An intermolecular hydroxylation of α,β-unsaturated gold carbene intermediates, generated from readily accessible 3-propargylindoles through a tandem 1,2-indole migration–hydroxylation sequence using water as an external nucleophile, has been developed. Under mild reaction conditions and employing gold(I) catalysts bearing bulky and electron-rich phosphine ligands, a significant range of hydroxy-functionalized indole derivatives was synthesized in high yields. Mechanistic studies support the selective addition of water to the β-position of the electrophilic α,β-unsaturated gold carbene intermediate, whereas competing attack at the carbene center or direct hydration of the activated alkyne was not observed.
α-Hydroxyphosphonates and α-hydroxyphosphine oxides are important intermediates for additional biologically active species. While (hydroxy(phenyl)methyl)(diphenyl)phosphine oxide did not even undergo chlorination with thionyl chloride, the reaction of diethyl chloro(phenyl)methylphosphonate with potassium diphenylphosphide followed by oxidation with hydrogen peroxide resulted in the expected bis(>P(O)-functionalized) product only as a minor component. The similar reaction of the analogous (methanesulfonyloxy)(phenyl)methyl derivative afforded a mixture of a diethyl (diethoxyphosphonyl)(phenyl)methyl phosphate, a diethyl (diphenylphosphinyl)(phenyl)methyl phosphate, and a ((diphenylphosphinyl)(phenyl)methyl) diphenylphosphinate. The formation of the unexpected products was explained assuming rearrangements and reversible formation of the hydroxymethylene-bis(>P(O)-functionalized) intermediate. Contrary to the earlier experiences, the reaction of ((methanesulfonyloxy)(phenyl)methyl)(diaryl)phosphine oxides with potassium diphenylphosphide followed by oxidation took place in a clear-cut manner providing, with one exception, the corresponding α-phosphinylated α-hydroxyphosphine oxides that could also be synthesized by direct phosphinylation of the starting α-hydroxyphosphine oxide. Cell viability assays performed on U266 myeloma cells revealed concentration-dependent antiproliferative effects of the synthesized compounds on U266 myeloma cells, highlighting the key role of the phosphinoyloxy moiety in the cytotoxic activity, which may be enhanced further by 4-methyl groups in the P-phenyl rings.
The incorporation of CF2 moieties into drug molecules offers unique advantages in improving metabolic stability and target affinity, making their efficient construction a major focus in pharmaceutical process chemistry. This review systematically examines the synthetic processes of 12 FDA-approved CF2-containing drugs from 2016 to 2025, categorizing them according to the chemical environment of the CF2 group (alkyl-CF2, heteroaryl-CF2, and ArO-CF2). For each drug, the industrial routes for CF2 construction and the reasons for eliminating alternative routes are analyzed. Methods for CF2 formation are classified into two major strategies: fluorinating reagent-based approaches and building block-based approaches. Key process steps and scale-up data are summarized in Table 1. The article systematically discusses four types of reaction mechanisms - nucleophilic fluorination, electrophilic fluorination, radical pathways, and carbene insertion - and evaluates their applicability in industrial production. The analysis shows that for alkyl-CF2 groups, the industry strongly favors preformed CF2 building blocks or indirect fluorination strategies to avoid hazardous reagents and harsh conditions. Continuous flow technology using SF4 has emerged as an important complement to traditional fluorination methods. For heteroaryl-CF2 groups, metal-catalyzed direct introduction of the CF2 unit still faces challenges for industrial application, whereas the difluorocarbene route for ArO-CF2 has been validated. This review provides a reference for process development of new CF2-containing drugs, from strategic design to scale-up evaluation.
Three rare cyano-substituted indole N -glycosides, SF-2140 ( 1 ) and its two previously undescribed derivatives, sugarnitriles A ( 2 ) and B ( 3 ), were isolated from a sugarcane endophytic actinomycete Amycolatopsis sp. JS-O27. The planar structures of 1 – 3 were established by HRESIMS data and detailed 1D/2D NMR spectroscopic analysis, and the conformations of the sugar moieties were deduced by the analysis of 3 J H-H coupling constants and NOESY data, and comparison of their electronic circular dichroism (ECD) spectra. Compounds 1 and 3 exhibited moderate to weak antibacterial activity against Escherichia coli at 100 μg/mL.
With the goal to develop coralyne-based ligands for abasic site-containing DNA (AP-DNA), different synthetic routes towards the functionalization of coralyne were tested. In particular, the alkylation of the benzylic position in papaverine and subsequent cyclization by treatment with acetic anhydride in sulfuric acid led to the synthesis of a coralyne derivative with an alkoxyamine-functionalized linker attached at position C13. Firstly, it was demonstrated with a resembling model compound that the alkylation of the coralyne scaffold does not influence the DNA-binding properties. Furthermore, it was shown that the alkoxyamine function can be readily released from a Boc-protected precursor and that the corresponding coralyne–alkoxyamine conjugate can operate as a ligand for AP-DNA and as inhibitor of enzymatic repair of abasic sites.
α-Costic acid is a natural sesquiterpene possessing diverse biological activities. Among these, the most promising property for practical application is its acaricidal activity against Varroa destructor, considered the most important and dangerous parasite of the honeybee (Apis mellifera L.). Infestations of V. destructor can decimate bee populations in just a few years, resulting in substantial environmental and economic losses. This study reports the synthesis of α- and γ-costic acid diesters with ethylene glycol and evaluates their acaricidal efficacy against V. destructor in comparison with their parent acids. Although the resulting dimers were approximately 50% less active than the parent costic acids, they exhibited higher potency than the previously reported α-costic acid methyl ester. Among all, γ-costic acid, whose acaricidal activity is reported here for the first time, shows the highest activity with mortality higher than 90%, thus emerging as the most promising candidate for the development of effective and environmentally friendly strategies for the control of V. destructor. Furthermore, it may hold potential for the biocontrol of other mite pests affecting economically important crops such as legumes and cereals, which are currently associated with significant yield losses and extensive reliance on synthetic pesticides.
A new bicyclic metabolite, rhodopyran ( 1 ), was isolated from the culture broth of Rhodococcus sp. strain RD066637. The planar structure was elucidated by 1D/2D NMR analyses and HRMS spectrometry, and the relative configuration was assigned from vicinal coupling constants and NOESY correlations, while the absolute configuration remains undetermined. Rhodopyran represents a structurally unusual carboxylated hexahydrocyclopenta[ b ]pyran and expands the known metabolite diversity of Rhodococcus , highlighting Rhodococcus as a source of uncommon natural-product scaffolds.
Gold(III) complexes and amphiphiles have been extensively investigated over a decade. Supramolecular assemblies of gold(III) amphiphiles in aqueous media exhibit high sensitivities to external stimulations for soft functional materials. Herein, we introduce a new molecular design of a tridentate cyclometalated gold(III) amphiphile ( GA ) with flexible molecular structure modifications. Counterion exchange with sodium tosylate induces notable luminescent enhancement and enables control over supramolecular assembly processes. This approach drives a supramolecular assembly transformation of GA from disordered nanosheets to well-ordered nanoribbons upon the additions of multiple equivalents of counterion, enabling a tunable pathway for controlled supramolecular transformation.
Antimicrobial therapy is becoming increasingly ineffective over infections due to the gradual microbial resistance to conventional treatments. This aspect highlights the urgent need for the development of new antimicrobial agents. In this context, the amino acid-derived surfactants have proven to be a promising alternative to eradicate numerous microorganisms and their biofilms. The antimicrobial action of these agents can be explained by their amphiphilic structure, a configuration that allows interactions with structural components, such as the microorganism membranes and extracellular matrices of biofilms, promoting destructive effects on the cellular integrity and microbial vital processes. In addition, these surfactants can be easily synthesized using green chemistry principles, are biodegradable and more biocompatible than commercial quaternary ammonium surfactants. This paper aimed to elucidate the relevance of amino acid-derived surfactants with antimicrobial properties, presenting their structural compositions and connecting to the novel evidences on their mechanism of action. An integrative review was conducted, drawing upon findings from scientific articles published in the last 20 years (between 2005 and 2025), exclusively in English, retrieved from the PubMed database. This research employs a qualitative approach, adopting a basic research design with descriptive objectives, using a bibliographic method to explore the topic. The results indicate that the search for new amino acid-derived surfactants with antimicrobial activity has gradually grown over the last years. These molecules have shown promising characteristics, singular structures leading to innovative mechanisms of action, capable of overcoming the defenses of resistant microorganisms. In conclusion, the ability of these compounds to inhibit the growth of bacteria, yeasts, and fungi has been demonstrated, offering an effective approach to prevent and combat the spread of infections, especially in the context of microbial resistance.
A concise and efficient synthetic route to novel 1,2,4-oxadiazole-isoxazoline hybrids 7 has been developed via regioselective 1,3-dipolar cycloaddition of in situ-generated nitrile oxides with 3-( p -substituted-aryl)-5-vinyl-1,2,4-oxadiazoles 6 . The target compounds 7a–ay were obtained in moderate to excellent yields (16–97%) and fully characterized by IR, NMR, and HRMS analyses. The reactions exhibited high regioselectivity, exclusively affording 5-isoxazoline derivatives, while substituent effects played a decisive role in modulating reaction efficiency. In silico studies revealed that all hybrids 7a–ay display strong binding affinities toward the adenosine A₁ receptor (−10.0 to −8.3 kcal/mol), surpassing the co-crystallized ligand and engaging in key stabilizing interactions within the binding pocket. Furthermore, ADMET predictions indicated favorable drug-likeness, high gastrointestinal absorption, and suitable physicochemical properties. Overall, these findings identify 1,2,4-oxadiazole-isoxazoline hybrids as promising and tunable scaffolds for the development of adenosine A₁ receptor-targeted agents; however, further structural optimization and comprehensive biological evaluation are required to fully validate their therapeutic potential.
Dithiocarbamates are widely recognized for their versatile applications in both agriculture as effective pesticides and medicine, where they serve as antifungal and anticancer agents. As a result, their synthesis has garnered significant attention in recent years. In this study, we present an efficient one-pot four-component approach for the synthesis of these scaffolds, utilizing aldehydes, ethyl acetoacetate, carbon disulfide (CS2), and amines. Initially, α,β-unsaturated carbonyl compounds, serving as Michael acceptors, were generated from aldehydes and ethyl acetoacetate through a decarboxylative Knoevenagel reaction under mild conditions, using lipase as a biocatalyst. These intermediates then sequentially undergo a nucleophilic addition reaction with dithiocarbamate anions, which are generated in situ by reacting CS2 with amines. This sequence successfully yields 15 derivatives of S-alkylated dithiocarbamates with high to excellent yields ranging from 69% to 96%.
The known lichen depside, lecanoric acid (1), was identified as a scaffold of interest for the generation of a unique semisynthetic biodiscovery screening library. Large-scale extraction and isolation on the Australian-sourced lichen Parmotrema tinctorum resulted in the purification of ≈1 g of the desired scaffold 1, along with other known lichen metabolites that included divaricatic acid (2), orcinol (3), orsellinic acid (4), and methyl orsellinate (5). Parallel solution-phase synthesis using amidation chemistry on the abundant scaffold 1 afforded a series of novel amide derivatives 6–13 in high purity (>95%) and low to moderate yields (12–53%). All new semisynthetic compounds were fully characterised following 1D/2D NMR, MS and UV data analysis. Crystalline lecanoric acid was obtained during the chemical investigations of the lichen extract, enabling the first X-ray crystallographic analysis to be undertaken on this depside. Compounds 1–13 were evaluated for antibacterial activity against the human pathogen Pseudomonas aeruginosa using a biofilm inhibition assay. Of the new semisynthetics, amide analogue 12 showed the greatest planktonic cell growth inhibition (13% at 50 µM), whilst amide analogue 11 was the most active at inhibiting the formation of biofilm (21% at 50 µM).
Vicinal diamines based on a rigid polycyclic framework such as homoadamantane remain underexplored. We anticipated that the unique steric and lipophilic properties of chiral trans-4,5-diaminohomoadamantane could provide the necessary stereoinduction in metal-catalyzed asymmetric reactions. In addition, such structures may serve as a novel scaffold for bioactive compounds. Herein, we report a synthetic approach to this previously inaccessible chiral scaffold. 4,5-Diaminohomoadamantane was prepared as a mixture of cis- and trans-isomers by reduction of the corresponding vicinal azidoxime with LiAlH4. In contrast, the trans-isomer was selectively obtained via ring-opening of an N-Tf-protected aziridine. The racemic trans-4,5-diaminohomoadamantane was resolved with dibenzoyl-ʟ-tartaric acid. The absolute (4R,5R)-configuration was proposed on the basis of TDDFT calculations of the specific optical rotation using the CAM-B3LYP functional and the 6-311G++(2d,2p) basis set with solvation by CH2Cl2 in the SMD model on the base of conformational analysis. Catalytic systems based on (4R,5R)-4,5-diaminohomoadamantane derivatives exhibited low to moderate asymmetric induction in Henry and Michael reactions. These results suggest that further molecular design of homoadamantane-based chiral N,N-ligands is promising.
A Ni/Lewis acid dual-catalytic system has been developed for the Z-selective semihydrogenation of alkynes. Utilizing DMF as both the hydrogen donor and reaction medium, this method affords Z-alkenes in high yield with excellent stereoselectivity under mild conditions. The protocol employs cost-effective and readily available catalysts, and demonstrates broad applicability across a wide range of substrates.
2-Arylimidazolines were annulated with cyclic diazo-1,3-dicarbonyl compounds under Rh(III)-catalysis for the first time. The developed general and efficient approach based on CH-activation allowed the efficient preparation of five novel types of tetraheterocyclic systems derived from 2,3-dihydroimidazo[2,1-a]isoquinolines fused with an additional five-, six- or seven-membered carbocycle or N-/O-heterocycle.
Spacer length is a key molecular parameter governing the self-assembly of short peptides. Here, we investigate isoleucine-cysteine-alanine (ICA) tripeptides containing carbon spacers of 6, 3, or 0 methylene units linking the peptide backbone to a hydrophobic naphthalene (Nap) π-block. Using complementary spectroscopic and microscopic techniques, we show that spacer length controls the balance between conformational flexibility and directional non-covalent interactions, thereby dictating assembly pathways and material properties. The results establish a correlation between spacer length and assembly propensity, with the longest spacer (C 6 ) consistently promoting aggregation more effectively than the intermediate analogue (C 3 ), whereas peptides containing the rigid C 0 -spacer fail to develop ordered nanostructures. These findings identify spacer length as a powerful design parameter for tuning peptide self-assembly across multiple length scales.
Electrochemical reduction has emerged as a powerful alternative to conventional hydrogenation for unsaturated C–C bonds, enabling precise control without molecular hydrogen or stoichiometric reductants. This review summarizes recent advances in iron-, cobalt-, and nickel-catalyzed electroreduction of alkynes and alkenes, highlighting how electrochemical parameters and catalyst design unlock distinct, controllable reaction manifolds that are inaccessible under thermochemical conditions. These developments position 3d metal electrocatalysis as a versatile and programmable platform for selective hydrogenation and isotopic labeling under mild, sustainable conditions.
The capabilities of modern methods for the synthesis of sterically shielded piperidine nitroxides with acyclic substituents are largely limited to symmetrical tetraethyl structures and do not allow the introduction of functional groups into position 2. We propose an alternative approach that allows for the variation of substituents adjacent to the nitroxyl group, which significantly expands the potential of sterically hindered nitroxides for promising applications in materials science and structural biology. The new heterocyclization strategy implies the construction of a 2,2,6-trisubstituted piperidine scaffold from β-aminoketone acetals and dialkyl ketones under acid catalysis. The resulting amines were oxidized to the corresponding ketonitrones and subsequent reaction with moderately basic organometallic reagents, such as 2-alkynyl- and 2-allylmagnesium halides, enables the facile introduction of diverse substituents, including those with functional groups. If necessary, the multiple carbon–carbon bonds in the side chain can be subjected to hydrogenation to give saturated alkyl or functionalized alkyl groups. The study of reduction kinetics for alkyl and allyl-substituted piperidine nitroxides in ascorbate/glutathione media (30% EtOH, pH 7.5) yielded second-order rate constants of ≈10−2 M−1·s−1, which is close to that earlier reported for 2,2,6,6-tetraethylpiperidine (TEEPONE).
