Elena Borisovna Averina

This study presents a novel regioselective synthesis of 3-electron-withdrawing-group-(EWG)-substituted 5-sulfonyl- and 5-sulfinylisoxazoles from 3-EWG-5-nitroisoxazoles via nucleophilic aromatic substitution with thiophenols followed by oxidation with m -chloroperbenzoic acid (mCPBA). The scope of the reactions was explored, demonstrating high yields across a variety of functional groups and substituents. Optimized conditions enabled selective oxidation of thioaryl groups to sulfonyl or sulfinyl derivatives. Biological evaluation revealed that several compounds, especially 3-nitro-5-sulfonyl- and 5-sulfinylisoxazoles, exhibit potent antimicrobial activity against Gram-positive bacteria, fungi, and notably low MICs comparable to those of standard drugs. The mechanism of action studies indicate that these compounds induce the bacterial SOS response without inhibiting DNA synthesis-related enzymes such as DNA polymerase I, DNA gyrase, or topoisomerases I and IV, suggesting activation via bacterial reductases. These findings highlight the potential of these isoxazole derivatives as promising antimicrobial agents and provide new insights into their mechanism of action.

4-Aminotetrahydroquinazoline N-oxides form a prominent chemotype of orthoflavivirus reproduction inhibitors, attractive for the search of lead compounds for development as direct-action antiviral agents. Here we explored the relationship between the structure and antiviral activity within an extended series of adamantyl-containing 4-aminotetrahydroquinazolines, synthesized via S_NAr reactions of 4-chlorotetrahydroquinazolines with adamantyl-containing amines. Most of the obtained compounds inhibited the reproduction of tick-borne encephalitis, yellow fever, and West Nile viruses in phenotypic assays with micromolar EC₅₀s. The most favorable substituents at 4-amino group were 2-adamant-(1/2)-ylethyls, while the position 2 of heterocyclic core served as a toxicity switch, 2-chlorotetrahydroquinazolines being much less toxic than other analogues. Time-of-addition experiments for hit compounds against West Nile virus revealed a possibility for multi-factorial mechanism of action in the 4-aminotetrahydroquinazoline series.

Nucleophilic ring-opening of bis(oxiranes), containing several reactive centers, can be used to elaborate straightforward atom-economy and stereoselective approaches to polyfunctionalized compounds. In the present work, ring-opening of cis- and trans-diastereomers of a spirocyclic bis(oxirane), containing a cyclooctane core (namely, 1,8-dioxadispiro[2.3.2.3]dodecane), upon treatment with various amines, was studied. Trans-isomer afforded aminoalcohols with 9-oxabicyclo[3.3.1]nonane moiety, formed via domino-process, including opening of an oxirane ring followed by intramolecular cyclization. Ring-opening of cis-isomer gave aminosubstituted cis-cyclooctane-1,5-diols, derived from independent reaction of two oxirane moieties. Activation of oxirane rings by the addition of LiClO₄, acting as a Lewis acid, allowed the involvement of a number of primary and secondary aliphatic amines as well as aniline derivatives in the reaction. Scope and limitations of the reaction were studied and a series of aminoalcohols with a 9-oxabicyclo[3.3.1]nonane core and symmetric diaminodiols with a cyclooctane core were obtained.

Nucleophilic ring-opening of bis(oxiranes), containing several reactive centers, can be used to elaborate straightforward atom-economy and stereoselective approaches to polyfunctionalized compounds. In the present work ring-opening of cis- and trans-diastereomers of a spirocyclic bis(oxirane), containing a cyclooctane core (namely, 1,8-dioxadispiro[2.3.2.3]dodecane), upon the treatment with various amines was studied. Trans-isomer afforded aminoalcohols with 9-oxabicyclo[3.3.1]nonane moiety, formed via domino-process, including opening of an oxirane ring followed by intramolecular cyclization. Ring-opening of cis-isomer gave aminosubstituted cis-cyclooctane-1,5-diols, derived from independent reaction of two oxirane moieties. Activation of oxirane rings by the addition of LiClO4, acting as a Lewis acid, allowed involving a number of primary and secondary aliphatic amines as well as aniline derivatives into the reaction. Scope and limitations of the reaction were studied and a series of aminoalcohols with 9-oxabicyclo[3.3.1]nonane core and symmetric diaminodiols with cyclooctane core were obtained.

Pulmonary edema and acute respiratory failure, developing due to the vascular endothelium dysfunction, are common side effects of anticancer therapy. This study is the first approach to create an in vitro model system to estimate vascular response at the drug development/improvement stage and to determine whether it is possible to select an antitumor drug dose effectively suppressing malignant cells without a pathological effect on the endothelial cells function. In this study (1) the doses of several clinically used antitumor drugs suppressing the common tumor cell proliferation were determined experimentally; (2) the endothelial cell viability after exposure to selected doses of these drugs was assessed in vitro; (3) changes in the endothelial monolayer condition, as well as cultured endothelial cell reactions and intracellular disorders accompanying the effects of selected drugs doses were studied in vitro using the intravital observations and super‐resolution microscopy methods. This approach allowed to select antitumor drug concentrations inhibiting cell proliferation in selected tumor lines, but having no critical effect on the viability of endothelial cells and their cytoskeletal structures. As the result, an in vitro model system for studying the side effects of medications on vascular permeability was created.

An efficient approach to previously unknown 5-cyano-4-nitroisoxazoles has been developed using nitrosation of 4-nitroisoxazole-based enamines with tert-butyl nitrite (TBN) followed by a BF₃- or TFAA-mediated unusual C═C bond cleavage reaction. This two-step one-pot process is applicable to a broad range of substrates and provides the desired products in mild reaction conditions in moderate to high yields. The dichotomy of reactivity in the S_NAr reaction of the resulting 5-cyano-4-nitroisoxazoles has been demonstrated by the cyano-group substitution with N-nucleophiles and the nitro-group substitution with thiophenols and rationalized with DFT-calculations.

A large series of previously unknown isoxazole containing difluoroboron β‐diketonate has been designed and synthesized from the available starting compounds. The photophysical properties of obtained compounds were studied, and the effects of the substituents in aromatic and isoxazole cycles of the BF₂ complexes on the fluorescence were investigated. The effect of solvatochromism were demonstrated. Cytotoxic activity against MCF‐7 (breast carcinoma), HCT‐116 (colon carcinoma), A549 (pulmonary carcinoma) and WI38 (fibroblasts from lung tissue) cell lines was tested and moderate toxicity in the concentration range of 10–100 μM was found for several compounds.