Ihor Yushyn

The purpose of the present study is the synthesis of 6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-8-(4-methoxyphe- nyl)-3-methyl-2-thioxo-3,4a,7a,8-tetrahydropyrrolo[3',4':5,6]thiopyrano[2,3-d]thiazole-5,7(2H,6H)-dione and its biological evaluation as a potential bioactive compound.Materials and methods: organic synthesis, 1H, and 13C NMR spectroscopy, liquid chromatography-mass spectrometry, in vitro antimi- crobial and anticancer screening, drug-like prediction.Results. The title compound was obtained via a one-pot/two-step protocol of 4-aminoantipyrine and maleic anhydride with 5-(4-meth- oxybenzylidene)-3-methylthiazolidine-2,4-dithione. The structure of the synthesized compound (yield 69%) was confirmed by 1H, 13C NMR, and LC-MS spectra. According to US NCI protocols, the compound displayed a moderate level of antimitotic activity against melanoma MDA-MB-435 and breast cancer cell lines HS 578T. The synthesized derivative 4 was evaluated for antimicrobial activity against 17 strains of Gram-positive and Gram-negative bacteria, as well as yeasts, demonstrating moderate efficacy against drug-resistant Klebsiella strains. The drug-like properties of the synthesized compound were assessed using SwissADME, showing favorable drug-like parameters.Conclusions. The one-pot/two-step protocol for synthesizing thiopyrano[2,3-d]thiazole derivative is proposed. The title compound was fully characterized by spectral analysis methods. The tested compound displayed moderate activity against melanoma and breast cancer cell lines and moderate antimicrobial activity against drug-resistant Klebsiella strains. The synthesized thiopyrano[2,3-d]thiazole exhibits favora- ble predicted physicochemical and drug-like properties based on in silico analysis and demonstrates promising antimicrobial activity in vitro.The obtained results indicate the potential of this compound for further investigation against antibiotic-resistant microbial strains and tumors that are unresponsive to conventional anticancer agents. Метою цієї роботи був синтез тіопірано[2,3-d]тіазолу шляхом трьохкомпонентної одностадійної реакції 4-аміноантипірину, малеїнового ангідриду та 5-(4-метоксибензиліден)-3-метилтіазолідин-2,4-дитіону, а також дослідження його біологічної активності.Структуру синтезованої сполуки підтверджено за допомогою спектрів ¹H, ¹³C ЯМР-спектроскопією та хромато-мас-спектрометрією.На основі результатів скринінгу Національного інституту раку США синтезована сполука продемонструвала помірний рівень антимітотичної активності проти меланоми MDA-MB-435 та клітинних ліній раку молочної залози HS 578T. Синтезована молекула досліджувалася на протимікробну активність щодо 17 штамів грампозитивних і грамнегативних бактерій, а також дріжджів, демонструючи помірну ефективність відносно стійкого до лікарських засобів штаму Klebsiella. Лікоподібність синтезованої сполуки оцінювалася за допомогою онлайн-сервісу SwissADME, що дало можливість охарактеризувати її потенційні лікоподібні параметри.Отримані результати свідчать про перспективу дослідження цієї сполуки проти антибіотикорезистентних штамів мікроорганізмів та пухлин, які нечутливі до лікування класичними протипухлинними агентами.

Мета - здійснити синтез 5-іноліденроданінів та дослідити їх протипухлинну активність та цитотоксичність. Матеріали і методи. Протягом дослідження використали методи органічного синтезу, виконали фізико-хімічний аналіз синтезованих сполук. Протимікробну активність було проведено методом дифузї в агар. Оцінку цитотоксичності проведено на основі даних MTT аналізу. Результати й обговорення. У результаті скринінгу протимікробної активності було ідентифіковано сполуки із помітним впливом на грампозитивні штами мікроорганізмів, зокрема стафілококи, які утворюють біоплівки (МІК 0,93 mM). Досліджувані сполуки володіли низькою цитотоксичністю на пухлинні та нормальні та псевдонормальні клітинні лінії. Висновки. Результати свідчать про наявність помітної протимікробної активності похідних роданіну з індольним фрагментом у молекулах, що обґрунтовує перспективу поглибленого дослідження даного класу сполук.

A novel 4-thiazolidinone derivative Les-6490 (pyrazol-4-thiazolidinone hybrid) was designed, synthesized, and characterized by spectral data. The compound was screened for its antimicrobial activity against some pathogenic bacteria and fungi and showed activity against Staphylococcus and Saccharomyces cerevisiae (the Minimum Inhibitory Concentration (MIC) 820 μM). The compound was studied in the rat adjuvant arthritis model (Freund’s Adjuvant) in vivo. Parietal and fecal microbial composition using 16S rRNA metagenome sequences was checked. We employed a range of analytical techniques, including Taxonomic Profiling (Taxa Analysis), Diversity Metrics (Alpha and Beta Diversity Analysis), Multivariate Statistical Methods (Principal Coordinates Analysis, Principal Component Analysis, Non-Metric Multidimensional Scaling), Clustering Analysis (Unweighted Pair-group Method with Arithmetic Mean), and Comparative Statistical Approaches (Community Differences Analysis, Between Group Variation Analysis, Metastat Analysis). The compound significantly impacted an increasing level of anti-inflammatory microorganisms (Blautia, Faecalibacterium prausnitzii, Succivibrionaceae, and Coriobacteriales) relative recovery of fecal microbiota composition. Anti-Treponemal activity in vivo was also noted. The tested compound Les-6490 has potential prebiotic activity with an indirect anti-inflammatory effect.

The aim of the work. Synthesis 2-aminoisoindole thizolidinone derivatives via [2+3]-cyclocondensation reaction using different equivalents of electrophilic synthon [C2]2+ and the anticancer activity screening in vitro of synthesized molecules. Materials and Methods. Organic synthesis, NMR spectroscopy, pharmacological screening in vitro. Results and Discussion. The [2+3]-cyclocondensation reaction of 1-(1,3-dioxoisoindolin-2-yl)thiourea with chloroacetic acid, N-arylmaleimides and β-aroylacrylic acids in glacial acetic acid allowed to obtain 5-substituted 2-aminoisoindole thizolidinone hybrids. Synthesis of indole-containing 2-aminoisoindole thizolidinones was performed by the one-pot three-component synthetic protocol of 1-(1,3-dioxoisoindolin-2-yl)thiourea, appropriative isatin, and monochloroacetic acid. The anticancer activity of synthesized compounds was studied at a concentration of 10-5 M on a panel of sixty cancer cells according to the standard protocols of the National Cancer Institute (NCI, Bethesda, MD, USA) Developmental Therapeutic Program (DTP). Conclusions. An efficient method for synthesis new isoindole-thiazolidinones was studied. Indole-containing 2-aminoisoindole thizolidinone derivative demonstrated a moderate level of anticancer activity with an impact on melanoma, renal, and breast cancer cell lines. Мета роботи. Синтез похідних 2-аміноізоіндол тіазолідинону шляхом реакції [2+3]-циклоконденсації шляхом використання різноманітних еквівалентів діелектрофільного синтону [C2]2+ та скринінг протипухлинної активності синтезованих сполук in vitro. Матеріали і методи. Органічний синтез, ЯМР спектроскопія, фармакологічний скринінг in vitro. Результати й обговорення. Шляхом реакції [2+3]-циклоконденсації 1-(1,3-діоксоізоіндолін-2-іл)тіосечовини з монохлороцтвою кислотою, N-арилмалеімідами and β-ароїлакриловими кислотами в середовищі льодяної оцтової кислоти було одержано 5-заміщені 2-аміноізоіндол тіазолідинонові гібриди. Синтез індолвмісних 2-аміноізоіндол тіазолідинонів було здійснено одностадійною трикомпонентною реакцією of 1-(1,3-діоксоізоіндолін-2-іл)тіосечовини, відповідного ізатину та монохлороцтової кислоти. Протиракова активність синтезованих сполук була вивчена в концентрації 10-5 M на панелі з 60 ракових клітин відповідно до стандартних протоколів Національного Інститут Раку (NCI, Bethesda, MD, USA) Developmental Therapeutic Program (DTP). Висновки. Досліджено ефективний метод синтезу нових ізоіндолтіазолідинонів. Індолвмісний 2-аміноізоіндолтизолідинон, продемонстрував помірний рівень протипухлинної активності з впливом на клітинні лінії меланоми, раку нирок і молочної залози.

Novel pyridine-thiazole hybrid molecules were synthesized and subjected to physico-chemical characterization and screening of their cytotoxic action towards a panel of cell lines derived from different types of tumors (carcinomas of colon, breast, and lung, glioblastoma and leukemia), and normal human keratinocytes, for comparison. High antiproliferative activity of the 3-(2-fluorophenyl)-1-[4-methyl-2-(pyridin-2-ylamino)-thiazol-5-yl]-propenone 3 and 4-(2-{1-(2-fluorophenyl)-3-[4-methyl-2-(pyridin-2-ylamino)-thiazol-5-yl]-3-oxopropylsulfanyl}-acetylamino)-benzoic acid ethyl ester 4 was revealed. The IC₅₀ of the compound 3 in HL-60 cells of the acute human promyelocytic leukemia was 0.57 µM, while in the pseudo-normal human cell lines, the IC₅₀ of this compound was >50 µM, which suggests that the compounds 3 and 4 might be perspective anticancer agents. The detected selectivity of the derivatives 3 and 4 for cancer cell lines inspired us to study the mechanisms of their cytotoxic action. It was shown that preincubation of tumor cells with Fluzaparib (inhibitor of PARP1) reduced the cytotoxic activity of the derivatives 3 and 4 by more than twice. The ability of these compounds to affect DNA nativity and cause changes in nucleus morphology allows for the suggestion that the mechanism of action of the novel pyridine-thiazole derivatives might be related to inducing the genetic instability in tumor cells.

The hetero-Diels–Alder reaction is the main synthetic tool for obtaining pharmacological agents with a thiopyrano[2,3-d]thiazole motif. In the present work, an efficient method for the synthesis of pyrazoline-containing thiopyrano[2,3-d]thiazole is described. The pyrazoline-bearing dienophile was proposed and used as effective building block for the synthesis of the title compound. The structure of the synthesized rel-2-[4-chloro-2-[(5R,6R,7S)-6-[5-(4-methoxyphenyl)-3-(2-naphthyl)-3,4-dihydropyrazole-2-carbonyl]-5-methyl-2-oxo-3,5,6,7-tetrahydrothiopyrano[2,3-d]thiazol-7-yl]phenoxy]acetic acid (3) was confirmed by ¹H, ¹³C, 2D NMR, and LC-MS spectra. Anticancer activity in “60 lines screening” (NCI DTP protocol) was studied in vitro for the title compound.

Thiazolidine-2,4-dione core is widely used in the medicinal chemistry of different types of potential drug-like small molecules. In the present work, the synthesis of a novel non-condensed thiazolidine-2,4-dione-bearing derivative is reported by the two-step cost-effective approach including alkylation and Knoevenagel condensation. The structure of the synthesized 3-(2-diisopropylaminoethyl)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione was determined and characterized using ¹H, ¹³C NMR, LC-MS spectra and the X-ray diffraction method.

The pharmacophore hybridization approach is widely used for the design of drug-like small molecules with anticancer properties. In the present work, a “cost-effective” approach to the synthesis of the novel non-condensed pyrazoline-bearing hybrid molecule with 1,3,4-thiadiazole and dichloroacetic acid moieties is proposed. The 5-amino-1,3,4-thiadiazole-2-thiol was used as a starting reagent, and the synthetic strategy includes stepwise alkylation of the sulfur atom and acylation of the nitrogen atom to obtain the target title compound. The structure of the synthesized 2,2-dichloro-N-[5-[2-[3-(4-methoxyphenyl)-5-phenyl-3,4-dihydro-2H-pyrazol-2-yl]-2-oxoethyl]sulfanyl-1,3,4-thiadiazol-2-yl]acetamide (yield 90%) was confirmed by ¹H, ¹³C, 2D NMR and LC-MS spectra. Anticancer activity in “60 lines screening” (NCI DTP protocol) was studied in vitro for the title compound.

A series of 5-methyl-7-phenyl-3H-thiazolo[4,5-b]pyridin-2-ones has been designed, synthesized, and characterized by spectral data. Target compounds were screened for their antimicrobial activity against some pathogenic bacteria and fungi, and most of them showed moderate activity, especially compound 3g, which displayed the potent inhibitory effect against Pseudomonas aeruginosa and Escherichia coli with MIC value of 0.21 μM. The active thiazolopyridine derivatives 3c, 3f, and 3g were screened for their cytotoxicity effects on HaCat, Balb/c 3T3 cells using MTT assay, which revealed promising results. In silico assessment for compounds 3c, 3f, and 3g also revealed suitable drug-like parameters and ADME properties. The binding interactions of the most active compound 3g were performed through molecular docking against MurD and DNA gyrase, with binding energies and an inhibitory constant compared to the reference drug ciprofloxacin. The tested thiazolo[4,5-b]pyridines constitute an exciting background for the further development of new synthetic antimicrobial agents.

Background : Anthraquinone derivatives, frequently occurring motifs in many various natural compounds, have attracted a great deal of interest as compounds with a wide spectrum of biological activities. Introduction: The hybrid pharmacophore approach has become an object of considerable interest due to the incorporation of a five- or six-membered heterocyclic rings in the structure of various natural compounds, especially anthraquinone derivatives. Methods: A series of polyfunctionalized anthraquinonehydrazones have been synthesized via the azo-coupling reaction between anthraquinone-based triazenes and methylene active compounds. The structures of synthesized compounds were confirmed by spectral data. Some of the synthesized compounds were screened for their in vitro anticancer activity according to US NCI protocols. The screening of antimicrobial and antifungal activities against Candida albicans and Lactobacillus sp. was carried out. The synthesized compounds were evaluated for their antioxidant (DPPH free radical scavenging assay) and herbicidal activity. Results: The synthesized 1-[N'-(5-oxo-2-thioxoimidazolidin-4-ylidene)-hydrazino]-anthraquinone 1.5 displayed a high level of antimitotic activity against tested human tumor cells with mean GI₅₀/TGI values 4.06/78.52μM. The screening of antimicrobial and antifungal activities led to the identification of 1.8 and 1.9 with a moderate effect on Candida albicans and Lactobacillus sp. Antioxidant activity evaluation allowed the identification of 1-[N'-(3-methyl-5-oxo-1-phenyl-1,5- dihydropyrazol-4-ylidene)-hydrazino]-anthraquinone 1.8 with an IC50 value of 3.715 mM. The herbicidal activity screening led to compound identification 1.8 with growth inhibition of Agrostis stolonifera at 25 %. Conclusion: The obtained anthraquinonehydrazones constitute an interesting template for the design of new synthetic agents with polypharmacological activities.