Corresponding author: Taras Chaban (
Synthesis of novel N3 and C5 substituted thiazolo[4,5-
Inflammation is a major pathogenetic component of many diseases of different etiology and one of the most important problems of general pathology and clinic. This reaction of the body to damage, is involved in the formation of many diseases. The problem of the pharmacological regulation of inflammation is relevant to modern medicine (
The development of chemistry of heterocyclic compounds is largely due to the practical direction of research. It is sufficient to note that among the most well-known and widely used drugs, more than 60% belong to heterocyclic compounds (
All chemicals were of analytical grade and commercially available. All reagents and solvents were used without further purification and drying.
All the melting points were determined in an open capillary and are uncorrected. 1H- spectra were recorded on a Varian Mercury 400 (400 MHz for 1H) instrument with TMS or deuterated solvent as an internal reference. Mass spectra were run using Agilent 1100 series LC/MSD, Agilent Technologies Inc. with an API–ES/APCI ionization mode. Satisfactory elemental analyses were obtained for new compounds (C ± 0.17, H ± 0.21, N ± 0.19). Ibuprofen was purchased from a medical store.
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The experiment was performed on nonlinear white rats of both sexes weighing 180–200 g. Rats were kept in the animal house under standard conditions of light and temperature on the general diet prior to the experiment. Total swelling was caused by aseptic injection of 0.1 ml of a 2% solution of carrageenan under aponeurosis of the sole of the hind limb of the rat for 0.5 h. animals were intraperitoneally injected with the test substance at a dose of 50 mg/kg prior to administration of the carrageenan solution. The presence of an inflammatory reaction was determined by changing the volume of the limb oncometric method at the beginning of the experiment and 4 hours after the introduction of the phlogogenic agent. For comparison, the anti-inflammatory effect of a known anti-inflammatory drug-ibuprofen in medium therapeutic doses was studied in similar conditions. The Ethics Committee of the Danylo Halytsky National Medical University, established by the Ministry of Health of Ukraine, approved the experimental protocol. The suppression of the inflammatory reaction was expressed as a percentage reduction in the volume of the paw, and it was calculated by the following equation:
where Vcontrol is the increase in paw volume in control group animals;
V is the increase in paw volume in animals injected with the test substances.
Continuing the systematic study of thiazolo[4,5-
Synthesis of 3-aryl-5-hydroxy-7-methyl-3
To expand the combinatorial library of thiazolo[4,5-
Compound
Synthesis of 7-methyl-3-phenyl-2-oxo-2,3-dihydrothiazolo[4,5-
Synthesis of hetarylsulfanyl derivatives of chloro-acetic acid 7-methyl-2-oxo-3-phenyl-2,3-dihydro-thiazolo[4,
The structure of the compounds obtained and the interpretation of the chemical studies were confirmed by elemental analysis and 1H NMR spectroscopy. All these new compounds gave spectroscopic data in accordance with the proposed structures.
Exudative is considered to be a classic example of acute inflammation. The effect of the synthesized substances on the course of the exudative phase of inflammation was studied on the basis of a carrageenan model of inflammatory edema of the paws of white rats (
Anti-inflammatory effect of thiazolo[4,5-
|
% |
||
|
2.20 ± 0.050 | – | |
|
1.27 ± 0.020 | 42.1 |
|
|
1.69 ± 0.035 | 23.2 |
|
|
1.06 ± 0.015 | 51.8 |
|
|
1.14 ± 0.015 | 48.3 |
|
|
1.66± 0.035 | 24.4 |
|
|
1.39 ± 0.025 | 36.7 |
|
|
1.71 ± 0.040 | 22.2 |
|
|
1.42 ± 0.040 | 35.4 |
|
|
1.68 ± 0.035 | 23.6 |
|
|
1.24 ± 0.020 | 43.5 |
|
|
1.74 ± 0.040 | 21.1 |
|
|
1.31 ± 0.020 | 40.5 |
|
|
1.75 ± 0.040 | 20.6 |
|
|
1.51 ± 0.030 | 31.2 |
|
|
1.38 ± 0.025 | 37.2 |
|
|
1.52 ± 0.030 | 30.8 |
|
|
1.71± 0.040 | 22.1 |
|
|
1.69 ± 0.035 | 23.4 |
|
|
1.76 ± 0.040 | 20.2 |
|
|
1.72 ± 0.040 | 21.8 |
|
|
1.32 ± 0.035 | 40.2 |
|
According to the anti-inflammatory activity pharmacological screening for synthesized products, in a significant number of cases the anti-inflammatory effect is equivalent to that of the reference drug Ibuprofen. For some compounds, the anti-inflammatory effect was less than the of the reference drug. The inflammatory response inhibition for them are in the range of 20.2–35.4%. However, some substances activity exceeds Ibuprofen, which gives reason to consider this condensed system as a promising molecular framework for the design of potential anti-inflammatory agents.
The results of pharmacological screening and analysis of the structure of molecules and the nature of the substituents in different positions of the thiazolopyridine cycle allow us to distinguish a number of patterns of dependence «structure – anti-inflammatory action» among the derivatives of thiazolo[4,5-
5-Hydroxy-7-methyl-3-phenyl-3
The results obtained demonstrate that the anti-inflammatory effect of the synthesized compounds is probably due to the contribution of 5-hydroxy-7-methyl-3-phenyl-3
As a result of the [3 +3]cyclocodensation, acylation and alkylation reactions, the synthesis of novel thiazolo[4,5-