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1.
Bioorg Med Chem Lett ; 29(22): 126720, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610942

RESUMO

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.

2.
J Agric Food Chem ; 67(43): 11867-11876, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31584805

RESUMO

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.

3.
Pestic Biochem Physiol ; 160: 87-94, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31519261

RESUMO

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.

4.
Org Biomol Chem ; 17(34): 7854-7857, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31408075

RESUMO

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.

5.
Bioorg Med Chem ; 27(19): 115048, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31439387

RESUMO

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.

6.
Bioorg Med Chem ; 27(18): 4048-4058, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31350154

RESUMO

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.

7.
Bioorg Med Chem ; 27(15): 3364-3371, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31204227

RESUMO

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.

8.
Int J Mol Sci ; 20(4)2019 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-30813400

RESUMO

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.


Assuntos
Oryza/microbiologia , Bibliotecas de Moléculas Pequenas/farmacologia , Sistemas de Secreção Tipo III/metabolismo , Xanthomonas/metabolismo , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Genes de Plantas , Oryza/efeitos dos fármacos , Oryza/genética , Doenças das Plantas/microbiologia , Regiões Promotoras Genéticas , Bibliotecas de Moléculas Pequenas/análise , Bibliotecas de Moléculas Pequenas/química , Tabaco/microbiologia , Xanthomonas/efeitos dos fármacos , Xanthomonas/crescimento & desenvolvimento
9.
Bioorg Med Chem Lett ; 28(19): 3276-3280, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30131240

RESUMO

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.

10.
Bioorg Med Chem Lett ; 28(19): 3271-3275, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30131242

RESUMO

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.

11.
Pestic Biochem Physiol ; 149: 89-97, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30033022

RESUMO

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.


Assuntos
Antibacterianos/farmacologia , Cianamida/farmacologia , Oryza/microbiologia , Tiazolidinas/farmacologia , Sistemas de Secreção Tipo III/efeitos dos fármacos , Xanthomonas/efeitos dos fármacos , Antibacterianos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Genes Bacterianos , Genes Reguladores , Regiões Promotoras Genéticas , Espectroscopia de Prótons por Ressonância Magnética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espectrometria de Massas por Ionização por Electrospray , Virulência/genética , Xanthomonas/genética , Xanthomonas/crescimento & desenvolvimento , Xanthomonas/patogenicidade
12.
Eur J Med Chem ; 151: 546-556, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29656198

RESUMO

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.


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/química
13.
Bioorg Med Chem ; 25(20): 5709-5717, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28888661

RESUMO

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.


Assuntos
Desenho de Drogas , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/farmacologia , Animais , Asma/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Modelos Animais de Doenças , Humanos , Concentração Inibidora 50 , Conformação Molecular , Simulação de Acoplamento Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Rolipram/química , Rolipram/farmacologia , Rolipram/uso terapêutico , Sepse/tratamento farmacológico , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/uso terapêutico
14.
Bioorg Med Chem ; 25(6): 1852-1859, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28196708

RESUMO

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 Drogas , 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-Atividade
15.
Sci Rep ; 7: 42096, 2017 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-28176837

RESUMO

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.


Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Botrytis/efeitos dos fármacos , Fungicidas Industriais/química , Sulfonamidas/química , Sulfonamidas/farmacologia , Antifúngicos/síntese química , Técnicas de Química Analítica , Cucumis/microbiologia , Fungicidas Industriais/síntese química , Fungicidas Industriais/farmacologia , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Doenças das Plantas/prevenção & controle , Plântula/microbiologia , Relação Estrutura-Atividade
16.
Bioorg Med Chem Lett ; 27(2): 271-276, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-27914797

RESUMO

A series of novel 2-substituted aminocycloalkylsulfonamides were designed and synthesized by highly selective N-alkylation reaction, whose structures were characterized by 1H NMR, 13C NMR and HRMS. Among them, the configuration of compounds III12 and III20 were confirmed by X-ray single crystal diffraction. Bioassays demonstrated that the title compounds had considerable effects on different strains of Botrytis cinerea and Pyricularia grisea. Comparing with positive control procymidone (EC50=10.31mg/L), compounds III28, III29, III30 and III31 showed excellent fungicidal activity against a strain of B. cinerea (CY-09), with EC50 values of 3.17, 3.04, 2.54 and 1.99mg/L respectively. Their in vivo fungicidal activities were also better than the positive controls cyprodinil, procymidone, boscalid and carbendazim in pot experiments. Moreover, the fungicidal activity of III28 (EC50=4.62mg/L) against P. grisea was also better than that of the positive control isoprothiolane (EC50=6.11mg/L). Compound III28 would be great promise as a hit compound for further study based on the structure-activity relationship.


Assuntos
Botrytis/efeitos dos fármacos , Desenho de Drogas , Fungicidas Industriais/farmacologia , Pyricularia grisea/efeitos dos fármacos , Sulfonamidas/farmacologia , Tiazóis/farmacologia , Relação Dose-Resposta a Droga , Fungicidas Industriais/síntese química , Fungicidas Industriais/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Tiazóis/síntese química , Tiazóis/química
17.
Org Biomol Chem ; 14(28): 6691-702, 2016 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-27241813

RESUMO

Two partially acylated oligorhamnoside derivatives 1 and 2 structurally related to the natural product mezzettiaside-6 were synthesized via a '2 + 1 + 1' convergent strategy. The bioassay results showed that the introduction of the acetyl groups to the 2-position of the terminal l-rhamnose was helpful to improve in vitro cytotoxicity. Compound 1 showed both extensive in vitro cytotoxicity in tumor cell lines and potential antimultidrug resistance capability. Preliminary mechanistic studies demonstrated that compound 1 could inhibit cell growth by inducing apoptosis, arresting cell cycle progression at the S phase in K562 cells.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Ramnose/análogos & derivados , Ramnose/farmacologia , Acilação , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Células K562 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neoplasias/metabolismo , Ramnose/síntese química
18.
Bioorg Med Chem Lett ; 26(15): 3632-5, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27289320

RESUMO

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/biossíntese
19.
Sci Rep ; 6: 22977, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26960713

RESUMO

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-Atividade
20.
Mol Plant Pathol ; 17(9): 1398-1408, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-26814706

RESUMO

Dickeya zeae is a causal agent of rice root rot disease. The pathogen is known to produce a range of virulence factors, including phytotoxic zeamines and extracellular enzymes, but the mechanisms of virulence regulation remain vague. In this study, we identified a SlyA/MarR family transcription factor SlyA in D. zeae strain EC1. Disruption of slyA significantly decreased zeamine production, enhanced swimming and swarming motility, reduced biofilm formation and significantly decreased pathogenicity on rice. Quantitative polymerase chain reaction (qPCR) analysis confirmed the role of SlyA in transcriptional modulation of a range of genes associated with bacterial virulence. In trans expression of slyA in expI mutants recovered the phenotypes of motility and biofilm formation, suggesting that SlyA is downstream of the acylhomoserine lactone-mediated quorum sensing pathway. Taken together, the findings from this study unveil a key transcriptional regulatory factor involved in the modulation of virulence factor production and overall pathogenicity of D. zeae EC1.


Assuntos
Proteínas de Bactérias/metabolismo , Enterobacteriaceae/patogenicidade , Oryza/microbiologia , Toxinas Biológicas/metabolismo , Biofilmes , Parede Celular/metabolismo , Enterobacteriaceae/genética , Enterobacteriaceae/metabolismo , Genes de Plantas , Genoma Bacteriano , Germinação , Macrolídeos/metabolismo , Movimento , Mutação/genética , Poliaminas/metabolismo , Sementes/microbiologia , Transcrição Genética , Virulência
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