Синтез нових піразолін-тіазолів та їх біологічна активність

The application of the [2+3]-cyclocondensation reaction for the synthesis of 2-pyrazoline substituted thiazolidinones, as well as bioisosteric pyrazoline-thiazoles has been analyzed. Following the literature data 4,5-dihydro- 1-carbothioamides are used as S,N-binucleophiles in the [2+3]-cyclocondensation reaction with different equivalents of the dielectrophilic synthon [C2]2+ (α-halogencarboxylic acids, derivatives of maleic acid, aroylacrylic acids, dimethyl ester of acetylenedicarboxylic acid, α-bromoacetophenones and ethyl 4-chloroacetoacetate). It has allowed to identify the highly active compounds with the antimicrobial, antiviral, anti-inflammatory, antitumor and antiparasitic activities. Aiming to enlarge a scope of 3,5-diaryl-4,5-dyhidropyrazol-1-carbothioamides as S,N-binucleophiles in [2+3]-cyclization and to find a new chemotherapeutic agents the synthesis of new pyrazoline-thiazoles has been carried out; it is based on the reaction between the carbothioamides mentioned and ethyl 2-chloroacetoacetate or 3-chloroacetyl acetone in the presence of fused sodium acetate in refluxing acetic acid. The structure of the compounds synthesized has been confirmed by 1H NMR spectra. The screening of the antitumor and antitrypanosomal activities of some compounds synthesized has been conducted. As a result of in vitro experiments their moderate cytotoxicity in the concentration of 10-5 mol/l for individual cancer cell lines has been identified. At the same time a high trypanocidal activity of compounds 2h and 2j has been determined against Trypanosoma brucei gambiense strain with the values of ІC50 of 3.82 and 2.61μM, respectively; and it exceeds the activity of the reference medicine nifurtomox.Проанализированы направления использования реакции [2+3]-циклоконденсации для синтеза 2-пиразолинзамещенных тиазолидинонов и биоозостерных пиразолин-тиазолов. В литературе описано использование 4,5-дигидропиразол-1-карботиоамидов как S,N-бинуклеофилов с разнообразными эквивалентами диэлектрофильного синтона [C2]2+ (производные α-галогенкарбоновых кислот, малеиновой кислоты, β-ароилакриловых кислот, диметиловый эфир ацетилендикарбоновой кислоты, α-бромоацетофеноны и 4-хлороацетоуксусный эфир), что позволило идентифицировать высокоактивные соединения с антимикробной, противовирусной, противовоспалительной, противоопухолевой и антипаразитической активностью. С целью расширения векторов использования 3,5-диарил-4,5-дигидропиразол-1-карботиоамидов в условиях реакции [2+3]-циклоконденсации и поиска новых химиотерапевтических агентов осуществлен синтез новых пиразолин-тиазолов, что основан на взаимодействии указанных тиоамидов с 2-хлорацетоуксусным эфиром и 3-хлорацетоацетоном в среде уксусной кислоты в присутствии ацетата натрия. Структура синтезированных веществ подтверждена спектрами ПМР. Осуществлен скрининг противоопухолевой и антитрипаносомной активности некоторых синтезированных соединений. В результате in vitro эксперимента установлено их умеренную цитотоксичность в концентрации 10-5 моль/л на отдельных линиях раковых клеток. Идентифицировано высокую трипаноцидную активность соединений 2h и 2j на штамме Trypanosoma brucei gambiense с показателями ІС50 3,82 и 2,61 мкM, соответственно, что превышает эфективность препарата сравнения – нифуртимокса.Проаналізовані напрямки використання реакції [2+3]-циклоконденсації для синтезу 2-піразолінзаміщених тіазолідинонів та біоізостерних піразолін-тіазолів. У літературі описано використання 4,5-дигідропіразол-1-карботіоамідів як S,N-бінуклеофілів з різноманітними еквівалентами діелектрофільного синтону [C2]2+ (похідні α-галогенокарбонових кислот та малеїнової кислоти, β-ароїлакрилові кислоти, диметиловий естер ацетилендикарбонової кислоти, α-бромоацетофенони та 4-хлороацетооцтовий ефір), що дозволило ідентифікувати високоактивні сполуки з антимікробною, противірусною, протизапальною, протипухлинною та антипаразитарною активністю. З метою розширення напрямків використання 3,5-діарил-4,5-дигідропіразол-1-карботіоамідів в умовах реакції [2+3]-циклоконденсації та пошуку нових хіміотерапевтичних агентів здійснено синтез нових піразолін-тіазолів, який ґрунтується на взаємодії вказаних тіоамідів з 2-хлороацетооцтовим ефіром чи 3-хлороацетоацетоном у середовищі оцтової кислоти в присутності ацетату натрію. Структура синтезованих сполук підтверджена спектрами ПМР. Здійснено скринінг протипухлинної та антитрипаносомної активності деяких синтезованих сполук. У результаті in vitro експерименту встановлено їх помірну цитотоксичність у концентрації 10-5 моль/л на окремих лініях ракових клітин. Водночас ідентифіковано високу трипаноцидну активність сполук 2h та 2j на штамі Trypanosoma brucei gambiense із показниками ІС50 3,82 та 2,61 мкМ, відповідно, котрі перевищують ефективність препарату порівняння – ніфуртимоксу

Morphological features of liver effect in patients with chronic hepatitis B with HIV-coinfection

The article presents modern views on morphological disturbances in liver tissue at HBV/HIV patients. It was shown that "matte-glass-like" hepatocytes, inflammatory cell lymphocytic infiltrate of varying degrees and liver fibrosis are specific signs of HBV/HIV patients. Specific morphological signs of liver damage in co-infected patients confirm that HIV-infection worsens histological structure as well as functional balance. Therefore, development of pathohistology method of diagnostics becomes more and more necessary in patients with complicated liver injuries. New findings can give opportunity for early screening HBV-infected patients for HIV-markers, prescribing antiviral treatment at early stages. The research will build new approach for avoiding fast fibrogenesis

A monoadduct generating Ru(ii) complex induces ribosome biogenesis stress and is a molecular mimic of phenanthriplatin

Ruthenium complexes are often investigated as potential replacements for platinum-based chemotherapeutics in hopes of identifying systems with improved tolerability in vivo and reduced susceptibility to cellular resistance mechanisms. Inspired by phenanthriplatin, a non-traditional platinum agent that contains only one labile ligand, monofunctional ruthenium polypyridyl agents have been developed, but until now, few demonstrated promising anticancer activity. Here we introduce a potent new scaffold, based on [Ru(tpy)(dip)Cl]Cl (tpy = 2,20:60,200-terpyridine and dip = 4,7-diphenyl-1,10-phenanthroline) in pursuit of effective Ru(II )-based monofunctional agents. Notably, the extension of the terpyridine at the 40 position with an aromatic ring resulted in a molecule that was cytotoxic in several cancer cell lines with sub-micromolar IC50 values, induced ribosome biogenesis stress, and exhibited minimal zebrafish embryo toxicity. This study demonstrates the successful design of a Ru(II ) agent that mimics many of the biological effects and phenotypes seen with phenanthriplatin, despite numerous differences in both the ligands and metal center structure

(5E)-5-(2,4-Dichloro­benzyl­idene)-2-(piperidin-1-yl)-1,3-thia­zol-4(5H)-one

In the title compound, C15H14Cl2N2OS, the piperidine ring adopts a chair conformation. The dihedral angle between the thia­zolidine ring and the dichloro­benzene ring is 9.30 (4)°; this near coplanar conformation is stabilized by the formation of an intra­molecular C—H⋯S hydrogen bond, which generates an S(6) ring. In the crystal, mol­ecules are linked by C—H⋯O hydrogen bonds, forming [001] chains. Weak π–π inter­actions [centroid–centroid separation = 3.5460 (5) Å] consolidate the structure

Synthesis, characterization, molecular docking and biological activities of novel pyrazoline derivatives

PubMed: 31125504In this study, synthesis of ethyl 2-((4-bromophenyl)diazenyl)-3-oxo-phenylpropanoate 1 was carried out and a series of new 3H-pyrazol-3-ones (P1–7) were synthesized from 1 as well as various hydrazines. The obtained yields of the synthesized compounds were moderate (40–70%) and these compounds were confirmed by spectral data. These novel pyrazoline derivatives were effective inhibitor compounds of the human carbonic anhydrase I and II isozymes (hCAs I and II) and of the acetylcholinesterase (AChE) enzyme, with Ki values in the range of 17.4–40.7 nM for hCA I, 16.1–55.2 nM for hCA II, and 48.2–84.1 nM for AChE. In silico studies were performed on the compounds inhibiting hCA I, hCA II, and AChE receptors. On the basis of the findings, the inhibition profile of the new pyrazoline compounds at the receptors was determined. © 2019 Deutsche Pharmazeutische GesellschaftThis study was supported by Scientific Research Fund of Iğdır University. Project Number: 2018-SBE-A01. A certain part of this study was carried out in Igdır University Research Laboratory Practice and Research Center

Study of antineoplastic action of novel isomeric derivatives of 4-thiazolidinone

Pyrazole- and aryl-substituted derivatives of 4-thiazolidinone belong to a perspective group of compounds with potential antitumor action. Earlier, we have demonstrated high toxicity in vitro of several 4-thiazolidinones derivatives towards tumor cell lines. To further enhance the antitumor activity of novel 4-thiazolidinones, their chemical scaffold was optimized, and new pyrazole-thiazolidinones were synthesized. That allowed us to combine in one molecule the potential pharmacophore centres of previously tested compounds. As a result, “hybrid” 4-thiazolidinones exhibit higher toxicity in vitro toward tumor cells of various origin. The molecular mechanisms of antineoplastic activity of these compounds and intensity of induction of apoptosis strongly depended on the position of the substituent in the thiazolidinone cycle. In particular, Les-3661 compound, containing pyrazoline fragment in the 4th position of thiazolidinone core, exhibits 14 times higher cytotoxic activity towards tumor cells (LC50 = 3 µM) in comparison to its 2-substituted isomer Les-3713 (LC50 = 42 µM). It is demonstrated that in terms of underlying molecular mechanisms for cytotoxic effect the Les-3661 compound induced caspase-8 and caspase-9 dependent mixed-type of apoptosis, while Les-3713 induced apoptosis mediated only by the caspase-8

Study of rat blood serum biochemical indicators of cardiotoxic action of novel antitumor 4-thiazolidinone derivatives and doxorubicin in complexes with polyethylenglycol-containing polymeric carrier in the rat blood serum

The aim of this study was to measure the activity of enzymes which reflect cardiotoxic action in rats of novel synthetic 4-thiazolidone derivatives – 3882, 3288 and 3833 that demonstrated antineoplastic effect in vitro towards 60 lines of human tumor cells tested in the framework of the program of screening new anticancer drugs at the National Cancer Institute (USA). Such action of these compounds was compared with the effect of well known anticancer agent doxorubicin and after conjugation of all above mentioned substances with new polyethylenglycol-containing polymeric comb-like carrier that was synthesized by the authors. Among the biochemical indicators of cardiotoxic action of anticancer agents, activity of the following enzymes in rat blood serum showed to be the most informative: creatine kinase, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase. Tenfold injection of doxorubicin in a dose of 5.5 mg/kg of weight caused rats’ death, while 3882, 3288 and 3833 preparations had not such action. Application of the doxorubicin in combination with polymeric carrier prolonged the survival time to 20 days. Thus, the injection of anticancer agents in a complex with polymeric carrier provides a significant decrease in their cardiotoxicity that was confirmed by the corresponding changes in the activity of marker enzymes: creatine kinase, lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase in blood serum of treated rats