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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.
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.

4.
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
5.
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
6.
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
7.
Guang Pu Xue Yu Guang Pu Fen Xi ; 37(3): 704-9, 2017 Mar.
Artículo en Chino, Inglés | MEDLINE | ID: mdl-30148548

RESUMEN

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.


Asunto(s)
Color , Análisis de Componente Principal , Algoritmos , Iluminación
8.
Bioorg Med Chem Lett ; 26(15): 3632-5, 2016 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-27289320

RESUMEN

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.


Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Inhibidores de Fosfodiesterasa 4/farmacología , Pirazoles/farmacología , Triazoles/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Estructura Molecular , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/química , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesis
9.
Sci Rep ; 6: 22977, 2016 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-26960713

RESUMEN

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.


Asunto(s)
Hidrazinas/química , Insecticidas/química , Hormonas Juveniles/química , Larva/efectos de los fármacos , Animales , Culex/efectos de los fármacos , Culex/patogenicidad , Humanos , Hidrazinas/síntesis química , Hidrazinas/farmacología , Insecticidas/síntesis química , Insecticidas/farmacología , Hormonas Juveniles/síntesis química , Hormonas Juveniles/farmacología , Espectroscopía de Resonancia Magnética , Simulación del Acoplamiento Molecular , Spodoptera/efectos de los fármacos , Spodoptera/patogenicidad , Relación Estructura-Actividad
10.
Sci Rep ; 6: 20204, 2016 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-26822318

RESUMEN

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.


Asunto(s)
Antifúngicos , Phytophthora infestans/crecimiento & desarrollo , Tiadiazoles , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Phytophthora infestans/ultraestructura , Tiadiazoles/síntesis química , Tiadiazoles/química , Tiadiazoles/farmacología
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