RESUMO
With the increasing reports of antibiotic resistance in this species, Pseudomonas aeruginosa is a common human pathogen with important implications for public health. Bacterial quorum sensing (QS) systems are potentially broad and versatile targets for developing new antimicrobial compounds. While previous reports have demonstrated that certain amide compounds can inhibit bacterial growth, there are few reports on the specific inhibitory effects of these compounds on bacterial quorum sensing systems. In this study, thirty-one amide derivatives were synthesized. The results of the biological activity assessment indicated that A9 and B6 could significantly inhibit the expression of lasB, rhlA, and pqsA, effectively reducing several virulence factors regulated by the QS systems of PAO1. Additionally, compound A9 attenuated the pathogenicity of PAO1 to Galleria mellonella larvae. Meanwhile, RT-qPCR, SPR, and molecular docking studies were conducted to explore the mechanism of these compounds, which suggests that compound A9 inhibited the QS systems by binding with LasR and PqsR, especially PqsR. In conclusion, amide derivatives A9 and B6 exhibit promising potential for further development as novel QS inhibitors in P. aeruginosa.
Assuntos
Amidas , Antibacterianos , Descoberta de Drogas , Simulação de Acoplamento Molecular , Pseudomonas aeruginosa , Percepção de Quorum , Pseudomonas aeruginosa/efeitos dos fármacos , Percepção de Quorum/efeitos dos fármacos , Amidas/farmacologia , Amidas/química , Amidas/síntese química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Testes de Sensibilidade Microbiana , Relação Dose-Resposta a Droga , AnimaisRESUMO
To find potential type III secretion system (T3SS) inhibitors against citrus canker caused by Xanthomonas citri subsp. citri (Xcc), a new series of 5-phenyl-2-furan carboxylic acid derivatives stitched with 2-mercapto-1,3,4-thiadiazole were designed and synthesized. Among the 30 compounds synthesized, 14 compounds significantly inhibited the promoter activity of a harpin gene hpa1. Eight of the 14 compounds did not affect the growth of Xcc, but significantly reduced the hypersensitive response (HR) of tobacco and decreased the pathogenicity of Xcc on citrus plants. Subsequent studies have demonstrated that these inhibitory molecules effectively suppress the T3SS of Xcc and significantly impair the pathogen's ability to subvert citrus immunity, resulting in a reduction in the level of disease progression. As a result, our work has identified a series of potentially attractive agents for the control of citrus canker.
Assuntos
Citrus , Xanthomonas , Sistemas de Secreção Tipo III/genética , Virulência , Doenças das Plantas/prevenção & controleRESUMO
Agrochemical science prioritizes the discovery and effective synthesis of innovative and promising lead compounds. Herein, we developed an efficient column chromatography-free synthesis for ß-carboline 1-hydrazides via a mild CuBr2-catalyzed oxidation and investigated the antifungal and antibacterial activities and mechanisms for these compounds. In our study, compounds 4de (EC50 = 0.23 µg·mL-1) and 4dq (EC50 = 0.11 µg·mL-1) displayed the best efficacy, demonstrating enhancements in inhibitory activity of more than 20-fold against Ggt compared to silthiopham (EC50 = 2.39 µg·mL-1). Additionally, compound 4de (EC50 = 0.21 µg·mL-1) demonstrated outstanding in vitro antifungal activities as well as in vivo curative activities against Fg. According to preliminary mechanistic studies, ß-carboline 1-hydrazides led to the accumulation of reactive oxygen species, destruction of cell membranes, and dysregulation of histone acetylation. Furthermore, several substances exhibited antibacterial activity against Psg and Cms by preventing the development of bacterial biofilms.
Assuntos
Antibacterianos , Antifúngicos , Antifúngicos/farmacologia , Relação Estrutura-Atividade , Antibacterianos/farmacologia , Carbolinas/químicaRESUMO
Ligand-enabled Pd-catalyzed regioselective α,ß-dehydrogenation of carbonyl compounds via ß-methylene C-H activation has recently emerged as a promising transformation. Herein, we report the realization of ß,γ-dehydrogenation and subsequent vinyl C-H olefination reactions of free carboxylic acids, thus providing a unique method for the structural diversification of aliphatic acids containing α-quaternary centers through sequential functionalizations of two ß-C-H bonds and one γ-C-H bond. This tandem dehydrogenation-olefination-lactonization reaction offers a one-step preparation of ß-alkylidene-γ-lactones, which are often difficult to prepare through conventional methods, from inexpensive and abundant free aliphatic acids. A variety of free aliphatic acids, such as isosteviol and grandiflorolic acid natural products, and olefins are compatible with the reported protocol. The newly designed bidentate oxime ether-pyridone and morpholine-pyridone ligands are crucial for this tandem reaction to proceed. Notably, these ligands also enable preferential methylene C-H activation over the previously reported, competing process of methyl C-H bond olefination.
Assuntos
Ácidos Graxos , Lactonas , Catálise , Lactonas/química , Ligantes , PiridonasRESUMO
Nitrogen-centered radicals are versatile synthetic intermediates with the ability to undergo diverse reactions such as hydrogen atom transfer (HAT), ß-scission, and addition across unsaturated systems. A long-standing impediment to the wider adoption of these intermediates in synthesis has been the difficulty of their generation. Herein we disclose a new hydrazonyl carboxylic acid precursor to nitrogen-centered radicals and its application toward remote C-H fluorination and chlorination reactions of sulfonyl-protected alkyl amines via 1,5-HAT.
Assuntos
Halogenação , Nitrogênio , Aminas , HidrogênioRESUMO
At the forefront of chemistry and biology research, development timelines are fast-paced and large quantities of pure targets are rarely available. Herein, we introduce a new framework, which is built upon an automated, online trapping-enrichment multi-dimensional liquid chromatography platform (TE-Dt-mDLC) that enables: 1)â highly efficient separation of complex mixtures in a first dimension (1 D-UV); 2)â automated peak trapping-enrichment and buffer removal achieved through a sequence of H2 O and D2 O washes using an independent pump setup; and 3)â a second dimension separation (2 D-UV-MS) with fully deuterated mobile phases and fraction collection to minimize protic residues for immediate NMR analysis while bypassing tedious drying processes and minimizing analyte degradation. Diverse examples of target isolation and characterization from organic synthesis and natural product chemistry laboratories are illustrated, demonstrating recoveries above 90 % using as little as a few micrograms of material.
Assuntos
Produtos Biológicos , Cromatografia Líquida , Espectroscopia de Ressonância Magnética , SolventesRESUMO
The development of C(sp3 )-H functionalizations of free carboxylic acids has provided a wide range of versatile C-C and C-Y (Y=heteroatom) bond-forming reactions. Additionally, C-H functionalizations have lent themselves to the one-step preparation of a number of valuable synthetic motifs that are often difficult to prepare through conventional methods. Herein, we report a ß- or γ-C(sp3 )-H carbonylation of free carboxylic acids using Mo(CO)6 as a convenient solid CO source and enabled by a bidentate ligand, leading to convenient syntheses of cyclic anhydrides. Among these, the succinic anhydride products are versatile stepping stones for the mono-selective introduction of various functional groups at the ß position of the parent acids by decarboxylative functionalizations, thus providing a divergent strategy to synthesize a myriad of carboxylic acids inaccessible by previous ß-C-H activation reactions. The enantioselective carbonylation of free cyclopropanecarboxylic acids has also been achieved using a chiral bidentate thioether ligand.
Assuntos
Anidridos/síntese química , Monóxido de Carbono/química , Ácidos Graxos/química , Catálise , Ciclopropanos/química , Ligantes , Estrutura Molecular , Molibdênio/química , Sulfetos/químicaRESUMO
The development of practical C-H/C-H coupling reactions remains a challenging yet appealing synthetic venture because it circumvents the need to prefunctionalize both coupling partners for the generation of C-C bonds. Herein we report a cyclative C(sp3)-H/C(sp2)-H coupling reaction of free aliphatic acids enabled by a cyclopentane-based mono-N-protected ß-amino acid ligand. This reaction uses inexpensive sodium percarbonate (Na2CO3·1.5H2O2) as the sole oxidant and generates water as the only byproduct. A range of biologically important scaffolds, including tetralins, chromanes, and indanes, can be easily prepared by this protocol. Finally, the synthetic application of this methodology is demonstrated by the concise total synthesis of (±)-russujaponol F in a four-step sequence starting from readily available phenylacetic acid and pivalic acid through sequential functionalizations of four C-H bonds.
Assuntos
Cromanos/química , Indanos/química , Tetra-Hidronaftalenos/química , Catálise , Ciclização , Estrutura Molecular , Compostos Organometálicos/química , EstereoisomerismoRESUMO
The development of C-H activation reactions that use inexpensive and practical oxidants remains a significant challenge. Until our recent disclosure of the ß-lactonization of free aliphatic acids, the use of peroxides in C-H activation reactions directed by weakly coordinating native functional groups was unreported. Herein, we report C(sp3)-H ß-acetoxylation and γ-, δ-, and ε-lactonization reactions of free carboxylic acids enabled by a novel cyclopentane-based mono-N-protected ß-amino acid ligand. Notably, tert-butyl hydrogen peroxide is used as the sole oxidant for these reactions. This reaction has several key advantages over other C-H activation protocols: (1) exclusive monoselectivity was observed in the presence of two α-methyl groups; (2) aliphatic carboxylic acids containing α-hydrogens are compatible with this protocol; (3) lactonization of free acids, affording γ-, δ-, or ε-lactones, has been achieved for the first time.
Assuntos
Ácidos Carboxílicos/química , Ligantes , Oxidantes/química , Estrutura MolecularRESUMO
Alkoxy radicals have long been known to enable remote C-H functionalization via 1,5-hydrogen atom abstraction. However, methods for their generation traditionally have relied upon highly oxidizing metals, ultraviolet radiation, or preformed peroxide intermediates, which has prevented the development of many desirable transformations. Herein we report a new bench-stable precursor that decomposes to free alkoxy radicals via a previously unreported single-electron oxidation pathway. This new precursor enables the fluorination and chlorination of remote C-H bonds under exceptionally mild conditions with exceedingly high monoselectivity. Iterative use of this precursor enables the introduction of a second halogen atom, granting access to remote dihalide motifs, including CF2 and CFCl.
Assuntos
Álcoois/química , Halogenação , Catálise , Oxirredução , Paládio/química , Processos FotoquímicosRESUMO
Enantioselective carbon-hydrogen (C-H) activation reactions by asymmetric metallation could provide new routes for the construction of chiral molecules1,2. However, current methods are typically limited to the formation of five- or six-membered metallacycles, thereby preventing the asymmetric functionalization of C-H bonds at positions remote to existing functional groups. Here we report enantioselective remote C-H activation using a catalytic amount of a chiral norbornene as a transient mediator, which relays initial ortho-C-H activation to the meta position. This was used in the enantioselective meta-C-H arylation of benzylamines, as well as the arylation and alkylation of homobenzylamines. The enantioselectivities obtained using the chiral transient mediator are comparable across different classes of substrates containing either neutral σ-donor or anionic coordinating groups. This relay strategy could provide an alternative means to remote chiral induction, one of the most challenging problems in asymmetric catalysis3,4.
Assuntos
Carbono/química , Hidrogênio/química , Alquilação , Benzilaminas/química , Catálise , Norbornanos/química , EstereoisomerismoRESUMO
The synthesis of vinyl boronates and vinyl silanes was achieved by employing a Ru-catalyzed alkene-alkyne coupling reaction of allyl boronates or allyl silanes with various alkynes. The double bond geometry in the generated vinyl boronates can be remotely controlled by the juxtaposing boron- and silicon groups on the alkyne substrate. The synthetic utility of the coupling products has been demonstrated in a variety of synthetic transformations, including iterative cross-coupling reactions, and a Chan-Lam-type allyloxylation followed by a Claisen rearrangement. A sequential one-pot alkene-alkyne-coupling/allylation-sequence with an aldehyde to deliver a highly complex α-silyl-ß-hydroxy olefin with a handle for further functionalization was also realized.