The paper presents the synthesis of new naphthyl-containing derivatives of thiosemicarbazide and thiourea, their water-soluble inclusion complexes with β-cyclodextrin, as well as an assessment of their potential antiviral and hemorheological activity. As a criterion for the specific antiviral effect of new compounds, their chemotherapeutic indices were calculated using predictive analytics tools driven by artificial intelligence and molecular docking methods. Molecular docking studies with three protein targets PknB (2FUM), DprE1 (6HEZ), and InhA (1ENY) confirmed strong and specific ligand–protein interactions. The effects of structural features of new compounds on the rheological characteristics of blood were considered, and the most promising samples were identified for further in-depth in vitro study of their specific biological activity. The performed thermoanalytical study showed that the structure of the included ligand, as well as the shape of the receptor, significantly affect the thermal stability and kinetic parameters of the decomposition of the inclusion complex. In silico evaluation of the newly synthesized compounds revealed promising biological activity profiles, with all compounds demonstrating predicted antimycobacterial and antituberculosis potential. In silico analysis of the newly synthesized compounds revealed favorable biological activity profiles, with all candidates demonstrating predicted antimycobacterial and antituberculosis potential.

The year 2024 marked the 80th anniversary of Woodward’s total synthesis of quinine. Quinine is a natural alkaloid from the bark of the cinchona tree that has been used for years as an antimalarial drug. The antibacterial effect of quinine salts has also been regarded. With this in mind, a series of original 9-deoxycinchone alkaloid derivatives bearing a dialkylamino- or heterocyclic moiety at the 4 position of the 9-(((4-X-but-2-ynyloxy)methyl)-1,2,3-triazolyl)-substituent was synthesized. The copper-catalyzed three-component A3-coupling reaction of 9-(((4-prop-2-ynyloxy)methyl)-1,2,3-triazolyl)- substituted cinchona alkaloid derivatives with secondary amines and formaldehyde was the main route of synthesis. The present study attempted to examine the antibacterial properties of 9-substituted 9-desoxyquinine-derived compounds and their antibacterial activity against pathogenic bacterial strains, e.g., Staphylococcus aureus, Bacillus subtillis, Bacillus cereus, and Escherichia coli. The difference in the antibacterial activity profile of diastereoisomeric 9-(((4-X-but-2-ynyloxy)methyl)-1,2,3-triazolyl)-substituted derivatives of cinchona alkaloids indicated the importance of the nature of nitrogen substituents in the molecules. In a concentration-dependent pattern, (9R)- and (9S)- (((4-asocan-1yl)-but-2-ynyl-oxy)methyl)-1,2,3-triazolyl)-substituted compounds demonstrated considerable biofilm-inhibitory efficacy against the S. aureus bacterial strain. A detailed study of the molecular interactions with the targeted protein MurB was performed using docking simulations, and the obtained results are quite promising.

The synthetic availability and wide range of biological activity of hydrazides and hydrazones make them attractive subjects for investigation. In this study, we focused on synthesis of 2-methyl-5-nitro-6-phenylnicotinohydrazide-based hydrazones derived from the corresponding substituted aldehydes. The structure of the obtained compounds was studied using NMR spectroscopy and DFT calculations. After repeated recrystallization, all the synthesized compounds remained as mixtures of isomers. As a result of a detailed analysis, we found that the duplication and bifurcation of signals in the 1H NMR spectra for some atoms is a consequence of the existence of four isomers, namely Z-I, Z-II, E-I and E-II. Duplicate proton signals with a chemical shift difference of 0.1–0.2 ppm and in a ratio of about 2:1 were noticed in the experimental data. By modeling the structures of individual configurations and conformations, Gibbs free energy values were obtained, which allowed us to estimate the approximate content of rotamers for the E-isomer equal to 3:2, which coincided with experimental data. We also tested the antibacterial and antifungal activity of the synthesized compounds.

This study presents the results of a study of the synthesis and properties of 2-hydroxy-β-cyclodextrin functionalized by silver nanoparticles and its loading with a bioactive component. As a reducing agent and stabilizer, 2-Hydroxy-β-cyclodextrin (2gβCD) was used in the production of silver nanoparticles. The use of 2gβCD-AgNPs in loading molecules of the plant alkaloid lupinine (Lup) and its acetyl derivative (Lac) with bactericidal properties were studied. The formation of Lup-2gβCD-AgNPs and Lac-2gβCD-AgNPs was confirmed by UV spectroscopy and X-ray diffraction spectroscopy (XRD). Transmission electron microscopy (TEM) showed that the synthesized AgNPs had a spherical shape. 1H-, 13C-NMR nuclear magnetic resonance spectroscopy and Fourier transform infrared spectroscopy (FT-IR) confirmed the reduction and encapsulation of AgNPs by 2gβCD. Thermographic data show that the obtained Lup and its derivative inclusion complexes reduced energy barriers. This makes them promising components for thermosensitive functional materials. Encapsulated complexes of Lup and its acetate inclusion with silver nanoparticles demonstrated significantly (p < 0.05) higher antibacterial, cytotoxic, and moderately pronounced analgesic activity.

A synthetic methodology of the CuAAC “click” approach was exploited for the construction of 1,2-azolyltriazole quinine derivatives by the reaction of O-propargylquinine with azidomethyl-1,2-azoles in methanol. Quinine–piperidine and quinine–anabasine conjugates were obtained using a chloroacetate linker by reacting quinine chloroacetate with piperidine or anabasine in a diethyl ether medium. Cinchophene ester was obtained by the acylation of quinine with cinchophen acid chloride in methylene chloride. The antibacterial, fungicidal, analgesic and cytotoxic properties of the obtained compounds were examined.

In this study, the synthesis and properties of β-cyclodextrin-functionalized silver nanoparticles and their loading with a drug component are considered. β-Cyclodextrin was used as a reducing agent and stabilizer in the preparation of silver nanoparticles. The use of β-CD-AgNPs in loading molecules of the alkaloid cytisine (Cz) and its O,O-dimethyl-N-cytisinilphosphate (CzP) derivative, which have pronounced antiviral properties, was studied. The formation of β-CD-Cz-AgNPs and β-CD-CzP-AgNPs was confirmed by UV spectroscopy and X-ray diffraction spectroscopy. Scanning electron microscopy and transmission electron microscopy showed that the obtained β-CD-Cz-AgNP and β-CD-CzP-AgNP nanocomposites were well dispersed with particle sizes in the range of 3–20 nm. 1H-, 13C-NMR and COSY, HMQC, HMBC and Fourier transform infrared spectroscopy revealed the reduction and encapsulation of AgNPs by β-Cz, and the TEM imaging results showed an increase in the size of nanoparticles after the introduction of cytisine and its phosphorus derivative. The kinetic parameters of the thermal degradation process of β-CD, Cz, CzP and their inclusion complexes Cz(CzP)-β-CD-AgNPs under isothermal conditions, which ensure the preservation of the kinetic triplet, were determined. The differences in the mechanism of thermal decomposition of the studied materials are described by the parameters of the Šesták–Berggren model (m and n), which demonstrated differences for different compounds: for β-CD, the values of the parameters m and n are 0.47 and 0.53, respectively, while for CzP-β-CD-AgNPs they reach values of 0.66 and 1.34. These results indicate differences in the mechanism of thermal decomposition of the studied materials.

Influenza is a disease of significant morbidity and mortality. The number of anti-influenza drugs is small; many of them stimulate the appearance of resistant strains. This article presents the results of assessing the antiviral activity of 1,2,3-triazole-containing derivatives of alkaloid lupinine for their ability to suppress the reproduction of orthomyxoviruses (influenza viruses: A/Vladivostok/2/09 (H1N1) and A/Almaty/8/98 (H3N2)). The ability of (1S,9aR)-1-[(1,2,3-triazol-1-yl)-methyl]octahydro-1H-quinolizines with aryl-, 4-((4-formylphenoxy)methyl)- or 4-((3-tert-butyl-5-ethyl-2-hydroxy-benzoyloxy)methyl)- substituents at the C-4 position of the triazole ring to reduce the infectivity of the virus when processing virus-containing material was established, indicating good prospects for the studied compounds as virucidal agents affecting extracellular virions. The experimental results demonstrated that the triazolyl lupinine derivatives exhibited varying degrees of affinity for both hemagglutinin and neuraminidase proteins. Furthermore, these compounds demonstrated inhibitory effects on the replication of influenza viruses with different antigenic subtypes. The obtained biological data are in agreement with the results of molecular docking, which showed strong binding energies of the investigated compounds under study with biological targets—hemagglutinin and neuraminidase proteins. Following the evaluation of antiviral efficacy among the studied triazolyl derivatives of lupinine, four compounds have been identified for subsequent comprehensive in vitro and in vivo investigations to further elucidate their antiviral properties.

Бас редактор: ЖҰРЫНОВ Мұрат Жұрынұлы, химия ғылымдарының докторы, профессор, ҚР ҰҒА академигі, Қазақстан Республикасы Ұлттық ғылым академиясының президенті, АҚ «Д.В.Сокольский атындағы отын, катализ және электрохимия институтының» бас директоры (

В статье представлены результаты исследований по получению водорастворимых комплексов биологически активных гидразидов и гидразонов, получаемых на основе производных о- и п-гидроксибензойных кислот. Гидразоны находят широкое применение медицине в качестве противотуберкулезных антибактериальных и противовоспалительных препаратов, антисептиков, консервантов и других биоактивных субстратов. Для большинства из них характерно низкая растворимость в воде, что ограничивает дальнейшее их изучение на биологическую активность. В статье показано, что гидразиды о- и п- гидроксибензойных кислот и их гидразоновые производные могут образовывать различные комплексы включений с природными макромолекулярными биополимерами. Рассмотренные в статье новые гидразоновые продукты, способны растворяться в воде, а также образовывать устойчивые водные дисперсии. Получение водорастворимых комплексов указанных соединений могут привести к повышению их биологической доступности, что соответственно позволит значительно сократить их терапевтическую концентрацию. Показано, что комплексы между молекулами биополимера и субстрата являются достаточно стабильными. При этом молекула комплексообразователя будет способствовать защите молекулы субстрата от взаимодействия с различными высоко реакционноспособными молекулами, снижая скорость окисления, гидролиза и/или деструкции, а также вероятность стерических перегруппировок и рацемизации. Описанные в работе новые комплексы включений гидразидов и гидразонов о- и п-гидроксибензойных кислот охарактеризованы с помощью ИК- и ЯМР-1Н спектроскопии, дифференциальной сканирующей термогравиметрии и сканирующего электронного микроскопа.

Производные никотиновой кислоты обладают широким спектром биологической активности и находят различное применение в медицинской практике в качестве препаратов первой линий для лечения туберкулеза [1], легочной артериальной гипертензии [2], эпилепсии, зависящей от витамина B6 [3], ингибиторов фактора свертывания крови IXa [4,5], ингибиторов вируса иммунодефицита человека [6,7] и др. Следует отметить, что пиридиновый цикл входит в состав многих жизненно важных органических соединений, что определяет одну из его доминирующих ролей среди гетероциклов. Поэтому разработка удобных методов синтеза новых производных никотиновой кислоты является актуальной проблемой, поскольку эти соединения представляют интерес как в практическом, так и в теоретическом плане. Целью данной работы является целенаправленный синтез азида никотиновой кислоты и осуществление его дальнейшей модификации с целью получения новых фармакологически активных соединений. В настоящей работе осуществлен синтез азида никотиновой кислоты взаимодействием нитрита натрия с гидразидом никотиновой кислоты с выходом 99%. Изучено взаимодействие азида никотиновой кислоты со спиртами (изопропиловый и бутиловый спирты) и вторичным амином (алкалоидом цитизином). Показано, что при нагревании в среде сухого бензола азид никотиновой кислоты претерпевает перегруппировку Курциуса, с образованием изоцианата, который далее реагирует in situ со спиртами и амином (алкалоидом цитизином) с образованием соответствующих уретанов и мочевины. С целью синтеза производных 1,2,3-триазола осуществлено взаимодействие азида никотиновой кислоты с терминальным ацетиленом - проп-2-иниловым эфиром 3-трет-бутил-5-этил-2-гидроксибензойной кислоты в среде ДМФА и нагревании (70-80оС) в присутствии медного купороса СuSO4×5H2O и аскорбата натрия (NaAsc). Установлено, что в результате реакции образуется не ожидаемое 1,2,3-триазольное соединение, а 3-аминопиридин и исходное ацетиленовое соединение. Показано, что при нагревании получаемый азид разлагается с образованием промежуточной частицы - нитрена, и последующая миграция пиридильного радикала к атому азота (перегруппировка Курциуса) приводит к изоцианату. В результате гидратации изоцианата и последующего декарбоксилирования из образовавшейся карбаминовой кислоты получается 3-аминопиридин. Строение синтезированных соединений подтверждено на основании анализа данных ЯМР 1Н- и 13С-спектроскопии, а также двумерных спектров COSY (1H-1H) и HMQC (1H-13C).

The article presents the results of a study of the amination reaction of nicotinic acid chlorohydride with amines morpholine, cytisine, and 1-aminoadamantane, which are often used in the search and creation of drugs for respiratory and circulatory stimulants. The study was conducted to search for new biologically active compounds with anti-inflammatory activity. The synthesis of new aminoamides was carried out by the interaction of nicotinic acid with molecules of morpholine, cytisine, and adamantane in anhydrous ethanol. As a result of the conducted studies, new amides of nicotinic acid with high yields (90.7–93.1%) were obtained. The structures of the new compounds were determined using NMR 1H and 13C spectroscopy methods, as well as data from two-dimensional spectra of COSY (1H-1H), HMQC (1H-13C), HMBC (1H-13C) and mass spectrometry. The results of an experimental study of the anti-inflammatory activity of synthesized new amides are presented. The anti-inflammatory effect of nicotinic acid N-adamantylamide was established, other new amides were ineffective compared with ibuprofen (p2 < 0.05).

The data on the synthesis of N-aminomorpholine hydrazones are presented. It is shown that the interaction of N-aminomorpholine with functionally substituted benzaldehydes and 4-pyridinaldehyde in isopropyl alcohol leads to the formation of corresponding hydrazones. The structure of the synthesized compounds was studied by 1H and 13C NMR spectroscopy methods, including the COSY (1H-1H), HMQC (1H-13C) and HMBC (1H-13C) methodologies. The values of chemical shifts, multiplicity, and integral intensity of 1H and 13C signals in one-dimensional NMR spectra were determined. The COSY (1H-1H), HMQC (1H-13C), and HMBC (1H-13C) results revealed homo- and heteronuclear interactions, confirming the structure of the studied compounds. The antiviral, cytotoxic, and antimicrobial activity of some synthesized hydrazones were investigated. It is shown that 2-((morpholinoimino)methyl)benzoic acid has a pronounced viral inhibitory property, comparable in its activity to commercial drugs Tamiflu and Remantadine. A docking study was performed using the influenza virus protein models (1930 Swine H1 Hemagglutinin and Neuraminidase of 1918 H1N1 strain). The potential binding sites that are complementary with 2-((morpholinoimino)methyl)benzoic acid were found.

Alkaloid-based urea derivatives were produced with high yield through the reaction of anabasine and cytisine with isoxazolylphenylcarbamates in boiling benzene. Their antitumor activity, in combination with the commonly used five anticancer drugs, namely cyclophosphane, fluorouracil, etoposide, cisplatin, ribomustine with different mechanisms of action, was investigated. Based on the quantum chemical calculations data and molecular docking, hypotheses have been put forward to explain their mutual influence when affecting C6 rat glioma model cells.

Мақалада лупинин алкалоидының екіорынбасылған 1Н-1,2,3-үшазол туындылары қатарының синтезі мен құрылымдық ерекшеліктері туралы зерттеулердің нәтижелері келтірілген. Лупинин алкалоидының химиялық трансформациясы хинолизин қаңқасының С-1 жағдайда орналасқан гидроксиметилен тобы бойынша жүзеге асырылды. Реакциялар үш кезеңде әр түрлі еріткіштерде жүргізілді. Лупининнің метансульфохлоридпен үшэтиламиннің қатысуымен өзара әрекеттесуі кезінде жоғары шығымдылықпен лупининнің мезилаты оңай түзілетіні көрсетілді. Осы қосылысты диметилформамид ерітіндісінде натрий азидімен ары қарай қыздырып өңдеу нәтижесінде жоғары шығыммен лупинин азидінің түзілуі жүреді. Жаңа азидтің мыс купоросының сулы және натрий аскорбаты қатысуымен диметилформамид ерітіндісінде әртүрлі сипаттағы функционалды орынбасылған ароматты алкиндермен өзара әрекеттесуі кезінде оларға сәйкес 4-алмастырылған лупининнің үшазолды туындыларының түзілуі мүмкін екендігі анықталды. Лупининнің үшазолды циклінің негізінде С-4 жағдайында орынбасылған ароматты жаңа туындылары синтезделді. Синтезделген үшазолдықосылыстардың құрылысы ЯМР 1Н және 13С спектрлерін талдау негізінде дәлелденілді. Жаңа заттардың ЯМР 13С спектрлеріндегі сигналдардың мультиплеттілігі J-модуляция режимінде (JMOD) жазылған спектрлер бойынша анықталды. Синтезделген қосылыстардың құрылысы сондай-ақ екі өлшемді COSY (1H-1H) және HMQC (1H-13C) спектрлерінің деректерімен зерттелген. ЯМР спектрлердегі химиялық ығысулардың мәндері 1Н және 13С сигналдарының мультиплеттілігі және интегралды қарқындылығы бір өлшемді ЯМР спектрлерімен анықталды.

Currently, the number of infections caused by strains of bacteria that are not sensitive to antibiotics and antiseptics is growing worldwide. A similar increase in bacterial resistance is observed for both nosocomial infections and community-acquired human-to-human infections. An important task for chemists and pharmacologists is the synthesis of new compounds and the establishment of a structure-bioactivity relationship. The purpose of this work is to study the effect of the structure of quaternary ammonium derivatives of hydrazones of isonicotinic and nicotinic acids on the manifestation of their anti-inflammatory properties. Results and discussion. The alkylation of nicotinic acid hydrazones produced their new quaternary ammonium salts (43.7-70.7%). The methodology for the synthesis of quaternary ammonium compounds of hydrazones included obtaining a variety of structures by introducing one or two fluorine and bromine-containing fragments into their structure. The structure of compounds was confirmed by 1H, 13C NMR spectroscopy. Conclusion. New quaternary ammonium salts of nicotinic acid hydrazones have been obtained. The study of anti-inflammatory activity was carried out using the method of formalin paw edema in rats. The acute inflammatory reaction was reproduced by subplantar administration of 2% formalin solution. Compared with ibuprofen at a dosage of 100 mg/kg, these compounds were ineffective (p2<0.05). According to the results of the analysis of possible pharmacological effects, it was also revealed that new compounds may have an effect on the regulation and production of ketone bodies, the enzymatic activity of transaminases. New alkylated hydrazones of isonicotinic and nicotinic acids may be of interest for studying their antituberculous and antiviral activities.

The reactions of lupinine alkaloid and its chlorine derivative with cinnamoyl chloride and 2-K-isoindole-1,3-dione were investigated to obtain 3-phenylacrylic acid octahydroquinolizin-1-ylmethyl ester and 2-(octahydroquinolizin-1-ylmethyl)isoindole-1,3-dione, respectively. The optimal conditions for carrying out the aforementioned reactions were determined, taking into account the nature of the solvent and medium. It was established that acylation of the molecule in a benzene medium, in the presence of trimethylamine, resulted in the formation of 3-phenylacrylic acid octahydroquinolizin-1-ylmethyl ester, with an 82% yield. It was demonstrated that the interaction of chlorolupinine with 2-K-isoindole-1,3-dione under Gabriel reaction conditions resulted in the formation of 2-(octahydroquinolizin-1-ylmethyl)isoindole-1,3-dione. The conformer with an axial orientation of the isoindole-1,3-dione substituent was observed to exhibit greater stability than the conformer with an equatorial orientation. The structure of the synthesized compounds was investigated by IR, 1H, and 13C NMR spectroscopy. The use of two-dimensional spectra in COSY (1H-1H) and HMQC (1H-13C) formats enabled the establishment of homo- and heteronuclear interactions, thereby confirming the structure of the compounds under investigation. The values of chemical shifts, multiplet and integrated intensity of 1H and 13C signals in one-dimensional NMR spectra of the novel compounds were determined. The crystal structures of 3-phenylacrylic acid octahydroquinolizin-1-ylmethyl ester and 2-(octahydroquinolizin-1-ylmethyl)isoindole-1,3-dione were elucidated through X-ray analysis.

The reaction of nicotinic and isonicotinic acid hydrazides with o-formyl benzoic acid in ethanol led to the formation of the corresponding hydrazones. It was found that o-formyl benzoic acid reacted in aldehyde form with hydrazides to form hydrazones. When heated in acetic anhydride, the latter are smoothly cyclized into 3-acetoxyisoindolin-1-ones. Structure of the synthesized compounds was proved by 1H and 13C NMR spectroscopy data. Antiradical and antiviral activity of the synthesized hydrazones and 3-acetoxyisoindolin-1-ones was studied. A compound with a wide spectrum of virus-inhibiting action against strains of the A virus was identified.

There has been presented data on the synthesis of monoamides and cyclic imides which are derivatives of isonicotinic acid hydrazide. Cyclic anhydrides of carboxylic acids (succinic, maleic and phthalic) easily react with the hydrazide of isonicotinic acid with cycle opening, forming isonicotinoylhydrazide of dicarboxylic acids, and under more severe conditions the latter are transformed into cyclic acid imides. The structures of the synthesized compounds were studied using 1H- and 13C-NMR spectroscopy, as well as data from twodimensional COSY (1H-1H) and HMQC (1H-13C) spectra. The values of chemical shifts, multiplicity and integral intensity of 1H and 13C signals in one-dimensional NMR spectra were determined. Homo- and heteronuclear interactions confirming the structure of the studied compounds were established using spectra in the COSY (1H-1H) and HMQC (1H-13C) formats. In the approximation of the density functional B3LYP with a base set of 6-31G(d), the enthalpy of the reactions ΔHr in the absence and in the presence of a solvent — isopropanol (self-consistent reaction field method) were calculated quantum-chemically

The condensation reaction of 4- and 2-hydroxybenzoic acid hydrazides with substituted benzaldehydes led to the formation of a series of hydrazones. The synthesis of hydrazones was carried out successfully in good yields. The structure of compounds was proved by spectral methods. The crystal structures of the methanol solvate of the (E)-N'-[4-(diethylamino)-benzylidene]-4-hydroxybenzohydrazide and the crystalline hydrate of the (E)-N'-[(2-hydroxy-4-diethylamino)-benzylidene]-4-hydroxybenzohydrazide were described with attention to conformational features and hydrogen bonding. The antimicrobial and antiradical activity of hydrazones was studied using molecular docking and in vitro assays.