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Planta ; 251(2): 43, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31907627


MAIN CONCLUSION: Co-expression and regulatory networks yield important insights into the growth-defense tradeoffs mechanism under jasmonic acid (JA) signals in Arabidopsis. Elevated defense is commonly associated with growth inhibition. However, a comprehensive atlas of the genes associated with the plant growth-defense tradeoffs under JA signaling is lacking. To gain an insight into the dynamic architecture of growth-defense tradeoffs, a coexpression network analysis was employed on publicly available high-resolution transcriptomes of Arabidopsis treated with coronatine (COR), a mimic of jasmonoyl-l-isoleucine. The genes involved in JA-mediated growth-defense tradeoffs were systematically revealed. Promoter enrichment analysis revealed the core regulatory module in which the genes underwent rapid activation, sustained upregulation after COR treatment, and mediated the growth-defense tradeoffs. Several transcription factors (TFs), including RAP2.6L, MYB44, WRKY40, and WRKY18, were identified as instantly activated components associated with pathogen and insect resistance. JA might rapidly activate RAV1 and KAN1 to repress brassinosteroid (BR) response genes, upregulate KAN1, the C2H2 TF families ZF2, ZF3, ZAT6, and STZ/ZAT10 to repress the biosynthesis, transport, and signaling of auxin to arrest growth. Independent datasets and preserved analyses validated the reproducibility of the results. Our study provided a comprehensive snapshot of genes that respond to JA signals and provided valuable resources for functional studies on the genetic modification of breeding population that exhibit robust growth and defense simultaneously.

J Agric Food Chem ; 67(47): 13185-13194, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31697490


In searching for novel fungicidal leads, the novel bioactive succinate dehydrogenase inhibitor (SDHI) derivatives were designed and synthesized by the inversion of carbonyl and amide groups. Bioassay indicated that compound 5i stood out with a broad spectrum of in vitro activity against five fungi. Its EC50 value (0.73 µg/mL) was comparable to that of boscalid (EC50 of 0.51 µg/mL) and fluxapyroxad (EC50 of 0.19 µg/mL) against Sclerotinia sclerotiorum. For Rhizoctonia cerealis, 5i and 5p with EC50 values of 4.61 and 6.48 µg/mL, respectively, showed significantly higher activity than fluxapyroxad with the EC50 value of 16.99 µg/mL. In vivo fungicidal activity of 5i exhibited an excellent inhibitory rate (100%) against Puccinia sorghi at 50 µg/mL, while the positive control boscalid showed only a 70% inhibitory rate. Moreover, 5i showed promising fungicidal activity with a 60% inhibitory rate against Rhizoctonia solani at 1 µg/mL, which was better than that of boscalid (30%). Compound 5i possessed better in vivo efficacy against P. sorghi and R. solani than boscalid. Molecular docking showed that even the carbonyl oxygen atom of 5i was far from the pyrazole ring. It could also form hydrogen bonds toward the hydroxyl hydrogen and amino hydrogen of TYR58 and TRP173 on SDH, respectively, which consisted of the positive control fluxapyroxad. Fluorescence quenching analysis and SDH enzymatic inhibition studies also validated its mode of action. Our studies showed that 5i was worthy of further investigation as a promising fungicide candidate.

Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteínas Fúngicas/antagonistas & inibidores , Fungicidas Industriais/síntese química , Fungicidas Industriais/farmacologia , Succinato Desidrogenase/antagonistas & inibidores , Ascomicetos/química , Ascomicetos/efeitos dos fármacos , Ascomicetos/enzimologia , Inibidores Enzimáticos/química , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Fungicidas Industriais/química , Simulação de Acoplamento Molecular , Rhizoctonia/química , Rhizoctonia/efeitos dos fármacos , Rhizoctonia/enzimologia , Relação Estrutura-Atividade , Succinato Desidrogenase/química , Succinato Desidrogenase/metabolismo
Eur J Med Chem ; 178: 767-781, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31234030


By the analysis of different binding modes with Bruton's tyrosine kinase (BTK), series of novel diphenylthiazole derivatives were rationally designed, synthesized and characterized. Biologically evaluation in biochemistry and cellular assay indicated that, compounds 5m, 5o, 6b, 6c, 6g, 6i, 7h, 7i, 7k, 7m, 7n, 7o and 7s exhibited improved potency against Ramos cell (IC50 = 1.36-8.60 µM) and Raji cell (IC50 = 1.20-14.04 µM) as compared with ibrutinib (IC50 = 14.69 and 15.99 µM, respectively). Especially, compounds 7m and 7n showed 10-time improved potency against Ramos cell viability over ibrutinib. Compound 6b improved 13-fold activity against Raji cell viability than ibrutinib. In addition, active compound 7o potently inhibited C481S mutant BTK with IC50 value of 0.061 µM. Apoptosis analysis of both Ramos and Raji cells indicated that 7o was remarkably more potent than CGI-1746 and ibrutinib. Compound 7o potently inhibited BTK Y223 phosphorylation in Raji cells, and arrested cell cycle progression in the G0/G1 phase in Raji and Ramos cells. This study expanded the structural diversity of BTK inhibitors and compound 7o was discovered as an active lead inhibitor with great potential for further studies.

Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/farmacologia , Descoberta de Drogas , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Tiazóis/farmacologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Células Tumorais Cultivadas
J Agric Food Chem ; 67(5): 1360-1370, 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30640452


Oxathiapiprolin is one of the best active fungicides discovered for oomycetes control. To develop a fungicide candidate with a broad spectrum of activity, 22 new piperidinylthiazole derivatives were designed and synthesized. Compound 5l showed the best activity against Pseudoperonospora cubensis (Berk. et Curt.) Rostov and Phytophthora infestans in vivo with 100% and 80% of inhibition, respectively, at 1 mg/L, and 72.87% of field efficacy against P. cubensis at 1 g ai/667 m2 validated these results. Compound 5i exhibited a broad spectrum of excellent activity against Sclerotinia sclerotiorum with EC50 = 0.30 mg/L (>10 times more active than oxathiapiprolin and azoxystrobin in vitro), good activity against Botrytis cinerea, Cercospora arachidicola, and Gibberella zeae with EC50 of 14.54, 5.57, and 14.03 mg/L in vitro and against P. cubensis and P. infestans with 60% and 30% inhibition rates, respectively, at 1 mg/L in vivo. Mode of action studies by RNA sequencing analysis discovered oxysterol-binding protein (OSBP), chitin synthase (CHS1), and (1,3)-ß-glucan synthase (FKS2) as the potent target of 5i against S. sclerotiorum. Quenching studies validated that OSBP was the same target of both 5i and oxathiapiprolin; it was quenched by both of them. Our studies discovered isothiazole-containing piperidinylthiazole as an OSBP target-based novel lead for fungicide development.

Fungicidas Industriais/química , Fungicidas Industriais/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Ascomicetos/efeitos dos fármacos , Ascomicetos/crescimento & desenvolvimento , Botrytis/efeitos dos fármacos , Botrytis/crescimento & desenvolvimento , Cucumis sativus/microbiologia , Descoberta de Drogas , Lycopersicon esculentum/microbiologia , Phytophthora infestans/efeitos dos fármacos , Phytophthora infestans/crescimento & desenvolvimento , Doenças das Plantas/microbiologia , Relação Estrutura-Atividade
J Agric Food Chem ; 67(6): 1647-1655, 2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30669828


To contribute molecular diversity for novel fungicide development, a series of novel thiazole carboxamides were rationally designed, synthesized, and characterized with the succinate dehydrogenase (SDH) as target. Bioassay indicated that compound 6g showed the similar excellent SDH inhibition as that of Thifluzamide with IC50 of 0.56 mg/L and 0.55 mg/L, respectively. Some derivatives displayed improved in vitro fungicidal activities against Rhizoctonia cerealis and Sclerotinia sclerotiorum with EC50 of 1.2-16.4 mg/L and 0.5-1.9 mg/L. Surprisingly, 6g showed promising in vitro fungicidal activities against R. cerealis and S. sclerotiorum with EC50 of 6.2 and 0.6 mg/L, respectively, which was superior to Thifluzamide with the EC50 of 22.1 and 4.4 mg/L, respectively. Additionally, compounds 6c and 6g displayed excellent in vivo fungicidal activities against S. sclerotiorum on Brassica napus L. leaves with protective activity of 75.4% and 67.3% at 2.0 mg/L, respectively, while Thifluzamide without activity at 5.0 mg/L. Transcriptomic analysis of S. sclerotiorum treated with 6g by RNA sequencing indicated the down-regulation of succinate dehydrogenase gene SDHA and SDHB, and the inhibition of the TCA-cycle.

Inibidores Enzimáticos/farmacologia , Proteínas Fúngicas/antagonistas & inibidores , Fungicidas Industriais/farmacologia , Succinato Desidrogenase/antagonistas & inibidores , Tiazóis/farmacologia , Ascomicetos/efeitos dos fármacos , Ascomicetos/enzimologia , Descoberta de Drogas , Inibidores Enzimáticos/química , Proteínas Fúngicas/metabolismo , Fungicidas Industriais/química , Estrutura Molecular , Rhizoctonia/efeitos dos fármacos , Rhizoctonia/enzimologia , Relação Estrutura-Atividade , Succinato Desidrogenase/metabolismo , Tiazóis/química
J Agric Food Chem ; 66(46): 12439-12452, 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30350975


Target identification is an essential basis for novel-pesticide development in new molecular design and lead optimization. 3-(4-Methyl-1,2,3-thiadiazolyl)-6-trichloromethyl[1,2,4]triazolo[3,4- b][1,3,4]thiadizole (YZK-C22) is a novel fungicide candidate with specific antifungal activity. We investigated its mode of action, and our studies indicated that YZK-C22 showed no cross resistance against Saccharomyces cerevisiae mutants with classic fungicide targets. Mec1 and Rad53 are two kinases that respond to DNA-replication damage, and the efficacy test showed that YZK-C22 could not perform its fungicidal activity by inhibiting DNA repair. Target screening by drug-affinity-responsive target stability (DARTS) showed that pyruvate kinase (PK), a key enzyme in the glycolytic pathway, was the potent new fungicidal target of YZK-C22. Fifty-eight differentially expressed proteins (DEPs) primarily involved in the metabolic process were identified by isobaric tags for relative and absolute quantification analysis (iTRAQ) in S. cerevisiae, and protein expression in the citrate cycle decreased with treatment of 5 mg/L YZK-C22, which was consistent with the results of DARTS. Molecular-docking analysis further validated that YZK-C22 could dock into the active center of PK instead of phosphoenolpyruvate. The enzyme activity of PK from S. cerevisiae was competitively inhibited with a Ki of 3.33 ± 0.28 µmol/L, and the cell-growth inhibition of S. cerevisiae was released by supplementation with pyruvic acid, whereas the growth of S. cerevisiae was not recovered by adding PK's substrate (phosphoenolpyruvate) or allosteric regulator (fructose-1,6-bisphosphate). The present studies uncovered and validated the primary target of the new, potent fungicidal candidate YZK-C22; our results provide a successful, valuable, and applicable case of target discovery and identification for novel-fungicide development.

Inibidores Enzimáticos/química , Fungicidas Industriais/química , Piruvato Quinase/antagonistas & inibidores , Proteínas de Saccharomyces cerevisiae/antagonistas & inibidores , Saccharomyces cerevisiae/efeitos dos fármacos , Tiadiazóis/química , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Fungicidas Industriais/farmacologia , Cinética , Simulação de Acoplamento Molecular , Piruvato Quinase/genética , Piruvato Quinase/metabolismo , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Tiadiazóis/farmacologia