Synthesis and biological properties of indol derivatives of 1,2,4-triazole

Topicality. Synthesis of heterocycles with the participation of indole synthons and 1,2,4-triazole is an interesting scientific direction. This interest is due to the possibility of synthesis on their basis of a variety of heterocyclic structures with significant potential for biological activity [1], [2], [3], [4], [5].

Purpose of the study. Synthesis of 5-indole-4-(amino, H, alkyl and aryl)-1,2,4-triazole-3-thiole in order to create derivatives based on them with a high potential for biological activity.

Materials and method. We selected indole-3-carboxylic acids as the starting compound. In this case, usually the strategy for obtaining the expected product was the following stages: synthesis of a carboxylic ester by the Fisher reaction, obtaining the corresponding acid hydrazide. Then carrying out the reaction with carbon disulfide in the presence of alkali or replacing isothiocyanate with the subsequent condensation reaction of 1,2,4-triazole hydrazine solution in the case with the intermediate reaction of hydrazide with carbon disulfide, or in alkali solution in the case of the intermediate reaction of hydrazide with substitution by isothiocyanate.

The One-pot reaction activated the carboxyl group of the indole-3-corboxylic acid by carbonyldiimidazole and attached an unsubstituted thiosemicarbazide tail. The resulting product was heated in a 10% solution of sodium hydroxide until complete dissolution, and after cooling, it was neutralized with acetate acid.

To confirm the structure of the resulting compounds and to prove the completeness of the chemical reactions, elemental analysis, 1H NMR - spectroscopy and IR - spectrophotometry were used.

The individuality of the synthesized substances is confirmed by chromatic mass spectrometry.

To determine the optimal direction of pharmacological screening, a prediction of the possible activity of synthesized substances was performed using the PASS On-line® service and molecular docking.

We obtained a series of 5-indole-4-(amino, H, alkyl and aryl)-1,2,4-triazol-3-thiole, the structure of which was proved using a gas chromato-mass-spectrometer and 1H-NMR spectroscopy.

In order to determine the pharmacological potential of the compounds obtained, a virtual screening was conducted using the «PASS» software product, and the «GUSAR» program was used for preliminary prediction of acute toxicity. The final stage of the work was the study of biological activity. For this purpose, a study of the substances obtained for antimicrobial and antifungal activity was conducted. Antimicrobial activity was analyzed in in vitro studies using the «serial dilution» method on a liquid nutrient medium. The fungicidal activity was studied in vitro on fungi of the genus C. albicans.

Results and discussion. As a result, 32 new substances (not including intermediate products) were obtained, which passed the test for authenticity. Indicators of acute toxicity obtained by the virtual method, allow you to preclassify the synthesized substances as low-toxic or practically non-toxic. Among all the compounds obtained, 2 substances showed a slight antimicrobial activity.

Conclusion. In the course of the work, the method of obtaining the starting material was optimized and the optimal conditions for obtaining its thio derivatives were revealed, the reactivity of 5-indole-4-(amino, H, alkyl and aryl)- 1,2,4-triazole-3-thiole was studied. For aryl, heteryl and alkylthio derivatives of the 5-indole-4-(amino, H, alkyl and aryl)-1,2,4-triazole-3-thiole, promising directions for the study of biological activity have been established.


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Year: 2018
City: Shymkent
Category: Medicine