Search Results (101)

One-pot protocols leading to target products in two or more sequential reactions, without the separation and isolation of intermediate products, are powerful synthetic tools. In fact, they surpass usual procedures based on single-step reactions in terms of efficiency, cost, and green aspects. The appeal of such methodologies is further increased with the use of catalysts, which makes the process easier and more efficient, minimizing unwanted byproducts. In this context, this paper describes three new one-pot protocols, based on an oxo-Re(V)-catalyzed Meyer–Schuster rearrangement of different secondary propargylic alcohols to the corresponding α,β-unsaturated ketones. These products, without isolation, subsequently, can undergo the 1,4-conjugate addition of a soft Gilman copper nucleophile or the intramolecular cyclocondensation with hydrazine hydrochloride to pyrazoles. Moreover, the ketone formed by the addition of a Gilman reagent can further be reduced in situ with LiAlH₄ to the corresponding secondary alcohol. The remarkable aspects of these novel procedures involving two and three one-pot consecutive steps are the high overall yields, the readily available reaction conditions, and the compatible presence of two transition metallic species in the same reaction medium. Full article

In this study, we developed two complementary synthetic routes to novel piperidine- and azetidine-containing 2,3-disubstituted propanoic acid derivatives as heterocyclic amino acid building blocks. The strategy employs ketone- and carboxylic acid-derived Meldrum’s acid intermediates, which are converted into common α,β-unsaturated methyl esters through methanolysis; they are subsequently diversified via DBU-promoted aza-Michael addition with saturated cyclic amines and aromatic NH-heterocycles. The ketone-derived approach provided piperidine-containing derivatives in 35–89% yield and the corresponding azetidine analogues in 61–92% yield, whereas the complementary acid-derived route afforded regioisomeric products in 59–85% and 61–89% yield, respectively. Both synthetic sequences tolerated a broad range of nitrogen nucleophiles, and no alternative regioisomeric aza-Michael products were detected for heterocycles containing multiple nitrogen atoms. The structures of the synthesized compounds were established via ¹H, ¹³C, ¹⁵N, and ¹⁹F NMR spectroscopy together with HRMS, including detailed multidimensional NMR analysis of representative products. The developed methodology provides efficient access to structurally diverse heterocyclic propanoic acid derivatives and expands the repertoire of amino acid building blocks available for peptide chemistry, medicinal chemistry, and DNA-encoded library synthesis. Full article

A systematic study of the chemoselectivity of the reduction of 3-methylcyclohex-2-enone (seudenone) to 3-methylcyclohex-2-enol (seudenol) was performed. Two approaches were investigated, namely the reduction of this ketone using NaBH₄ with modifiers and Catalytic Transfer Hydrogenation (CTH). The former resulted in higher conversions (95–99%) and high selectivity (up to 95%), whereas with CTH, a selectivity of 100% was achieved, albeit with a low conversion. The study therefore demonstrated that it is possible to chemoselectively reduce an α,β-unsaturated ketone in the liquid phase CTH using MgO as the catalyst and 2-pentanol as the hydrogen donor. The application of modifiers such as CeCl₃ · 7H₂O and MCl₂, where M = Be, Mg, Ca, Sr, and Ba, resulted in a significant improvement of the chemoselectivity (up to 95%) of the reduction with NaBH₄. The effect of parameters such as the solvent mixture composition, reaction temperature and modifier:NaBH₄ molar ratio was also investigated. In CTH, although high conversions of the ketone were observed for Al₂O₃, ZrO₂ and MgO in the vapor phase, the first two did not yield 3-methylcyclohex-2-enol among the obtained products. It was shown that 3-methylcyclohex-3-enol was the main product of the transformations of 3-methylcyclohex-2-enone in the presence of MgO, with yields of 25–33%. In a series of experiments, it was shown that 3-methylcyclohex-3-enol is formed as a result of the transformation of 3-methylcyclohex-2-enol in the presence of MgO as a catalyst. Full article

Friedelin, a pentacyclic triterpene, has been reported to inhibit potential reactive oxygen species (ROS)-scavenging activity. Accordingly, we modified the structure of this compound with the aim of obtaining derivatives. A new derivative (compound 4), with an α,β-unsaturated ketone moiety, was synthesized via an aldol condensation. Structural characterization of this compound was performed using nuclear magnetic resonance (NMR) spectroscopy and high-resolution electrospray ionization mass spectrometry. Full article

Chalcones are flavonoid compounds containing an α,β-unsaturated ketone core that are often found in plants and have diverse biological activities including antiviral activity. For example, chalcone 8o was previously shown to have antiviral activity against human cytomegalovirus (HCMV) and human immunodeficiency virus (HIV); two viruses that use a nuclear phase to complete their growth cycle. Here, we synthesized ten new derivatives of 8o and tested them for antiviral activity against four RNA viruses that replicate exclusively in the cytoplasm, including prototype members of the paramyxovirus, flavivirus, bunyavirus, and coronavirus families. For example, chalcones 8o and 8p showed potent inhibition of PIV5 replication with minimal cytotoxicity in human fibroblast cultures. Time-of-addition studies showed that these chalcones inhibit an early stage of viral replication and prevent viral spread through cell cultures. Most importantly, our top performing chalcones showed potent in vitro antiviral activity against Zika virus, La Crosse Virus, and the coronavirus OC43. These studies offer mechanistic insight into chalcone-mediated inhibition of viral replication, demonstrate the influence of functional group changes of chalcone scaffolds on their efficacy as antivirals, and support the development of chalcones as broad-spectrum antiviral compounds. Full article

Inhibitors of the tyrosine kinase Zap70 are actively searched to improve treatments of lymphoid malignancies and autoimmune diseases associated with an abnormal T-cell response. The natural product withaferin A (WFA) has been characterized as a covalent inhibitor of Zap70 capable of blocking the migration of human T-cells. By analogy, we postulated that other withanolides equipped with a thiol-reactive, α,β-unsaturated ketone may form covalent complexes with Zap70. The hypothesis was tested using a molecular modeling approach with a panel of 12 withanolides docked onto the kinase domain of Zap70. Seven natural products revealed a capability to form stable complexes with Zap70 comparable to that of WFA, including withangulatin A, 4β-hydroxywithanolide E, withaperuvin, and ixocarpalactone A. Withangulatin A surpassed all the other withanolides for its ability to engage an interaction with Zap70 kinase and to form covalent complexes via bonding to the Cys346 residue close to the enzyme active site. The physicochemical and ADMET properties of withangulatin A were analyzed via Density Functional Theory calculations and an analysis of its Fukui function descriptors. The C3 position of the enone moiety was identified as the most reactive (nucleophilic) site of the molecule. Withangulatin A revealed a satisfactory ADMET profile with no major toxicity anticipated. It represents a potential hit to guide the design of Zap70 inhibitors. Full article

In response to the urgent need for innovative fungicides to ensure food security and safety, a series of twenty-three novel trifluoromethylpyridine compounds were designed and synthesized using a scaffold hopping strategy derived from dehydrozingerone. This approach involved converting the α, β-unsaturated ketone moiety into a pyridine ring. Bioassay results indicated that the majority of these compounds exhibited promising in vitro antifungal activity, particularly against Rhizoctonia solani and Colletotrichum musae. Notably, compound 17 showed the highest efficacy and broad-spectrum activity, with median effective concentrations (EC₅₀) ranging from 2.88 to 9.09 μg/mL. Phenoxytrifluoromethylpyridine derivatives, including compound 17, exhibited superior antifungal activity compared to benzyloxytrifluoromethylpyridine derivatives. In vivo tests revealed that both compounds 17 and 23 exhibited moderate control effects against C. musae. The degradation half-lives of compounds 17 and 23 in bananas were determined to be 176.9 h and 94.8 h, respectively, indicating the stability of their structures in the environment. Molecular docking studies indicated that compound 23 interacts with succinate dehydrogenase, offering valuable insights for the structural optimization of compound 23. Full article

The phytochemical profile and antioxidant activities of Prunus africana bark, Leea indica and Paullinia pinnata leaves from Cameroon were investigated in this study. The yields of pure methanolic extraction were 11.9%, 11.1% and 10.8% in P. africana bark, L. indica and P. pinnata leaves, respectively. The total phenolic content was 189.0 ± 16.93, 163.6 ± 14.73 and 114.6 ± 10.38 mg GAE/g and total flavonoid content was 43.25 ± 6.43, 28.31 ± 4.44, and 19.75 ± 4.03 mg RU/g in P. africana bark, L. indica and P. pinnata leaves, respectively. The antioxidant activities of the plants were evaluated by DPPH, ABTS and FRAP assays. The IC₅₀ evaluated in P. africana bark, L. indica and P. pinnata leaves was 109.5 ± 13.2, 132.1 ± 18.7 and 156.1 ± 21.9 µg/mL for DPPH and 98.1 ± 4.8, 101.3 ± 12.1 and 133.9 ± 16.0 µg /mL for ABTS assay. The FRAP value was 61.1 ± 1.5, 50.5 ± 1.5 and 43.4 ± 2.1 µMFe²⁺/g in the same sequence. The functional groups for the corresponding phytochemicals, including alkane, alkene, aliphatic ether, ester, amine, α, β-unsaturated ester, alcohol, phenol, carboxylic acid, and aliphatic ketone, were identified through fourier-transform infrared analysis. The identified and quantified phenolic acids in this study were methyl-4-hydroxybenzoic, caffeic, protocatechuic and p-coumaric acid, identified using high-performance liquid chromatography. Full article

Background/Objectives: Microcolins A–M are cytotoxic marine lipopeptides produced by the cyanobacterium Moorena producens, also known as Lyngbya majuscula. Recent studies have shown that two compounds in the series, microcolins B and H, can form covalent complexes with phosphatidylinositol transfer proteins α and β (PITPα/β) upon the reaction of their α,β-unsaturated ketone group with the thiol group of a key cysteine residue of PITP. These observations prompted us to compare the binding of all microcolins and a few related derivatives (VT01454 and (deoxy)majusculamide D) to PITP to delineate structure–binding relationships. Methods: A molecular docking analysis led to the identification of microcolin E as the potentially best PITPα binder in the series, followed by microcolins B and H and analog VT01454. The computational data agree well with the published experimental results. Results: The binding of microcolin H into a large cavity of PITPα positions its reactive electrophilic α,β-unsaturated ketone close to the thiol of Cys95, enabling the facile formation of a covalent C-S linkage. A similar bonding can occur with the Cys94 of PITPβ. Molecular models of microcolins bound to PITP were compared to identify structural elements chiefly implicated in the recognition process. Conclusions: This computational study provides guidance in the design of microcolin derivatives targeting PITPα/β considered targets for cancer and inflammatory pathologies. Full article

Human lactate dehydrogenase A (hLDHA) is a homotetrameric isozyme involved in the conversion of glyoxylate into oxalate in the cytosol of liver cells (hepatocytes) and partially responsible for the overproduction of oxalate in patients with the rare disease called primary hyperoxaluria (PH). Recently, hLDHA inhibition has been validated as a safe therapeutic method to try to control the PH disease. Stiripentol (STP) is an approved drug used in the treatment of seizures associated with Dravet’s syndrome (a severe form of epilepsy in infancy) which, in addition, has been drawing interest in recent years also for potentially treating PH, due to its hLDHA inhibitory activity. In this work, several new STP-related compounds have been synthesized and their hLDHA inhibitory activity has been compared to that of STP. The synthesis of these analogues to STP was accomplished using crossed-aldol condensation guided by lithium enolate chemistry and a successive regioselective reduction of the resulting α,β-unsaturated ketones. The target molecules were obtained as racemates, which were separated into their enantiomers by chiral HPLC. The absolute configurations of pure enantiomers were determined by the modified Mosher’s method and electronic circular dichroism (ECD) spectroscopy. For the inhibitory effect over the hLDHA catalytic activity, a kinetic spectrofluorometric assay was used. All the new synthesized compounds turned out to be more active at 500 μM (46–72% of inhibition percentage) than STP (10%), which opens a new line of study on the possible capacity of these analogues to reduce urinary oxalate levels in vivo more efficiently. Full article

The present article describes the successful performance of crossed aldol reactions of the CF₃-containing pseudo-C₂ symmetric cyclic imide with various aldehydes. The utilization of HMPA as an additive attained the preferential formation of the anti-products in good to excellent yields, which contrasts with our previous method without this additive, proceeding to furnish the corresponding syn-isomers. The effective participation of ketones and α,β-unsaturated carbonyl compounds in reactions with this imide was also demonstrated to expand the application of this imide. Full article

A novel and controllable synthesis of thioacetals/thioketals and β-sulfanyl ketones mediated by the reaction of aldehyde/acetone with thiols has been developed. In this protocol, β-sulfanyl ketones can be generated without the prior preparation of α, β-unsaturated carbonyl compounds. A variety of thiols reacted with aldehyde/acetone and provided the corresponding thioacetals/thioketals and β-sulfanyl ketones in good to excellent yields, respectively. This protocol is operationally simple, mild, and atom-economical, providing controllable access to thioacetals/thioketals and thia-Michael addition products under mild conditions. Full article

The coastal region of the Caribbean is notable for the chemical diversity found in its sponge products, resulting in the biosynthesis of a range of natural marine products, including polyketides. The objective of this manuscript is to summarize the isolated polyketides from sponges of the genus Plakortis located around the Caribbean coasts. This review provides a comprehensive overview of specimen location, isolation procedures, characterization methods, and biological assay studies of about 95 polyketides isolated from 1978 to 2024 in the Caribbean coasts of The Bahamas, Cayman Islands, Belize, Dominica, Jamaica, Martinique, Panamá, Puerto Rico, and Tobago. The Caribbean polyketides have been isolated from different types of Plakortis sp., such as P. simplex, P. halichondroides, P. zyggompha, and P. angulospiculatus, which have demonstrated antimicrobial, anticancer, anti-inflammatory, antiparasitic, and antiviral activities. A variety of linear polyketides with different functionalities have been reported, including endoperoxides (1,2-dioxane), lactones, indane-type bicyclics (spiculane and zyggomphic), alcohols, alkenes, styryl groups, α,β-unsaturated carboxylic acids, and ketones, as well as related natural products of biosynthetic origin. The aim is to encourage further exploration by researchers in the Caribbean’s coastal marine environments, promoting the discovery and investigation of novel polyketide cyclic peroxides and related secondary metabolites to identify additional bioactive medicinal natural products. Full article

4′-dihydrochalcones are secondary metabolites isolated from many medicinal plants and from the resin known as ‘dragon’s blood’. Due to their biological potential, our research objective was to determine the possibilities of using biocatalysis processes carried out in deep eutectic solvents (DESs) to obtain 4′-dihydrochalcones as a model compound. The processes were carried out in a culture of the yeast Yarrowia lipolytica KCh 71 and also in cultures of strains of the genera Rhodotorula and Debaryomyces. Based on the experiments carried out, an optimum process temperature of 35 °C was chosen, and the most suitable DES contained glycerol as a hydrogen bond donor (HBD). For a medium with 30% water content (DES 11), the conversion observed after 24 h exceeded 70%, while increasing the amount of water to 50% resulted in a similar level of conversion after just 1 h. A fivefold increase in the amount of added substrate resulted in a reduction in conversion, which reached 30.3%. Of the other yeast strains tested, Rhodotorula marina KCh 77 and Rhodotorula rubra KCh 4 also proved to be good biocatalysts for the bioreduction process. For these strains, the conversion reached 95.4% and 95.1%, respectively. These findings highlight the potential of yeast as a biocatalyst for the selective reduction of α,β-unsaturated ketones and the possibility of using a DESs as a reaction medium in this process. Full article

Chalcone (1,3-diaryl-2-propen-1-one) is an α, β-unsaturated ketone that serves as an active constituent or precursor of numerous natural substances, exhibiting a broad spectrum of pharmacological effects. In this study, the classical Claisen–Schmidt condensation method was used to synthesize the chalcone derivative 2′,4′-dimethoxychalcone (DTC) and evaluate its pharmacological activity. By upregulating the expression of the epithelial cell marker E-cadherin and downregulating the expression of the mesenchymal cell marker vimentin, DTC was found to inhibit transforming growth factor-β1 (TGF-β1)-induced epithelial–mesenchymal transition (EMT) process in A549 cells, maintaining the cells’ epithelial-like morphology and reducing the ability of the cells to migrate. Additionally, DTC demonstrated the ability to decrease the expression levels of nitric oxide (NO), tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in RAW264.7 cells, suggesting a possible anti-inflammatory effect. Furthermore, DTC was found to exhibit bacteriostatic activity against Staphylococcus aureus (S. aureus), Proteus vulgaris (P. vulgaris), methicillin-resistant Staphylococcus aureus (MRSA), and Candida albicans (C. albicans), indicating that this chemical may possess broad-spectrum antibacterial activity. Full article