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

(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

Synthesis and carbonic anhydrase inhibitory activities of new thienyl-substituted pyrazoline benzenesulfonamides

A series of new thienyl-substituted pyrazoline benzenesulfonamides were synthesized and their carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activities were tested on the human (h) isoforms hCA I and hCA II. The inhibition constant (Ki) of these sulfonamides were in the range of 232.16-637.70 nM toward the slow cytosolic isozyme hCA I, and in the range of 342.07-455.80 nM toward hCA II. Many of these compounds showed comparable inhibition with the reference sulfonamide acetazolamide, a clinically used drug. As the sulfonamide CA inhibitors (CAIs) show many therapeutic uses, these derivatives represent interesting examples of a novel class of such derivatives

Comparative study of the cytotoxic properties of isatin-containing derivatives of 4-thiazolidinone with different structure toward human tumor cells in vitro

Compounds on the basis of 4-thiazolidinone and its isatin-containing derivatives are characterized by a broad spectrum of biological activities and are potential antineoplastic agents. We have shown that the combination of 4-thiazolidinone and isatine (1H-indole-2,3-dione) in one molecule enhances the cytotoxic action of novel compounds towards lukemic and carcinoma cells in vitro. The level of cytotoxic action of ID-3833, ID-4522, ID-4523, ID-4524, ID-4525, ID-4526, ID-4527 compounds strongly depends on the presence of a halogen in the 5th position of the indoline moiety and the type of the atom (chlorine or bromine) in the aryl groups in the 3rd and 5th positions in pyrazoline moiety. Compound ID-3833 demonstrates the highest activity, which can be associated with the presence of bromine in the 5th position of indoline and 4-methoxyphenyl in the 5th position of pyrazoline and naphthyl in the 3rd position of pyrazoline. ID-4524 compound, whose molecule contains 5-bromindoline and two para-chlorophenyl groups also possessed high cytotoxic effect towards tumor cells. At the same time, ID-4522 compound was found to possess the lowest cytotoxic activity towards tumor cells. Like ID-4524 compound, it is characterized by the presence of two para-chlorophenyl groups in 3rd and 5th position of pyrazoline in isatin-pyrazoline-thiazolidinonr system, but it does not contain halogen in the 5th position of the indoline moiety. Thus, cytotoxic effect of isatin-containing 4-thiazolidinones mostly depends on the presence of halogen in the 5th position of the indoline, and the type of halogen in the 3rd and 5th position of the aryl groups of pirazoline cycle. All of these substances induce apoptosis in tumor cells. It has been shown that the ID-3833 substance induces apoptosis of mixed type, which includes the ER stress and mitochondrial apoptosis. The identified structure-functional relationships of 4-thiazolidones will be of high importance for further enhancement of their antineoplastic activity towards tumor cells

Biochemical indicators of hepatotoxicity in blood serum of rats under the effect of novel 4-thiazolidinone derivatives and doxorubicin and their complexes with polyethyleneglycol-containing nanoscale polymeric carrier

The aim of this study was to compare the effect of new synthetic 4-tiazolidinone derivatives (compounds 3882, 3288 and 3833) and doxorubicin (positive control) in free form and in their complexes with synthetic polyethyleneglycol-containing nanoscale polymeric carrier on the biochemical indicators of hepatotoxicity in blood serum of rats. The activity of enzymes considered as the markers of hepatotoxicity, as well as the concentration of total protein, urea and creatinine were measured in blood serum of rats. It was found that after injection of investigated compounds the activities of alanine aminotransferase, alkaline phosphatase and α-amylase increased in comparison to control. Doxorubicin injection was accompanied by 4-fold increase in the activity of γ-glutamyltransferase, and injection of compound 3833 led to 2.5-fold elevation of the activity of this enzyme. Complexation of these аntineoplastic derivatives with a synthetic nanocarrier lowered the activity of the investigated enzymes substantially if compared to the effect of these compounds in free form. The most evident decrease was measured for α-amylase, γ-glutamyltransferase and lactate dehydrogenase activities. The normalization of concentrations of total protein, urea and creatinine in blood serum of rats treated with complexes of the studied compounds with a polymeric carrier comparing with their introduction in free form was also detected. Thus, the immobilization by novel polymeric carrier of anticancer drugs possessing high general toxicity in the treated organism mitigates their toxic effect, which is evident as normalization of specific biochemical indicators of the hepatodestructive effects of the anticancer drugs