Vol. 15 No. 2(58) (2017)
Published:
2017-05-23
Original Researches
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The synthetic potential and the biological action of 1(2)-amino-9,10-anthracenediones and their functional derivatives
The review has systematized the literature data of the structural modification methods for 1(2)-amino-9,10-anthracenedione derivatives with alkyl, aryl, acyl, sulfur- and nitrogen-containing acyclic and heterocyclic condensed and non-condensing fragments; the results of the experimental studies of the biological activity of this class of compounds have been analyzed. The conditions of alkylation and arylation of the amino group of amino-9,10-anthracenediones are presented. The methods of acylfunctionalization of aminoanthracenediones have been analyzed. The use of bifunctional chloroanhydrides in obtaining various acyclic and heterocyclic derivatives has been shown. The synthetic potential of the dediazonization reaction has been discovered in production of a wide class of derivatives. Much attention has been paid to production of heterocyclic annelated (imidazole, oxazole, thiazole, azine, phenothiazine, pyrazole, phenanthroline, quinoline) and nonannelated (triazene, furane, pyridine, acridine, thiophene, pyrolytic, triazine, quinoxaline, thiazole) derivatives. In addition, the modification of the amino group has been clarified using aryliso(thio)cyanates, and the use of benzoyl isothiocyanates in the synthesis of thiazole, triazole and tetrazole derivatives has been demonstrated. The review shows that compounds of this type have different types of the biological activity. In particular, they are characterized by the antitumor, antiviral, antimicrobial, antifungal, antioxidant, antithrombotic activities. -
H2S Donors in creation of innovative drugs
Fundamental studies have identified a new group of gaseous signaling molecules – the so-called gasotransmitters – NO, CO, and H2S, which are involved in the regulation of a large number of metabolic processes. The results of these studies allowed determining a new direction in medicinal/pharmaceutical chemistry – creation of hydrogen sulfide donor compounds as potential drugs. The article presents the main achievements in the search for new H2S donors: the main stages of H2S metabolism and its biological effects; the classes of compounds that can release hydrogen sulfide based on the nature of sulfur-containing functional groups as well as the mechanism of H2S releasing. Additionally, the characteristic of the most successful direction – creation of the so-called hybrid molecules is given. The latter are compounds bearing fragments of the well known drugs covalently bounded with groups being capable to release H2S. -
Validation of the method for hydrochlorothiazide assay in extemporaneous preparations
Extemporaneous preparations that contain hydrochlorothiazide are widely prescribed and used in different countries for treating adults and children. The feature of the preparation of such dosage forms is the use of substances and commercial drugs as a source of the active pharmaceutical ingredient.
Aim. To validate the UV-spectroscopic assay method for determining hydrochlorothiazide in extemporaneous syrups and powders.
Results and discussion. For method proposed the conditions of analysis, sample preparation and validation characteristics were determined. The samples of syrups and the powder were dissolved in 0.01 M sodium hydroxide solution and assessed by spectrophotometry in the ultraviolet region of light at the wavelength of 273 nm. The samples comply with the Beer-Lambert Bouguer law within the concentration range of 8 × 10-3-1.2 × 10-2 mg/ml with the the correlation coefficients ≥ 0.9992. The uncertainty of the methods was within the critical value of the error (the powder – 1.14 %, the syrup – 0.72 %) for both samples of the syrup containing the pure substance and commercial tablets. The assay method of hydrochlorothiazide in the extemporaneous preparations meets the acceptance criteria for the assay limits of ± 7.5 % and ± 10 % by such validation parameters as specificity, linearity, precision, accuracy within the range of 80-120 % of the nominal content.
Experimental part. For research the volumetric glassware Class A, an UV-spectrophotometer (Thermoscientific Evolution 60S), analytical balances (AXIS ALN220), reagents and solvents corresponding to the requirements of the State Pharmacopoeia of Ukraine were used.
Conclusions. The validation results have proven that the method can be reproduced correctly and is suitable for use in pharmaceutical analysis.
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The synthesis of spiro-2-oxindole-derivative imides of pyrrolidine-3,4-dicarboxylic acid with biogenous sulfur amino acid residues and their antihypoxic activity
Modification of the spiro-2-oxindole skeleton due to introduction of pharmacophores of the known biologically active substances is a productive way for searching and creating new biologically active molecules with the non-planar structure.
Aim. To synthesize spiro-2-oxindole derivatives of pyrrolidine-3,4-dicarboxylic acid imides with residues of biogenic sulfur-containing α-amino acids and study their anti-hypoxic activity.
Results and discussion. Using a three-component one-pot reaction of isatin with sulfur-containing α-amino acids and maleimides a number of new spiro-imides, including 4’-R4-5’-alkylthio-S-R3-spiro[1-R1-5-R5-3H-indole-3,2(1’H)-pyrrolo[3,4-c]pyrrole]-2,3’,5’(1H,2’aH,4’H)-triones 6a-s, was synthesized with the yields of 55-92 %. The structure and the composition of the compounds synthesized are consistent with the results of X-Ray, elemental analysis, mass and NMR-spectra. It was found that only two of the eight possible enantiomers of spiro-imides were formed. Spiro-imide with a methionine residue in the dose of 10 mg/kg was the most active, and increased the life expectancy in rats with respect to the control group by 33.7 % on average. Against the background of acute asphyxia the preventive administration of piro-imide with a methionine residue in the dose of 5 mg/kg was the most effective; it increased the duration of the bioelectric activity of the heart by 12.1 %.
Experimental part. The synthesis of compounds was performed using a three-component condensation in the alcoholic-aqueous medium. The methods of X-Ray, 1H, 13C NMR-spectroscopy, and mass spectrometry were used. The study of the antihypoxic activity was carried out on models of acute normobaric hypoxic hypoxia with hypercapnia and acute asphyxia in male rats of the Wistar line. The antihypoxic effect was assessed by the bioelectric activity of the heart.
Conclusions. An effective approach to the synthesis of 4’-R4-5’-alkylthio-S-R3-spiro[1-R1-5-R5-3H-indole- 3,2’(1’H)-pyrrolo[3,4-c]pyrrole]-2,3’,5’(1H,2’aH,4’H)-triones has been developed; among them a compound with a moderate antihypoxic activity has been found.
