We report the direct synthesis of densely substituted spiroannulated cyclobutanes from indane-1,3-dione-based activated alkenes or their analogs and sulfur ylides under mild, Lewis acid-free conditions. The transformation proceeds through a Corey-Chaykovsky cyclopropanation that furnishes highly strained donor-acceptor spirocyclopropanes, followed by their (3 + 1)-annulation with stabilized sulfonium ylides that can be conducted in a telescoped or one-pot fashion. Preliminary mechanistic studies allowed a better understanding of the origin of both the observed high reactivity and diastereoselectivity.

The thermal properties of a series of recently synthesized protic ionic liquids based on the thiocyanate anion [SCN] and mono-, di-, and trialkylammonium cations, namely, methylammonium ([MA]), n-decylammonium ([DecA]), 2-phenylethylammonium ([PhEA]), 2-aminoethylammonium ([EDA]), diethylammonium ([DEA]), di-n-butylammonium ([DBA]), and tri-n-butylammonium ([TBA]), are examined. According to differential scanning calorimetry data, [DEA][SCN] and [EDA][SCN] are room-temperature ionic liquids, [DecA][SCN], [DBA][SCN], [TBA][SCN], and [PhEA][SCN] melt below 323 K, and [MA][SCN] melts below 373 K. Thermogravimetric analysis shows that the thermal stability of the studied ionic liquids under dynamic heating conditions exhibits no general correlation with the number of substituents on the nitrogen atom or with the alkyl chain length. However, primary ammonium thiocyanates have a worse long-term thermal stability. They undergo chemical changes when kept for several hours at temperatures between 353 and 373 K, which is well below the mass loss temperature in dynamic experiments. Secondary and tertiary ammonium salts do not decompose even at the temperature at which they start to lose mass due to evaporation. The operating temperature windows for thiocyanate protic ionic liquids have been determined. Among the studied liquids, [DEA][SCN] can be used within the widest temperature range (from 266 to 480 K) in various applications that require long-term thermal stability.

Solvent-dependent transformations of polysubstituted 2-acetyl-2,5-dihydrothiophenes to the corresponding 2-hydroxy- or deacetylated derivatives are described. The treatment of a methanolic solution of the dihydrothiophene substrates with sodium methoxide afforded the deacylated products. Conversely, the treatment with sodium ethoxide in an oxygen saturated ethanolic solution produced 2-hydroxy substituted 2,5-dihydrothiophenes.

Although the Knoevenagel condensation of aldehydes with various CH-acids has been known for more than 130 years, the efficiency of this reaction for phosphonoacetates remains poorly understood. We found that the preferred conditions for the formation of target 3-(hetero)aryl-2-(dialkoxyphosphoryl)acrylates depend on the electronic properties of the aldehyde used. Specifically, for the Knoevenagel condensation of trialkyl phosphonoacetates with electron-deficient (hetero)aromatic aldehydes, the best results are achieved using a combination of piperidine and acetic acid as a catalyst, whereas for aldehydes containing an electron-rich aromatic group, higher yields were obtained using the pyrrolidine/acetic acid catalytic system. Preferred amines for catalyzing the reactions of aldehydes with diverse electroneutral aromatic groups were also identified. Secondary amines themselves can also be used to carry out this reaction without loss of efficiency. In contrast, tertiary amines were ineffective both alone and in combination with carboxylic acids. Based on the obtained data, the mechanistic picture of the Knoevenagel condensation of trialkyl phosphonoacetates and its competition with the Horner-Wadsworth-Emmons condensation was refined.

We report a domino reaction of 2-(2-acylvinyl)indoles as well as the corresponding pyrroles with styrylsulfonium salts under mild conditions, affording cyclopropamitosene analogues in high yields and complete diastereoselectivity. A wide range of (E)-β-hetaryl-α,β-unsaturated ketones were successfully employed for the synthesis of potentially bioactive cyclopropa[3,4]pyrrolo[1,2-a]indoles and related cyclopropa[a]pyrrolizines, demonstrating the versatility of the developed method. In contrast, (Z)-isomers of the substrates fail to give cyclopropamitosene derivatives but undergo cyclopropanation of the terminal methyl group.

Ylides are versatile reagents known for their dual electrophilic and nucleophilic reactivity, mimicking carbenes in many reactions. In this study, we uncover a previously unreported reactivity pathway for ylides: a methylene insertion into C-C bonds. We show that sulfur ylides can achieve homologation of alkenes and aldehydes before proceeding through the classical Corey-Chaykovsky reaction. This process allows for the dual transfer of CH2 groups to both substrates, yielding benzylcyclopropanes and benzyloxiranes, valuable intermediates in organic synthesis. Remarkably, the same sulfur ylide reagent participates in two distinct carbene-like transformations within this cascade. Mechanistic studies reveal the role of a tightly coordinated stereoelectronic network playing a crucial role in facilitating anionic 1,2-aryl shifts.

Hyperexcitation of neuronal networks is believed to be the main reason for the excitotoxic death of neurons in different central nervous system pathologies, including epilepsy, ischemic stroke, and traumatic brain injury. Gi-coupled receptors can be considered as promising targets for the development of new neuroprotectors. Here, we studied the anticonvulsant activity of the agonists and positive allosteric modulators (PAM) of A1 adenosine receptors (A1Rs). Our experiments demonstrate that A1R agonists, CCPA and N[6][1]-cyclohexyladenosine (N[6][1]-CHA), suppress hyperexcitation in three different in vitro models, including acute glutamate excitotoxicity, NH4Cl– and bicuculline-induced epileptiform activity. We have found that the inhibitory action of the agonists is mediated by the activation of not only the neuronal A1Rs but also the astrocytic receptors. In astrocytes, A1R agonists enhance GABA release, possibly via induction of calcium transients. Using inhibitory analysis, we have demonstrated that Gβγ-mediated activation of phospholipase C and subsequent Ca2+ mobilization from internal stores are essential for generating calcium transients in astrocytes following N[6][1]-CHA application. We have shown first that Ca2+-dependent activation of protein kinase C, which is involved in the mechanism of GABA release by astrocytes, is a pivotal step in the realization of the antiepileptic action of A1R agonists. Moreover, using the model of epileptiform activity induced by GABAAR blockade, we have shown that PAMs, PD81723 and VCP171, also suppress hyperexcitation. Furthermore, using the picrotoxin-induced epilepsy model in mice, we demonstrated that A1R agonists exhibit significant anticonvulsant effects and improve animal survival. The PAMs PD81723 and VCP171, when administered one hour before seizure induction, did not significantly affect seizure severity or survival rates. However, chronic administration of VCP171 produced a pronounced anticonvulsant effect and significantly increased survival.. Importantly, PAMs provided therapeutic benefits without significantly affecting overall activity levels in mice. Thus, our study demonstrates that both agonists and PAMs of A1R can be considered as potential therapeutic agents with antiepileptic and neuroprotective activity. ### Competing Interest Statement The authors have declared no competing interest. This work was supported by the Ministry of Science and Higher Education of the Russian Federation within the framework of the state assignment of PSCBR RAS 075-00607-25-00 (No 1024032700128-8-1.6.4, Development of drugs for the treatment of brain injury and epilepsy: in vitro and in vivo studies). [1]: #ref-6

A methodology for the synthesis of substituted furans via an "ylide dance" sequence has been developed. The reaction involves phenacyl sulfonium salts and alkenyl- or propargyl sulfonium salts under basic conditions. The key feature is a stepwise evolution where a primary sulfur ylide, generated from phenacyl sulfonium salt and base, transforms into another ylide, which then undergoes conversion into yet another, a "third generation" ylide, culminating in the formation of the target furan.

A method for one-step conversion of (3-formylindol-4-yl)-substituted donor-acceptor cyclopropanes to 5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indoles has been developed. The scope and limitations of this reaction, as well as the Lewis acid effect on the process chemoselectivity, have been determined. Straightforward transformations of the obtained products provide direct access to alkaloid-like tetracyclic compounds.

An original method for the synthesis of a diverse array of hydroquinone thioethers with yields of 36% to 99% under mild conditions is described. The process is voltammetrically controlled and involves electrogenerating active protonated p-quinone followed by thiol addition.

Thiocyanate-containing protic ionic liquids (PILs) have previously proven to be useful reagents for conducting diverse chemical transformations. A fundamentally new concept of multi-purpose application of these PILs opens up new opportunities in organic synthesis. However, their safety has not been thoroughly assessed so far. In this work, we carried out a systematic investigation of cytotoxicity of a series of synthetically valuable thiocyanate-containing PILs towards normal human dermal fibroblasts (DF-1) and human embryonic kidney cells (HEK293T). In particular, the impact of anion on the cytotoxicity was studied for dual-purpose triethylamine-based PILs. The study of cellular damage markers yielded additional insights into the mechanisms of PILs’ cytotoxicity.

Tubulins are among the most successful targets for cancer chemotherapy. However, the emergence of drug resistance stimulates the continuous search for novel chemotherapeutics. Here, we discover that coumarin-30, a widely available laser dye, binds to the colchicine site of tubulin and inhibits microtubule dynamics and cancer cell division at submicromolar concentrations. By combining coumarin-30 as a fluorescent probe with the microscale thermophoresis approach, we develop a versatile assay for detecting tubulin–ligand interactions and simultaneously sorting ligands into binders of the colchicine site versus other protein pockets. The assay’s performance is demonstrated on a wide panel of compounds. Using this methodology, we identify several potent tubulin polymerization inhibitors and determine their binding sites. The results are verified with studies of microtubule dynamics in vitro and the cell cycle in cancer cell culture. Thus, the coumarin-30-based assay is a fast, accurate, and cost-effective method for characterizing tubulin ligands with diverse binding pockets.

Multi-purpose thiocyanate-containing protic ionic liquids were utilised in concert as a solvent, a Brønsted acidic catalyst, and a nucleophile source for the conversion of 4,5-dihydroxy-4,5-diarylimidazolidine-2-(thi)ones into imidazo[4,5-d]oxazolethiones and imidazo[4,5-d]thiazolones. A key advantage of this process is chemoselectivity switching by tuning the electron-donating nature of aryl substituents while carefully controlling the reaction temperature. In the case of unactivated arenes, oxazolethione was forced to rearrange into thiazolone in the new highly acidic protic ionic liquid, 1-methylpyrazolium triflate. The operationally simple experimental set-up is complemented by an eco-friendly aqueous work-up/filtration procedure providing pure crystalline products.

Tubulins are among the most successful targets for cancer chemotherapy. However, the emergence of drug resistance stimulates the continuous search for novel chemotherapeutics. We discovered that coumarin‐30, a widely available laser dye, binds to the colchicine site of tubulin, inhibiting microtubule dynamics and cancer cell division at submicromolar concentrations. Exploiting the excellent fluorescent properties of coumarin‐30, we developed a fast, accurate, and cost‐effective coumarin‐30‐based microscale thermophoresis (C‐MST) assay as an express method for detecting tubulin–ligand interactions and discriminating colchicine site binders from ligands targeting other protein pockets. Using this assay, we identified several potent tubulin polymerization inhibitors associating with the colchicine site and validated them through in vitro microtubule dynamics and cell cycle assays in cancer cells. Furthermore, the C‐MST assay was demonstrated to detect ligands targeting a novel binding site on tubulin, recently established through crystallographic fragment screening. We confirmed detection of a small‐molecule ligand targeting that site and further designed and characterized a series of its analogs. The ability of the C‐MST assay to detect tubulin binders regardless of their binding site or their effect on microtubule dynamics opens new avenues for developing unconventional modulators of tubulin–tubulin and tubulin–effector interactions thereby facilitating anticancer drug discovery.

Ytterbium triflate catalysed domino reaction of (3-formyl-4-indolyl)-derived donor-acceptor cyclopropane with primary amines provides a simple approach to an unprecedented tetracyclic skeleton in which tropane system is peri-annulated with an indole core. This process involves the formation of an imine and its (3+2)-cross-cycloaddition with donor-acceptor cyclopropane moiety, yielding tropane-fused indole core under mild reaction conditions. These products are of significant interest for pharmacology as potential hybrid molecules with a dual mode of action.

Here, we present a new approach for activation of donor-acceptor cyclopropane systems in ring-opening reactions, which does not require the use of Lewis or Brønsted acid as a catalyst. Under treatment with a base, donor-acceptor cyclopropanes containing a phenolic group as the donor undergo deprotonation and fast isomerisation to the corresponding quinone methides. This innovative strategy was applied to realise [4+1] annulation of 2-(2-hydroxyaryl)-substituted DA cyclopropanes with sulfur ylides, affording functionalised dihydrobenzofurans. A plausible mechanism of this process has been proposed based on theoretical calculations. Additionally, the generated ortho- and para-quinone methides as well as their aza-analogues can be trapped by deprotonated CH-acids as nucleophiles providing a simple path toward acyclic polyfunctional compounds as promising building blocks for the synthesis of more complexed and biologically interesting cyclic structures.

Protic ionic liquids have numerous promising applications as solvents and are more straightforward and less expensive to synthesize than aprotic ionic liquids. This study expands the scarce knowledge on the solvation properties of protic ionic liquids by considering three triethylammonium salts: acetate, trifluoroacetate, and triflate. Additionally, they were characterized by means of TG/DSC analysis and low-temperature DSC in order to determine the liquid range temperature. The limiting activity coefficients of alkanes, alkenes, aromatic hydrocarbons, cycloalkanes, cyclohexene, and thiophene at 298.15 K were measured in these liquids. A higher solubility of hydrocarbons in triethylammonium salts than in many aprotic and several studied protic ionic liquids was observed. The selectivity of triethylammonium triflate for n-hexane/benzene separation is higher than that of sulfolane and N-methyl-2-pyrrolidinone used in industrial extraction processes.