Molecular , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/química , Inhibidores de Fosfodiesterasa 4/farmacología , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Rolipram/química , Rolipram/farmacología , Rolipram/uso terapéutico , Sepsis/tratamiento farmacológico , Relación Estructura-Actividad , Tetrahidroisoquinolinas/química , Tetrahidroisoquinolinas/uso terapéutico
19.
Bioorg Med Chem ; 25(6): 1852-1859, 2017 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-28196708

RESUMEN

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.


Asunto(s)
Oxazoles/química , Inhibidores de Fosfodiesterasa 4/química , Inhibidores de Fosfodiesterasa 4/farmacología , Pirazoles/química , Animales , Asma/tratamiento farmacológico , Espectroscopía de Resonancia Magnética con Carbono-13 , Modelos Animales de Enfermedad , Diseño de Fármacos , Femenino , Concentración 50 Inhibidora , Masculino , Ratones , Simulación del Acoplamiento Molecular , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Espectroscopía de Protones por Resonancia Magnética , Ratas , Ratas Sprague-Dawley , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-Actividad
20.
Sci Rep ; 7: 42096, 2017 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-28176837

RESUMEN

In order to discover new antifungal agrochemicals that could have highly active and novel motifs, thirty-six new 2-acylaminocycloalkylsulfonamides (IV) were synthesized. Their structures were characterized and confirmed by 1H NMR, 13C NMR, IR, MS, elemental analysis and X-ray single crystal diffraction. In vitro and in vivo activities against various Botrytis cinerea strains were evaluated. Bioassay results revealed that most of the title compounds exhibited excellent in vitro fungicidal activity, in which compound IV-26 showed the highest activity against sensitive, low-resistant, moderate-resistant and high-resistant strains of B. cinerea compared with the positive fungicide procymidone. Meanwhile in vivo fungicidal activity of compound IV-31 was better than the commercial fungicides procymidone and chesulfamide in greenhouse trial. The structure activity relationship (SAR) was also discussed and the results were of importance to the structural optimization and development of more potent sulfonamides antifungal agents.


Asunto(s)
Antifúngicos/química , Antifúngicos/farmacología , Botrytis/efectos de los fármacos , Fungicidas Industriales/química , Sulfonamidas/química , Sulfonamidas/farmacología , Antifúngicos/síntesis química , Técnicas de Química Analítica , Cucumis/microbiología , Fungicidas Industriales/síntesis química , Fungicidas Industriales/farmacología , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Enfermedades de las Plantas/prevención & control , Plantones/microbiología , Relación Estructura-Actividad
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...