Corresponding author: Taras Chaban (
Novel N3 substituted derivatives of 4-iminothiazolidine-2-one were synthesised under the reactions of [2+3]cyclocondensation, thionation and aminolysis. The functionalisation of 3-phenyl-4-imino-thiazolydine-2-one was carried out in its C5 position under condensation Knoevenagel and nitrosation reactions. The antioxidant activity of the synthesised compounds was evaluated
There is an increasing evidence of the implication of free radicals in a variety of diseases. Free radicals are being formed during normal cellular metabolism and they are known to contribute to healthy functions of the human body and development when they are not excessive. At high concentrations, free radicals can cause damage to cell structures, nucleic acids, lipids and proteins (
Thiazolidine derivatives are a known group of biologically active compounds in modern medical chemistry (
4-Iminothiazolidine-2-ones, in comparison with isomeric 2-imino derivatives, have been unsufficiently studied in modern organic and pharmaceutical chemistry. Taking into account these circumstances, the synthesis of new substances, as potential drug-like molecules, is relevant.
The objective of the present work was to synthesise a series of novel 4-iminothiazolidine-2-ones by the structural modification of the core heterocycle in its N3 and С5 positions for further pharmacological screening
All chemicals were of analytical grade and commercially available obtained from Sigma-Aldrich, Germany. All reagents and solvents were used without further purification and drying. 1H NMR spectra of compounds in DMSO-d6 solution were registered on a spectrometer Varian Mercury VX-400, USA (400 MHz), internal reference TMS. The elemental analysis experimental data on contents of Carbon, Hydrogen and Nitrogen correspond to those calculated (±0.3%) and were registered on a Elementar Vario L cube, Germany. Chemical shifts are reported in ppm units with use of δ scale.
Ascorbic acid was purchased from a medical store.
The antioxidant activity was determined on the basis of the free radical scavenging activity of stable 2,2-Diphenyl-1-picrylhydrazyl (
where A
Each experiment was performed in triplicate and average values were recorded. Results are expressed as the means ± S.D.
A classical approach to the formation of the 4-thiazolidone ring is the reaction of [2+3]-cyclocondensation. The corresponding 3-aryl-thiazolidine-2,4-diones obtained by the known method (
Synthesis of 3-aryl-4-imino-thiazolidine-2-ones (
This transformation was made possible by the fact that 3-aryl-4-thioxo-thiazolidine-2-ones are cyclic thioamides and, as a consequence, have a significant activity of the thiol group resulting from the greater electrophilicity of the carbon atom in thiocarbonyl group of the mentioned compounds as compared to the carbonyl position of C4 4-aryl-thiazolidine-2,4-diones. One of the proofs of the obtained compounds structure is their acid hydrolysis to the known 3-aryl-thiazolidine-2,4-diones (Scheme
Hydrolysis to the known 3-aryl-thiazolidine-2,4-diones.
The methylene group presence in C5 position of compound
Synthesis of 5-aryliden derivatives 3-phenyl-4-iminothiazolidine-2-one (
The next stage of our work was the further functionalisation of compound
Synthesis of 4-imino-3-phenyl-thiazolidine-2,5-dione 5-oxime (
The structures of the obtained compounds were confirmed by 1H NMR spectroscopy and elemental analysis. All these new compounds gave spectroscopic data in accordance with the proposed structures. The 1H NMR spectra of all compounds show the protons signals of the imino group in the thiazolidine ring as a singlet in the 8.48–8.57 ppm. The spectra of compounds
The antioxidant activity was determined on the basis of the free radical scavenging activity of the 2,2-diphenyl-1-picrylhydrazyl (
The
In the present paper, we demonstrate that the modified spectrophotometric method uses the
Values of absorbance and % inhibition of some novel 4-iminothiazolidine-2-ones.
The compound or standard | Absorbance of a sample, As | % Inhibition | The compound or standard | Absorbance of a sample, As | % Inhibition |
---|---|---|---|---|---|
|
|
– |
|
|
5.05 |
|
|
10.50 |
|
|
4.11 |
|
|
7.41 |
|
|
8.17 |
|
|
5.03 |
|
|
6.52 |
|
|
5.22 |
|
|
11.83 |
|
|
3.05 |
|
|
25.65 |
|
|
8.08 |
|
|
27.15 |
|
|
7.63 |
|
|
24.68 |
Antioxidant activity evaluation results showed that most of the researched compounds have a small effect on the release of free radicals in the range 3.05% - 11.83%. c (25.65%, 27.15%) exceeding that for ascorbic acid. Thus, the structure of the substituents in the 5 position of 3-phenyl-4-iminothiazolidin-2-one showed that 4-bromo-benzylidene and 4-nitro-benzylidene increases the antioxidant activity compared with the basic scaffold.
A series of novel 4-iminothiazolidine-2-ones derivatives, possessing antioxidant activity, were prepared by the structural modification of the core heterocycle in N3 and C5 positions. We have shown that the proposed approaches and developed synthetic protocols provided the possibility to design 4-iminothiazolidine-2-ones diversity with a considerable chemical novelty involving [2+3] cyclocondensation, thionation, aminolysis, condensation Knoevenagel and nitrosation reactions. The pharmacological screening allowed identification of only two lead compounds whose free radical scavenging activity exceeded that for ascorbic acid. Further optimisation of the structure to improve their activities is currently in progress.