Vol. 19 No. 2(74) (2021)
1,2-Benzoxathiin-4(3H)-one 2,2-dioxide – an underinvestigated building block with a high synthetic and pharmacological potential: synthesis, chemical properties, biological activity
Aim. To analyze the available literature data on the methods of synthesis, chemical transformations and the biological activity of derivatives containing a sultone core – 1,2-benzoxathiin-4(3H)-one 2,2-dioxide – and to show the possibilities of their further use in the construction of new molecular systems with attractive pharmacological properties.
Results and discussion. The most widespread method for the synthesis of 1,2-benzoxathiin-4(3H)-one 2,2-dioxides is the cyclization of salicylic acid derivatives. The known chemical transformations of 1,2-benzoxathiin-4(3H)-one 2,2-dioxides deal with all reaction centers of the heterocyclic fragment of the condensed system – C=O and CH2 groups, SO2–O bond, CH2CO fragment as a whole. It should be noted that the oxathiine nucleus is prone to undergo recyclizations. The use of 1,2-benzoxathiin-4(3H)-one 2,2-dioxides in multicomponent transformations still remains hardly explored. The “abnormal” course of some classical transformations involving 1,2-benzoxathiine 2,2-dioxides is also noteworthy. The study of the pharmacological properties of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide derivatives is scarce and mainly based on their structural similarity to the coumarin core, which led to the study of anticoagulant, antimicrobial and antitumor properties for the sultone derivatives.
Conclusions. The analysis has shown a limited number of studies in each aspect – approaches to the synthesis of 1,2-benzoxathiin-4(3H)-one 2,2-dioxides, their chemical transformations and the study of their pharmacological activity. In addition to a small number of publications on this heterocyclic system, there have been almost no sultone studies in the last 20 years. Taking this into account 1,2-benzoxathiin-4(3H)-one 2,2-dioxide and its derivatives deserve close attention as objects of research for experimental chemistry and pharmacology.
Synthesis, the antiexudative and antimicrobial activity of 6-arylidene substituted imidazo[2,1-b]thiazoles
Aim. To expand the range of 6-arylidene-2-methyl-2,3-dihydroimidazo[2,1-b]thiazolones as potential objects for studying the antiexudative and antimicrobial activities.
Results and discussion. It has been shown that the condensation of synthetically affordable 2-methyl-2,3-dihydroimidazo[2,1-b]thiazolone with aromatic aldehydes can be successfully used for obtaining the corresponding 6-ylidene-functionalized derivatives. The biological screening of the compounds synthesized revealed that they possessed a low or moderate anti-inflammatory activity and inhibited the inflammation process in the range from 3 to 44 %. During the study of the antimicrobial activity of the substances obtained it was determined that their minimum bacteriostatic and minimum fungistatic concentrations ranged from 31.25 to 250 μg/mL.
Experimental part. The interaction of 2-methyl-2,3-dihydroimidazo[2,1-b]thiazolone with a series of benzaldehydes and salicylic aldehydes in refluxing acetic acid in the presence of anhydrous sodium acetate leads to new 6-arylidene-2-methyl-2,3-dihydroimidazo[2,1-b]thiazolones. The antiexudative activity screening was performed on the model of carrageenan-induced paw oedema of white outbred male rats. The antimicrobial activity of the compounds was studied using the microtechnique of two-fold serial dilutions in a liquid nutrient medium.
Conclusions. It has been found that the Knoevenagel condensation of 2-methyl-2,3-dihydroimidazo[2,1-b]thiazolone with aromatic aldehydes is a convenient way for the structural modification of the position 6 of the heterocyclic system by the arylidene moiety. The arylidene derivatives obtained show a moderate antiexudative activity in the carrageenan-induced rat paw oedema assay, as well as the antimicrobial activity against some gram-positive and gram-negative bacteria and fungi.
The synthesis and antiviral activity against yellow fewer virus of 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides
Aim. To synthesize 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides and study their antiviral activity against yellow fever virus (YFV).
Results and discussion. The target 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides were obtained in three-step format from cyanuric chloride in good to high yields. The carbothioamides synthesized were estimated to possess the antiviral activity against YFV. The results obtained indicate that most of the compounds studied show the inhibitory activity against YFV in concentrations ≤10 μg/mL. For the most active substances, EC90 was in the range of 0.06 – 2.2 μg/mL. Good effective concentration values were accompanied by low levels of cytotoxicity resulting in excellent selectivity index values. The data obtained also indicate that the presence of an alkyl substituent in ortho-position of the N-aryl fragment is crucial for an effective inhibition of YFV growth.
Experimental part. 2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides were synthesized starting from cyanuric chloride in three steps by its successive interaction with two equivalents of pyrrolidine, hydrazine and a series of alkyl-/arylisothiocyanates. The antiviral and cytotoxic activities of the target carbothioamides were studied in the Southern Research Institute (SRI, Birmingham, Alabama) by the viral cytopathic effect reduction assay and the virus yield reduction assay.
Conclusions. 2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides synthesized have been proven to be a promising class of compounds for treating such a severe viral disease as yellow fever.
The study of the effect of ethyl alcohol concentrations on the antioxidant activity of ascorbic acid solutions
Much attention is currently paid to the study of the antioxidant properties of various objects – individual antioxidants, dietary supplements, medicines, liquid plant extracts. Antioxidant medicines are widely used as the main or additional correction agents in the treatment of a number of diseases. Therefore, the study and development of procedures for determining the antioxidant activity is a prospective task for today.
Aim. To determine the contribution of different concentrations of ethanol to the level of the antioxidant activity (AOA) of ascorbic acid solutions by the potentiometric method.
Results and discussion. The different ethanol content in the solution had the following percent of the contribution to the value of AOA of ascorbic acid solutions – 1.85, 3.56, 4.89, 6.76, 7.63 % for 20, 40, 60, 80, 96 % ethanol, respectively. The linearity of the procedure was proven in the range from 0.039 to 0.31 mmol/L.
Experimental part. The object of the study was solutions of ascorbic acid prepared using ethanol of different concentrations – 20, 40, 60, 80, 96 %. Potentiometric measurements were conducted by a Hanna 2550 pH meter (Germany) with an EZDO 5010 combined platinum electrode. Weighing was carried out using an АN100 digital analytical balance (AXIS, Ukraine) with d = 0.0001 g. Ascorbic acid was purchased from Sigma Aldrich (≥ 99.0 %), K3[Fe(CN)6], K4[Fe(CN)6], NaHPO4, KH2PO4 were of analytical grade.
Conclusions. It has been found that ethyl alcohol affects the change of the potential in the electrochemical cell and the level of AOA of ascorbic acid solutions. The percentage of the contribution of different concentrations of ethyl alcohol to the AOA value ranges from 1.85 to 7.63 %. The approach and the formula for calculation that take into account the effect of ethyl alcohol on the final AOA result of the test sample of ascorbic acid in a water-alcohol solutions have been proposed. The results of this study can be used in the pharmaceutical and food industries to determine, assess and control the AOA level of dietary supplements, liquid extracts, tinctures, medicines, and alcoholic beverages.
Aim. To develop a principally new method, which would allow achieving the necessary accuracy and reproducibility of the analysis results, for determining the activity of the blood cholinesterase; to create safe working conditions when performing the analysis.
Results and discussion. The kinetic method proposed for determining the activity of cholinesterase consists in photometric measurement of the rate of the enzymatic hydrolysis of the acetylcholine substrate (by its residue) in the phosphate buffer using p-phenetidine as an indicator. The rate of the enzymatic hydrolysis of acetylcholine was determined by the tangent of the inclination angle of the linear part of the kinetic curve in the А–t coordinates at a wavelength of 358 nm. The linear dependence of the conditional reaction rate (tgα) on the enzyme concentration was observed in the concentration range of 0.12 – 0.36 mg/mL. Metrological characteristics of the method developed were: RSD = 2.0 % (n = 5; P = 0.95), correctness 0.4 %. These values indicate that the method for determining the activity of blood cholinesterase is sensitive, reliable and reproducible.
Experimental part. The experiments on determining the rate of the enzymatic hydrolysis were repeated three times with a specific concentration of the enzyme. Using the data obtained the kinetic curves were constructed in the А–t coordinates; on their basis the tangents of the angles of inclination in min-1 were calculated. The calibration graph was constructed using the average values of the tangents of the angles of inclination, which corresponded to a certain concentration of the solution of the working standard sample of the enzyme. The equation of the calibration dependence of tgα-enzyme concentration was calculated by the method of least squares and found to be tgα (min-1) = –0.17с + 9.13 (r = 0.999).
Conclusions. As a result of the studies conducted, a new method for determining the activity of the cholinesterase enzyme has been developed. The method is characterized by a high sensitivity, reliability and reproducibility and provides safe working conditions when performing the analysis.
5-R-1,2,4-triazole-3-thiones and their derivatives are easy to obtain; they have low toxicity and a broad spectrum of the biological activity. It makes this class of heterocyclic compounds promising for creating potential drugs.
Aim. To develop the preparative methods for the synthesis of 5-aryl-1,2-dihydro-3H-1,2,4-triazole-3-thiones and study their reactivity in the alkylation reaction.
Results and discussion. New 5-aryl-1,2-dihydro-3H-1,2,4-triazole-3-thiones were synthesized. The latter were used for the synthesis of 3-aryl-5-(alkylthio)-4H-1,2,4-triazoles.
Experimental part. Using a series of four successive reactions based on the substituted benzoic acids new 5-aryl-1,2-dihydro-3H-1,2,4-triazole-3-thiones were synthesized. Alkylation of the thiones allowed obtaining a series of S-alkyl derivatives. The structure of the compounds synthesized was confirmed by elemental analysis, IR and 1H NMR spectroscopy, and their individuality was determined by high-performance liquid chromatography.
Conclusions. The preparative methods have been developed, and new 5-aryl-1,2-dihydro-3H-1,2,4-triazole-3-thiones have been synthesized. Alkylation of the latter made it possible to obtain a series of 3-aryl-5-(alkylthio)-4H-1,2,4-triazoles with an alkylthio fragment of different length.
Aim. To study the moisture absorption properties of cathiazine – a new synthetic substance stimulating spermatogenesis and possessing hepatoprotective properties.
Materials and methods. The kinetics of the moisture absorption capacity (hygroscopicity) was determined using the weight method at relative ambient humidity of 44 % and 75 % at a temperature of (25 ± 2) °С.
Results and discussion. The weight gain of three batches of the substance cathiazine under research during the whole experiment under relative humidity conditions of 44 % was in the range from 0 to 0.041 %; when increasing humidity the percentage of the weight gain ranged from 0 to 0.082 %. Thus, the hygroscopicity of the active pharmaceutical ingredient cathiazine in all three batches can be described as insignificant.
Conclusions. The results obtained indicate that the cathiazine original substance is non-hygroscopic, and this fact can be used in the development of a pharmacopoeial monograph.