Tetronic Acid Research Articles

Uncovering the Potent Antiviral Activity of the Sesterterpenoids from the Sponge Ircinia Felix Against Human Adenoviruses: from the Natural Source to the Total Synthesis.

Human Adenovirus (HAdV) infections in immunocompromised patients can result in disseminated diseases with high morbidity and mortality rates due to the absence of available treatments for these infections. The sponge Ircinia felix was selected for the significant anti-HAdV activity displayed by its organic extracts. Its chemical analysis yielded three novel sesterterpene lactams, ircinialactams J-L, along with three known sesterterpene furans which structures were established by a deep spectrometric analysis. Ircinialactam J displayed significant antiviral activity against HAdV without significant cytotoxicity, showing an effectiveness 11 times greater than that of the standard treatment, cidofovir®. Comparison of the antiviral evaluation results of the isolated compounds allowed us to deduce some structure-activity relationships. Mechanistic assays suggest that ircinialactam J targets an early step of the HAdV replicative cycle before HAdV genome reaches the nucleus of the host cell. The first total synthesis of ircinialactam J was also accomplished to prove the structure and to provide access to analogues. Key steps are a regio- and stereoselective construction of the trisubstituted Z-olefin at Δ7 by iron-catalyzed carbometallation of a homopropargylic alcohol, a stereoselective methylation to generate the stereogenic center at C18, and the formation of the (Z)-Δ20 by stereoselective aldol condensation to introduce the tetronic acid unit. Ircinialactam J is a promising chemical lead to new potent antiviral drugs against HAdV infections.

A Novel Approach for the Synthesis of 3,3′-((4-Methoxyphenyl)methylene)bis(4-hydroxyfuran-2(5H)-one) Employing Natural Deep Eutectic Solvents and Microwave Irradiation

Tetronic acid, a five-membered heterocyclic moiety present in various natural products, has emerged as a significant building block for many pharmaceutically active compounds. In this study, a novel protocol for the synthesis of the bis-tetronic acid 3,3′-((4-methoxyphenyl)methylene)bis(4-hydroxyfuran-2(5H)-one) (3) via a domino Knoevenagel–Michael reaction is presented. The natural deep eutectic solvent L-proline/glycerol 1:2 molar ratio was utilized as a solvent and catalyst, while the reaction was further promoted via microwave irradiation, providing the desired product in high yield (83%). The solvent was successfully recycled and reused up to three times.

Base-promoted cascade recyclization of allomaltol derivatives containing an amide fragment into substituted 3-(1-hydroxyethylidene)tetronic acids.

For the first time, recyclization of allomaltol derivatives with an amide fragment in the side chain were investigated. It was shown that the studied process leads to substituted tetronic acids bearing a pyrrolidinone moiety. The application of 1,1'-carbonyldiimidazole and DBU is necessary for implementation of the considered reaction. Based on the performed research a general method for the synthesis of a wide range of (3E,5E)-3-(1-hydroxyethylidene)-5-(5-oxopyrrolidin-2-ylidene)furan-2,4(3H,5H)-diones was elaborated. The advantages of the presented protocol are easily available starting compounds and simple isolation of the target products without chromatographic purification. The synthetic utility of the prepared tetronic acids was demonstrated by further transformations at the hydroxyethylidene fragment. The structures of one obtained tetronic acid and one product of derivatization were confirmed by X-ray analysis.

Repurposing Insecticides for Mosquito Control: Evaluating Spiromesifen, a Lipid Synthesis Inhibitor against Aedes aegypti (L.).

The growing resistance of Aedes aegypti (L.) to conventional insecticides presents a major challenge in arbovirus control, necessitating the exploration of alternative insecticidal chemistries. Spiromesifen, derived from spirocyclic tetronic acids, is widely used against agricultural pests and is crucial in resistance management due to its unique lipid synthesis inhibition. This study evaluates the insecticidal activity of spiromesifen against temephos-resistant Ae. aegypti populations, focusing on larval body weight, volume, biochemical composition, and adult female reproductive potential. Spiromesifen demonstrated effective larvicidal activity, significantly reducing adult emergence. Resistance to spiromesifen was not observed, with resistance ratios (RR50, RR90) ranging from 0.36- to 3.31-fold. Larvae exposed to LC50 showed significant reductions in body weight and volume, and reduced carbohydrate, lipid, and protein contents. Enhanced catalase activity and malondialdehyde levels indicated increased oxidative stress and lipid peroxidation, highlighting its effects on lipid metabolism. Spiromesifen also exhibited sterilizing effects, significantly reducing fecundity and fertility in adult females, thereby impacting Ae. aegypti reproductive capacity. These findings highlight the potential of spiromesifen as a component of integrated vector management strategies, especially in regions with prevalent insecticide resistance in Ae. aegypti, serving as an effective larvicide and impacting adult reproductive outcomes.

Synergistic action and mechanism of scoparone, a key bioactive component of Artemisia capillaris, and spirodiclofen against spider mites.

Plants have numerous defensive secondary metabolites to withstand insect attacks. Scoparone, which is extracted from the medicinal plant Artemisia capillaris, has potent acaricidal effects on Tetranychus cinnabarinus. Spirodiclofen, derived from a tetronic acid derivative, is a potent commercial acaricide that is extensively used globally. However, whether scoparone has synergistic effects when used in conjunction with spirodiclofen and the underlying synergistic mechanism remains unclear. Scoparone exhibited a potent synergistic effect when it was combined with spirodiclofen at a 1:9 ratio. Subsequently, cytochrome P450 monooxygenase (P450) activity, RNA-Seq and qPCR assays indicated that the enzyme activity of P450 and the expression of one P450 gene from T. cinnabarinus, TcCYP388A1, were significantly inhibited by scoparone and spirodiclofen + scoparone; conversely, P450 was activated in spirodiclofen-exposed mites. Importantly, RNAi-mediated silencing of the TcCYP388A1 gene markedly increased the susceptibility of spider mites to spirodiclofen, scoparone and spirodiclofen + scoparone, and in vitro, the recombinant TcCYP388A1 protein could metabolize spirodiclofen. Molecular docking and functional analyses further indicated that R117, which is highly conserved in Arachnoidea species, may be a vital specific binding site for scoparone in the mite TcCYP388A1 protein. This binding site was subsequently confirmed using mutagenesis data, which revealed that this binding site was the sole site selected by scoparone in spider mites over mammalian or fly CYP388A1. These results indicate that the synergistic effects of scoparone and spirodiclofen on mites occurs through the inhibition of P450 activity, thus reducing spirodiclofen metabolism. The synergistic effect of this potent natural product on the detoxification enzyme-targeted activity of commercial acaricides may offer a sustainable strategy for pest mite resistance management. © 2024 Society of Chemical Industry.

Ultrasound-Assisted, BF3·OEt2-Promoted, Multicomponent Synthesis of Chromene-Based Podophyllotoxin Analogues

AbstractA novel method was developed to synthesise chromene-lactone analogues of podophyllotoxin using an ultrasound-assisted multicomponent reaction (MCR). The MCR involved tetronic acid, phenols, and aromatic aldehydes and was promoted by BF3·OEt2, resulting in the production of ten derivatives with different substituents on the aromatic rings in yields ranging from 32% to 93%. These compounds are of interest due to their reported activity against tumour cells. Their ease of synthesis through the MCR may allow for more in-depth studies on anticancer activity, as well as investigations of other biological targets. The synthesised derivatives contain important pharmacophoric groups for potential applications in medicinal chemistry.

Silver Nanoparticles Supported on Covalent Organic Framework as a Catalyst for Carboxylative Cyclization with CO2 for Synthesis of Tetramic and Tetronic Acids

Silver Nanoparticles Supported on Covalent Organic Framework as a Catalyst for Carboxylative Cyclization with CO₂ for Synthesis of Tetramic and Tetronic Acids

Mapping and Characterization of Target-Site Resistance to Cyclic Ketoenol Insecticides in Cabbage Whiteflies, Aleyrodes proletella (Hemiptera: Aleyrodidae).

Cabbage whitefly, Aleyrodes proletella L., is an invasive hemipteran pest of cruciferous plants, particularly field brassica crops. Its importance has been increased over the last decade, particularly in European countries. The control of cabbage whiteflies largely relies on the application of synthetic insecticides, including tetronic and tetramic acid derivatives such as spiromesifen and spirotetramat (cyclic ketoenol insecticides), acting as insect growth regulators targeting acetyl-CoA carboxylase (ACC). In 2019, reduced efficacy against cabbage whiteflies of ketoenol insecticides at recommended label rates has been reported. Subsequently we collected field samples of A. proletella in different European countries and confirmed the presence of ketoenol resistance in laboratory bioassays. Reciprocal crossing experiments revealed an autosomal dominant trait, i.e., heterozygotes express a fully resistant phenotype. Transcriptome sequencing and assembly of ACC variants from resistant strains revealed the presence of an ACC target-site mutation, A2083V, as previously described and functionally validated in Bemisia tabaci (A2084V in A. proletella). Next, we employed a molecular genotyping assay to investigate the geographic spread of resistance and analyzed 49 populations collected in eight European countries. Resistance allele frequency was highest in the Netherlands, followed by Germany. Finally, we provide a proposal for the implementation of appropriate resistance management strategies.

Utility of silver nanoparticles embedded on a covalent organic framework as a highly active catalyst for carboxylative cyclization with CO2: a sustainable route for production of tetronic acids and oxazolidinones

The rising amount of carbon dioxide in our atmosphere is a concern regarding our environment.

Asymmetric Baeyer–Villiger Oxidation to Access Tetronic Acids

Asymmetric Baeyer–Villiger Oxidation to Access Tetronic Acids

Cytotoxic tetronic acid derivatives from the mangrove endophytic fungus Hypomontagnella monticulosa YX702

Three new tetronic acid derivatives, nodulisporacid A ethyl ester (3), isosporothric acid methyl ester (4), and (R)-3-(methoxycarbonyl)-2-methyleneundecanoic acid (5) were isolated from mangrove endophytic fungus Hypomontagnella monticulosa YX702, together with three known analogues nodulisporacid A (1), nodulisporacid A methyl ester (2), and dihydrosporothriolide (6). The structures of these new compounds were elucidated by analysis of NMR and HR-ESI-MS spectroscopic data. In addition, the absolute configuration of nodulisporacid A (1) was confirmed by single-crystal X-ray diffraction for the first time. Subsequently, the absolute configuration of compounds 2 and 3 were determined by chemical derivatization of nodulisporacid A (1). The absolute configuration of compound 4 and 5 were established by TDDFT ECD calculations. Compounds 1 and 2 exhibited cytotoxic activities against A549 and Hela cancer cell lines with the IC50 values between 5.64 and 8.14 μM.

Preparation of spirodiclofen monoclonal antibody and establishment of indirect competitive enzyme-linked immunosorbent assay.

Spirodiclofen, a spirocyclic tetronic acid derivative, has excellent acaricidal effect and is used worldwide to control the majority of important mite species. For monitoring its residue in food and environmental samples, two haptens containing different spacer arms were synthesized, a monoclonal antibody (mAb 5A4) against spirodiclofen was prepared, and a heterologous indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) was established. The 50% inhibition concentration (IC50) of ic-ELISA was 25.46ng/mL, and the working range was 5.59-133.85ng/mL. The ic-ELISA showed no cross-reactivity with structural analogs of spirodiclofen and other commonly-used acaricides. The average recoveries from Shiranui citrus samples and Yangtze River water were 85.62%-97.74% and 85.95%-99.30%, respectively. In the analysis of 12 citrus samples, the results of the ic-ELISA were quite similar to those of ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Hence, the new immunosorbent assay provides a substitute method for the qualitative and quantitative of spirodiclofen in food and environmental samples.

Catalytic Desymmetrizing Baeyer-Villiger Oxidation of Quaternary Carbon-Containing Cyclobutane-1,3-diones.

The first highly enantioselective Baeyer-Villiger oxidation of quaternary carbon-containing cyclobutane-1,3-diones using chiral phosphoric acid catalysis and commercially available oxidants was reported. According to the structure of the substrates, two optimized reaction conditions were developed to afford the corresponding chiral tetronic acid products in ≤93% and ≤95% ee values. This reaction offers the first catalytic asymmetric approach to chiral 5,5-disubstituted tetronic acid derivatives. The synthetic potential of this method has been demonstrated by the formal asymmetric synthesis of (-)-vertinolide and the first catalytic asymmetric total synthesis of plakinidone B.

The Residue and Dietary Risk Assessment of Spirotetramat and Its Four Metabolites in Cabbage Using Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry.

Spirotetramat is a potential tetronic acid pesticide for controlling various pests with piercing-sucking mouthparts. To clarify its dietary risk on cabbage, we established an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method and then investigated the residual levels of spirotetramat and its four metabolites in cabbage collected from field experiments under good agricultural practices (GAPs). The average recoveries of spirotetramat and its metabolites in cabbage were 74~110%, while the relative standard deviation (RSD) was 1~6%, and the limit of quantitation (LOQ) was 0.01 mg kg-1. The terminal residue of spirotetramat was in the range of <0.05~0.33 mg kg-1, the chronic dietary risk (RQc) was 17.56%, and the acute dietary risk (RQa) was 0.025~0.049%, which means an acceptable dietary intake risk. This study provides data to guide on the use of spirotetramat and to establish the maximum residue limits (MRLs) of spirotetramat on cabbage.

Tetronic acid and tetramic acid derived pesticides and their toxicity: a review

Tetronic acid and tetramic acid derived pesticides and their toxicity: a review

Design, synthesis, and biological evaluation of 1,4,7,8‐tetrahydro‐5H‐furo[3,4‐b]pyrazolo[4,3‐e]pyridin‐5‐one‐based azo dyes

AbstractSome 1,4,7,8‐tetrahydro‐5H‐furo[3,4‐b]pyrazolo[4,3‐e]pyridin‐5‐ones containing azo group were synthesized by a three‐component one‐pot reaction of a preformed azoaldehyde (AZA), tetronic acid, and 5‐aminopyrazole in ethanol in the presence of triethylamine under microwave irradiation. The structures of the products were confirmed by spectroscopic data. This method has the advantages of simpler operation to prepare a new dihydropyridines (1,4‐DHPs) ring with multi‐functional groups architecture, high efficiency, short reaction time, and exciting atom economical chemistry. All the products were evaluated regarding antibacterial activities. Some compounds exhibited potent antibacterial activity against both Gram‐negative (Escherichia coli) and Gram‐positive (Micrococcus luteus and Staphylococcus aureus) bacteria compared with erythromycin and tetracycline. The antioxidant activity (AOA) of the synthesized compounds was considered in comparison to vitamin C. Some compounds exhibited the highest AOA, even higher than vitamin C.

Microwave‐Assisted Multicomponent Synthesis of New 6‐Arylated 5‐Hydroxy‐benzo[a]phenazine Derivatives and Their Potential Anti‐inflammatory Activity

AbstractA convenient two step “one‐pot” four‐component synthetic approach was developed for the synthesis of new 6‐arylated 5‐hydroxy‐benzo[a]phenazine derivatives using 2‐hydroxy‐1,4‐naphthoquinone, a variety of aromatic aldehydes, benzene‐1,2‐diamine, and tetronic acid. In all cases, the synthesis proceededviathree key steps including condensation, Michael addition, and tautomerization. The structure of synthesized compounds was elucidated by spectral data. The inhibitory effect of newly synthesized compounds on nitric oxide (NO) production in lipopolysaccharide (LPS)‐ stimulated murine macrophage RAW 264.7 cells was assessed. All products exhibited the highly potential NO production inhibition activity with the IC50values in the range of 3.68–12.14 μM, indicating the critical role of these compounds in the development of potential anti‐inflammation agents.

Recent advances in the multicomponent synthesis of heterocycles using tetronic acid.

Tetronic acid, a versatile synthon, has been extensively investigated by numerous researchers in synthetic chemistry due to its crucial role in synthesizing heterocycles which makes this compound particularly advantageous in both pharmaceutical and biological fields. Various heterocycles can be synthesized using it as a precursor via multicomponent reactions (MCRs). Dicarbonyl groups can be considered the building blocks and key structural motifs of a wide range of natural compounds, which may contain different functional groups in the synthesis of heterocyclic frameworks. This review covers the literature from 2017 to 2022, and it encompasses the different one-pot protocols for synthesizing a variety of heterocyclic molecules.

The chemistry of 2-hydroxy-β-nitrostyrenes: versatile intermediates in synthetic organic chemistry.

The applications of 2-hydroxy-β-nitrostyrenes as efficient bifunctional intermediates in organic synthesis are investigated in this review. For this purpose, reactions of 2-hydroxy-β-nitrostyrenes with diverse molecules, including carbonyl compounds, 1,3-dicarbonyl compounds, α,β-unsaturated carbonyl compounds, hemiacetals, nitroalkenes, γ-butenolides, tetronic acid, azalactones, pyrazolones, enamines, malononitrile, methyleneindolinones, ylides, etc., were investigated to construct interesting biologically active scaffolds such as chromans, chromenes, coumarins, benzofurans and their fused and spiro rings, natural products, and other useful cyclic and acyclic compounds. The main focus is on the asymmetric synthesis of these compounds via cascade/domino/tandem reactions catalyzed by chiral organocatalysts. In this review, around 60 papers reported between the years 2000 and 2022 are presented.

Collective synthesis of aspulvinone and its analogues by vinylogous aldol condensation of substituted tetronic acids with aldehydes.

A mild, modular and efficient synthetic method with broad substrate scope was developed for aspulvinones. Nine natural aspulvinones were synthesized, six of which were for the first time. The aldol condensation delivered Z-configuration products predominantly in MeCN. Meanwhile, alkoxy exchange occurred in MeOH and EtOH. Aspulvinone O and E, and substrate 49, 50, and 51 exhibited modest anti-SARS-CoV-2 activity in a high-throughput screening and enzyme kinetics assay.