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Coronatine-insensitive 1 (COI1) has been identified as a target receptor of plant elicitor coronatine (COR). To discover novel plant elicitor leads, most of the potential molecules among 129 compounds discovered from the ZINC database by docking based virtual screening targeting COI1 were quinoline amides. On this lead basis, 2-benzothiadiazolylquinoline-4-carboxamides were rationally designed and synthesized for bioassay. All target compounds did not show significantly in vitro antifungal activity, compounds 4d, 4e and 4o displayed good in vivo systemic acquired resistance activity for Arabidopsis thaliana against Hyaloperonospora arabidopsidis isolate Noco2 with over 80% of inhibitory rate at the concentration of 50 µM. These results indicate that 2-benzothiadiazolylquinoline-4-carboxamides are promising plant elicitor leads for further study.
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With the encouragement of policies and the rapid development of the biopharmaceutical industry, the number of software as medical device (SaMD) registration applications in Shanghai has continued to increase in recent years, and this paper summarizes the GMP nonconformities found in the field inspection of SaMD in Shanghai from 2020 to 2023, and the results show that nearly 70% of the problems were found in the software development process. Through in-depth analysis, this paper proposes the corresponding countermeasures for the problems found in the five most common stages such as software requirements, software design, software testing, software defect management and software configuration management, combined with the characteristics of software development. These suggested measures have certain reference significance for medical device software development and quality control personnel, and technical reviewer and inspectors.
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Equipos y Suministros , Programas Informáticos , Control de Calidad , China , Diseño de SoftwareRESUMEN
Acid-catalyzed intramolecular cyclization or rearrangement of isoindolinone derivatives is described. 3-Hydroxy/ethoxy-3,4-dihydro-6H-[1,4]-oxazino-[3,4-a]-isoindol-6-ones are obtained in moderate to good yields. Further acid-catalyzed intramolecular rearrangement reactions give 6H-isochromeno-[4,3-b]-pyridin-6-ones. The mild reaction conditions with convenient starting materials show broad substrate scope and provide the target compounds as novel pesticide leads with good fungicidal or systemical acquired resistance activities.
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To search a novel lead structure for antiphytopathogenic fungus agent, a series of novel psoralen derivatives possessing sulfonohydrazide or acylthiourea structure were designed and synthesized, and their fungicidal activity against seven phytopathogens was evaluated. Their structures were confirmed by melting points, 1H NMR, 13C NMR and HRMS, and the typical crystal structure was determined by X-ray diffraction for validation. Preliminary fungicidal activity showed that some of the title compounds exhibited certain-to-high fungicidal activity. Compound I-13 exhibited good fungicidal activity against Botrytis cinerea, Cercospora arachidicola and Physalospora piricola with EC50 values of 12.49, 13.22 and 12.12 µg/mL, respectively. Compounds II-9 and II-15 showed over 90% inhibition against B. cinerea at 50 µg/mL in vitro. In particular, II-9 exhibited significant higher fungicidal activity with a lower EC50 value of 9.09 µg/mL than the positive control YZK-C22 (13.41 µg/mL). Our studies found that sulfonohydrazide or acylthiourea-containing psoralen derivatives were promising fungicide leads deserve for further study.
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Fungicidas Industriales , Furocumarinas , Relación Estructura-Actividad , Antifúngicos/farmacologíaRESUMEN
The development of new fungicides is vital for safeguarding crops and ensuring sustainable agriculture. Building on our previous finding that 4-(3,4-dichloroisothiazole)-7-hydroxy coumarins can be used as fungicidal leads, 44 novel coumarin ester derivatives were designed and synthesized to evaluate whether esterification could enhance their fungicidal activity. In vitro fungicidal bioassays indicated that compound 2ai displayed good activity against Alternaria solani, Botrytis cinereal, Cercospora arachidicola, Physalospora piricola and Sclerotinia sclerotiorum, with an EC50 value ranging from 2.90 to 5.56 µg/mL, comparable to the lead compound 1a, with its EC50 value ranging from 1.92 to 9.37 µg/mL. In vivo bioassays demonstrated that compounds 1a, 2ar and 2bg showed comparable, excellent efficacy against Pseudoperonospora cubensis at a dose of 25 µg/mL. Our research shows that the esterification of 4-(3,4-dichloroisothiazole) 7-hydroxycoumarins results in a fungicidal activity equivalent to that of its lead compounds. Furthermore, our density functional theory (DFT) calculations and 3D-QSAR modeling provide a rational explanation of the structure-activity relationship and offer valuable insights to guide further molecular design.
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Ésteres , Fungicidas Industriales , Ésteres/farmacología , Relación Estructura-Actividad , Fungicidas Industriales/farmacología , Cumarinas/farmacología , Antifúngicos/farmacologíaRESUMEN
The addition of active groups of known fungicides, or systemic acquired resistance inducers, into novel compound molecules to search for potential antifungal compounds is a popular and effective strategy. In this work, a new series of N-acyl-N-arylalanines was developed and synthesized, in which 1,2,3-thiadiazol-5-ylcarbonyl or 3,4-dichloroisothiazol-5-ylcarbonyl (fragments from synthetic plant resistance activators tiadinil and isotianil, respectively) and a fragment of N-arylalanine, the toxophoric group of acylalanine fungicides. Several new synthesized compounds have shown moderate antifungal activity against fungi in vitro, such as B. cinerea, R. solani and S. sclerotiorum. In vivo tests against A. brassicicola showed that compound 1d was 92% effective at a concentration of 200 µg/mL, similar to level of tiadinil, a known inducer of systemic resistance. Thus, 1d could be considered a new candidate fungicide for further detailed study. The present results will advance research and influence the search for more promising fungicides for disease control in agriculture.
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Fungicidas Industriales , Tiadiazoles , Fungicidas Industriales/farmacología , Antifúngicos/farmacología , Estructura Molecular , Tiadiazoles/farmacología , Plantas , Relación Estructura-ActividadRESUMEN
Pancreatic cancer (PC) is the most lethal malignancy worldwide due to its delayed diagnosis and limited treatment options. Despite great progress in clinical trials of immunotherapies for various cancers, their effectiveness in PC is very low, indicating that immune evasion is still a major obstacle to immunotherapy in PC. However, the mechanism of immune escape in PC is not fully understood, which substantially restricts the development of immunotherapy. As an important component of intercellular communication networks, extracellular vesicles (EVs) have attracted increasing attention in relation to immune escape. This review aims to provide a better understanding of the roles of EVs in tumor immune escape and the potential to expand their application in cancer immunotherapy. The relationship between PC and the tumor immune microenvironment is briefly introduced. Then, the mechanism by which EVs are involved in immune regulation is summarized, and the latest progress in determining the role of EVs in regulating PC immune escape is highlighted.
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Vesículas Extracelulares , Neoplasias , Neoplasias Pancreáticas , Humanos , Inmunoterapia , Neoplasias/patología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Escape del Tumor , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
Twenty-one novel 3,4-dichloroisothiazolocoumarin-containing strobilurins were rationally designed and synthesized. Preliminary bioassay showed that compounds 7c, 7h and 7l exhibited over 80% inhibitory rate against Sclerotinia sclerotiorum at 50 µg/mL, 7c exhibited good activity against S. sclerotiorum with median effective concentration (EC50) of 4.08 µg/mL, while the positive control coumoxystrobin showed EC50 of 1.00 µg/mL. In addition, 7d showed better fungicidal activity with a lower EC50 value of 7.65 µg/mL against Botrytis cinerea than that of positive control trifloxystrobin with its EC50 value of 21.96 µg/mL. This study indicated that 3,4-dichloroisothiazolocoumarin-containing strobilurin was a promising fungicide lead deserved for further study.
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Fungicidas Industriales , Fungicidas Industriales/farmacología , Estrobilurinas/farmacología , Relación Estructura-ActividadRESUMEN
Twenty-one novel pyrazole-thiazole carboxamide derivatives were rationally designed and synthesized. Bioassay results indicated that 6d (EC50 = 5.11 µg/mL) and 6j (EC50 = 8.14 µg/mL) exhibited better in vitro activities than fluxapyroxad (EC50 = 11.93 µg/mL) and thifluzamide (EC50 = 22.12 µg/mL) against Rhizoctonia cerealis. Particularly, compound 6j showed promising in vivo protective activity against Rhizoctonia solani and Puccinia sorghi Schw. with 80% and 90% inhibition at 10 µg/mL, respectively. Our studies found that pyrazole-thiazole is a promising fungicide lead deserving for further derivation.
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Fungicidas Industriales , Antifúngicos/farmacología , Fungicidas Industriales/farmacología , Pirazoles/farmacología , Relación Estructura-Actividad , Tiazoles/farmacologíaRESUMEN
Plant elicitors enhance plant defense against pathogen attacks by inducing systemic acquired resistance (SAR) with no or low direct fungicidal activity. Here we report the synthesis of a novel plant elicitor candidate LY5-24-2 [3,4-dichloro-N-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)isothiazole-5-carboxamide] and evaluation of its SAR inducing activity. Bioassays indicated that LY5-24-2 did not show significant anti-fungal activity but provided long-lasting resistance in Arabidopsis thaliana (A. thaliana) through promoting the accumulation of lignin, cellulose and pectin by 60.1%, 82.4% and 305.6%, respectively, at a concentration of 100 µM. LY5-24-2 also facilitated the closure of leaf stomata and increased the intracellular free Ca2+ by 47.8%, induced reactive oxygen species (ROS) accumulation, and inhibited the activity of ascorbate peroxidase (APX, EC 1.11.1.11) and catalase (CAT, EC 1.11.1.6) by 38.9% and 34.0%, respectively, as compared with the control at a concentration of 100 µM. LY5-24-2 induced SAR in plants and was dependent on the NPR1-mediated SA pathway by up-regulating expression of 2273 genes in A. thaliana. Meanwhile, LY5-24-2 also improved cucumber (Cucumis sativus L.) defense against Pseudoperonospora cubensis (P. cubensis) through promoting ROS accumulation and inhibiting activity of APX and CAT by 30.7% and 23.1%, respectively. Its expression of SA signaling genes CsNPR1, CsPR4 and CsPR5 was enhanced by 10.8, 5.8 and 6.6 times, respectively. These results demonstrated that LY5-24-2 is a novel elicitor candidate for plant protection via inducing SAR.
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Proteínas de Arabidopsis , Arabidopsis , Cucumis sativus , Oomicetos , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Cucumis sativus/genética , Oomicetos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de SeñalRESUMEN
Nitrogen- or oxygen-containing organic compounds which have significant antifungal activity, twenty one novel nitrogen or oxygen-containing (E)-3-acyl-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one analogues were designed and synthesized, and their structures were confirmed by 1H NMR, 13C NMR and HRMS. Preliminary bioassay showed that most of them exhibited certain-to-good antifungal activity. Compounds 5k-2, 5n, 5p and 5r exhibited over 80% inhibitory rate against Sclerotinia sclerotiorum at 50 µg/mL, and 5r exhibited good antifungal activity against S. sclerotiorum with EC50 of 7.21 µg/mL. Compounds 5a and 5r also showed over 90% inhibition against Botrytis cinerea. In particular, 5r showed significant higher activity with the lowest EC50 of 7.92 µg/mL than the positive control trifloxystrobin (21.96 µg/mL) and azoxystrobin (9.43 µg/mL). Providing a practical method for the synthesis of new scaffolds 1,2-Benzoxazepinone and systematically investigate their antifungal activity.
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Antifúngicos/síntesis química , Antifúngicos/farmacología , Oxazepinas/síntesis química , Oxazepinas/farmacología , Acetatos/farmacología , Ascomicetos/efectos de los fármacos , Botrytis/efectos de los fármacos , Iminas/farmacología , Nitrógeno/química , Oxígeno/química , Pirimidinas/farmacología , Estrobilurinas/farmacologíaRESUMEN
Plant G proteins are versatile components of transmembrane signaling transduction pathways. The deficient mutant of heterotrimeric G protein leads to defects in plant growth and development, suggesting that it regulates the GA pathway in Arabidopsis. However, the molecular mechanism of G protein regulation of the GA pathway is not understood in plants. In this study, two G protein ß subunit (AGB1) mutants, agb1-2 and N692967, were dwarfed after exogenous application of GA3. AGB1 interacts with the DNA-binding domain MYB62, a GA pathway suppressor. Transgenic plants were obtained through overexpression of MYB62 in two backgrounds including the wild-type (MYB62/WT Col-0) and agb1 mutants (MYB62/agb1) in Arabidopsis. Genetic analysis showed that under GA3 treatment, the height of the transgenic plants MYB62/WT and MYB62/agb1 was lower than that of WT. The height of MYB62/agb1 plants was closer to MYB62/WT plants and higher than that of mutants agb1-2 and N692967, suggesting that MYB62 is downstream of AGB1 in the GA pathway. qRT-PCR and competitive DNA binding assays indicated that MYB62 can bind MYB elements in the promoter of GA2ox7, a GA degradation gene, to activate GA2ox7 transcription. AGB1 affected binding of MYB62 on the promoter of GA2ox7, thereby negatively regulating th eactivity of MYB62.
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Proteínas de Arabidopsis/metabolismo , Subunidades beta de la Proteína de Unión al GTP/metabolismo , Giberelinas/metabolismo , Arabidopsis , Proteínas de Arabidopsis/genética , Sitios de Unión , Subunidades beta de la Proteína de Unión al GTP/genética , Oxigenasas de Función Mixta/genética , Oxigenasas de Función Mixta/metabolismo , Regiones Promotoras Genéticas , Unión ProteicaRESUMEN
Hydrolysis characteristics of a novel 3,4-dichloroisothiazole based fungicide with activating plant defense responses as a candidate plant-activator LY5-24-2 were investigated under different conditions (pH and temperature) using ultra-performance liquid chromatography (UPLC) and quadrupole Time-of-Flight (Q-TOF). The hydrolysis case complied with the first-order kinetic model, with half-lives ranging from 4.8 h to 3.2 days at pH 4, 7, 9 and temperature at 25 and 50â. One of the hydrolysis metabolite 3,4-dichloroisothiazole-5-carboxylic acid (metabolite 1, M1) was determined and quantified using authentic standard. The other hydrolysate 3-chloro-5-(trifluoromethyl) pyridin-2-amine (metabolite 2, M2) was determined and identified according to accurate mass information, fragmentation patterns and principle component analysis (PCA). By utilizing high-resolution mass spectrometry and multivariate statistical analysis, hydrolysis dynamic of the metabolites was characterized and figured out. This research provided a non-target screening method to analyze hydrolysis metabolites of a new plant-activator and to find its degradation products in aqueous solution.
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Cromatografía Líquida de Alta Presión , Cromatografía Liquida , Hidrólisis , Cinética , Espectrometría de MasasRESUMEN
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.
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Arabidopsis/metabolismo , Ciclopentanos/metabolismo , Oxilipinas/metabolismo , Aminoácidos/farmacología , Arabidopsis/efectos de los fármacos , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Regulación de la Expresión Génica de las Plantas/genética , Indenos/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Exosomes serve as significant information carriers that regulate important physiological and pathological processes. Herein, functionalized DNA is engineered to be a hinge that anchors quantum dots (QDs) onto the surface of exosomes, realizing a moderate and biocompatible labeling strategy. The QDs-labeled exosomes (exosome-DNA-QDs complex) can be swiftly engulfed by tumor cells, indicating that exosome-DNA-QDs can be applied as a specific agent for tumor labeling. Furthermore, the engineered artificial vesicles of M1 macrophages (M1mv) are constructed via a pneumatic liposome extruder. The results reveal that the individual M1mv can kill tumor cells and realize desirable biological treatment. To reinforce the antitumor efficacy of M1mv and the specificity of drug release, a target-triggered drug delivery system is constructed to realize a specific microRNA-responded delivery system for visual therapy of tumors. These strategies facilitate moderate labeling and functionalization of exosomes/vesicles and construct artificial drug-delivery vesicles that simultaneously possess biological treatment and chemotherapy functions, and thus have the potential to serve as a new paradigm for tumor labeling and therapy.
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ADN/metabolismo , Exosomas/metabolismo , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Diagnóstico por Imagen , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Sistemas de Liberación de Medicamentos , Exosomas/efectos de los fármacos , Exosomas/ultraestructura , Humanos , Células MCF-7 , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Distribución Tisular/efectos de los fármacosRESUMEN
Exosome-containing microRNAs (exomiRs) can be employed as potential biomarkers for tumor diagnosis and have drawn much attention in the past few years. However, the separation of exosomes and the detection of exomiRs are still inconvenient or even difficult to implement. Thus, it is important to develop a simple, accurate, and reliable strategy for the separation of exosomes and the biomedical analysis of exomiRs. Herein, a novel exosome-specific tumor diagnosis strategy was constructed by integrating the rapid magnetic exosome-enrichment platform and the Ru(bpy)32+-polymer amplified electrochemiluminescence (ECL) strategy. This strategy realized the rapid and efficient capture of tumor-derived exosomes through a biological-affinity identification platform of the EpCAM antibody. The biomedical analysis of exomiRs achieved a preferable specificity and high sensitivity of 103 particles. Furthermore, we investigated the performance index for clinical blood samples from tumor patients; the results indicated that the exosome-specific tumor diagnosis strategy readily and consistently responded to exomiRs. These results indicated that the exosome-specific tumor diagnosis strategy provided new opportunities for the sensitive and efficient analysis of tumor-derived exomiRs. This strategy greatly simplified the biomedical analysis process and established the non-destructive detection mode of fluid biopsy for tumors.
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Biomarcadores de Tumor/sangre , Exosomas/metabolismo , MicroARNs/sangre , Neoplasias/diagnóstico , Células A549 , Biomarcadores de Tumor/química , Técnicas Biosensibles/métodos , Técnicas Electroquímicas/métodos , Células Hep G2 , Humanos , Luminiscencia , Células MCF-7 , Nanopartículas de Magnetita/química , MicroARNs/química , Neoplasias/ultraestructura , Compuestos Organometálicos/química , Polímeros/química , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: PET/MR is transferring from a powerful scientific research tool to an imaging modality in clinical routine practice. Whole body PET/MR screening usually takes 30-50 minutes to finish, during which a few factors might induce patient discomfort and further cause degraded image quality. The aim of this report is to investigate the patients' perception of the imaging procedure and its correlation with image quality. METHODS: One hundred and twenty patients (63 males and 57 females, average age = 51.3 years, range 22-70 years) who had been diagnosed with cancer or had previous history of cancer were recruited and scanned with a simultaneous PET/MR system. A questionnaire was given to all patients retrospectively after the PET/MR scan, which has nine questions to assess patients' feeling of the scan on a Likert scale scoring system (1-5, 1 as most satisfied). All PET/MR images were also visually examined by two experts independently to evaluate the quality of the images. Six body locations were assessed and each location was evaluated also with a Likert scale scoring system (1-5, 5 as the best quality). Mann-Whitney U-test was used for statistical analysis to check if there is significant correlation between image quality and patient perceptions. RESULTS: With a total of 120 patients, 118 questionnaires were filled and returned for analysis. The patients' characteristics were summarized in Table 4. The statistics of the patients' perception in the questionnaire were illustrated in Tables 5-7. Statistical significant correlations were found between MR image quality and patients' characteristics/perception. CONCLUSION: Our results show that PET/MR scanning is generally safe and comfortable for most of the patients. Statistical analysis does not support the hypothesis that bad patient's perception leads to degraded image quality.
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Procesamiento de Imagen Asistido por Computador/métodos , Imagen Multimodal/métodos , Neoplasias/diagnóstico , Comodidad del Paciente/estadística & datos numéricos , Garantía de la Calidad de Atención de Salud/normas , Encuestas y Cuestionarios , Imagen de Cuerpo Entero/métodos , Adulto , Anciano , Estudios de Evaluación como Asunto , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Estudios Retrospectivos , Tomografía Computarizada por Rayos X/métodos , Flujo de Trabajo , Adulto JovenRESUMEN
An asymmetric cascade reaction between ß-keto acylpyrazoles and o-quinone methides in a formal [4 + 2] fashion to access potentially pharmacological active trans-3,4-dihydrocoumarins has been achieved efficiently by using a quinine-based chiral squaramide as the catalyst. The desired products were obtained in high yields with excellent diastereo- and enantioselectivities (up to 96% yield, >19/1 dr and 96% ee) under mild reaction conditions.
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Transketolase (TKL) plays a key role in plant photosynthesis and has been predicted to be a potent herbicide target. Homology modeling and molecular dynamics simulation were used to construct a target protein model. A target-based virtual screening was developed to discover novel potential transketolase inhibitors. Based on the receptor transketolase 1 and a target-based virtual screening combined with structural similarity, six new compounds were selected from the ZINC database. Among the structural leads, a new compound ZINC12007063 was identified as a novel inhibitor of weeds. Two novel series of carboxylic amide derivatives were synthesized, and their structures were rationally identified by NMR and HRMS. Biological evaluation of the herbicidal and antifungal activities indicated that the compounds 4u and 8h were the most potent herbicidal agents, and they also showed potent fungicidal activity with a relatively broad-spectrum. ZINC12007063 was identified as a lead compound of potential transketolase inhibitors, 4u and 8h which has the herbicidal and antifungal activities were synthesized based on ZINC12007063. This study lays a foundation for the discovery of new pesticides.
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Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Transcetolasa/antagonistas & inhibidores , Amidas/química , Inhibidores Enzimáticos/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Relación Estructura-ActividadRESUMEN
This paper summarizes the current research status of 3D printed customized medical devices regulations in US and EU. Based on the discussion of 3D printed customized medical devices in the US and the European Union, some thoughts are put forward from design, manufacturing, testing and other aspects.