Aim. Synthesis and in vivo study of acute toxicity, anti-inflammatory (anti-exudative) activity and side effects of pyrazoline-thiazolidin-4-one hybrid Les-5581 under conditions of therapeutic use in experimental animals. Methods. Traditional organic synthesis. The Litchfield-Wilcoxon method. Carrageenin-and formaldehyde-induced inflammatory paw edema models of white rats. Clinical laboratory tests: study of general blood parameters and biochemical profile of liver function (ALT, AST, LF and γ-GGT levels). Evaluation of ulcerogenic action. Results. The target hybrid Les-5581 has been synthesized in a convenient and efficient aminolysis of 5-etoxymethylidenerhodanine by 3,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-pyrazole. The LD50 value for Les-5581 was determined with intraperitoneal use and it was 510 mg/kg. Les-5581 exhibits significant anti-inflammatory activity at a dose of 50 mg/kg (intraperitoneal use) in an experiment on carrageenin-and formaldehyde-induced inflammatory models in white rats. The use of Les-5581 does not provoke a negative impact on the blood pattern, the liver enzymes function and has no ulcerogenic effect. Conclusions. The pyrazoline-thiazolidine-4-one hybrid Les-5581 is a good molecular platform for development of new potential lowtoxicity anti-inflammatory drugs without ulcerogenic action. K e y w o r d s: pyrazoline, thiazolidin-4-one, NSAIDs, molecular hybrid
In present work we report our studies of the interaction of 1-phenyl-1H-pyrrole-2,5-dione derivatives (N-arylmaleimides) and 3-bromodihydrofuran-2(3H)-one (α-bromo-γ-butyrolactone) as possible [C2] 2+ synthons with 1,2,4-triazole-3(5)-thiole targeting on synthesis of novel 5substituted thiazolo[3,2-b][1,2,4]triazole-6-ones. According to obtained results was establish that in above-mentioned interactions (conditions: convenient heating, range of solvents/reaction time) the thiol-ene click (for N-arylmaleimides) and SN (for α-bromo-γ-butyrolactone) processes take place, but not [2+3]-cyclocondensation reaction. The structure of compounds was studied using 1 H, 13 C NMR spectroscopy, LC-MS spectrometry and X-ray analysis. The prescreening of antimicrobial activity for synthesized compounds was performed against Gram-positive and Gram-negative bacteria, as well as yeasts.
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.
Background: Heterocyclic sulfone-bearing small molecules are particularly important objects in medicinal chemistry. Structure-diversified pyridinyloxy-substituted imidazo[2,1-b][1,3]thiazines are characterized with satisfactory drug-like parameters and possess significant anti-inflammatory effect in in vivo studies. Objective: Oxidation of a series of 6-(2-pyridinyloxy) imidazo[2,1-b][1,3]thiazines under the action of m-chloroperbenzoic acid with a view to anti-inflammatory activity enhancement and structure optimization. Methods: A series of appropriate sulfones was synthesized by the action of m-chloroperbenzoic acid on 6-[(pyridin-2-yl)oxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazines. The structure of the synthesized products was confirmed by 1H, 13C NMR, and LC-MS spectra. In vivo anti-inflammatory activity was studied using carrageenin model of inflammatory oedema on white rats. ADMET parameters of compounds were evaluated in silico using AdmetSAR. For the most active compounds, docking studies to COX-1,2, 5-LOX and FLAP were performed. Results: Results: It was found that transformation to sulfones could be achieved by soft oxidation at room temperature during 48 h using the 3-fold excess of oxidant in presence of sodium hydrogen phosphate. Anti-inflammatory activity screening results revealed that all synthesized sulfones showed significant anti-exudative action with inflammation inhibition index in the range 37.7 - 48.1%. The compound 2i was found the most active in the experiment, and its activity was equal to the reference drug effect; it also possesses satisfactory ADMET parameters and high energy of binding to 5-LOX and FLAP. Conclusion: The synthesized sulfone 2i is of an interest for in-depth studies and further design of new potential non-steroidal anti-inflammatory agents.
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