SYNTHESIS AND PRECLINICAL STUDY OF ANTIOXIDANT ACTIVITY OF [1,2,4]TRIAZOLO[1,5-A]PYRIDINE DERIVATIVES

Abstract

Purpose. Synthesis and study of antioxidant properties of [1,2,4]triazolo[1,5-a]pyridine derivatives and their potential toxicity using preclinical diagnostic methods.

Methodology. Derivatives of [1,2,4]triazolo[1,5-a]pyridine were synthesized on the basis of 2-aminopyridines and ethyl isothiacyanatocarbonate, with subsequent cyclization of intermediate adducts. The resulting 2-amino[1,2,4]triazolo[1,5-a]pyridines were reacted with isoamyl nitrite in the presence of CuHal2, which led to the synthesis of volatile 2-halogeno[1,2,4]triazolo[1,5- a]pyridine. The toxicity of the obtained compounds was studied by the degree of hemolysis of erythrocytes in a hypotonic NaCl solution. The intensity of free-radical oxidation of lipids was assessed spectrophotometrically by the formation of TBА-active products. The antioxidant activity of the substances was determined by inhibiting the oxidation of adrenaline under conditions of artificial oxidative stress.

Scientific novelty. For the first time, the antioxidant activity of the [1,2,4]triazolo[1,5-a]pyridine derivatives described in the paper was investigated and their toxicity was studied according to the degree of hemolysis of erythrocytes in a hypotonic NaCl solution.

Conclusions. The in vitro cytotoxicity study model showed that compounds 5a and 5b, which contain bromine atoms in the 2, 5, and 7 positions of the pyridinotriazole heterosystem, exert the greatest influence on the stability of erythrocyte membranes.

The study of antioxidant activity showed that the highest values of antioxidant activity are characteristic of compounds of the 4a-d series, namely compounds 4b and 4c, which are characterized by the presence of an amino group in the 2nd position and the presence of a bromine atom as a substitute in the 1st and 5th positions of the pyridine fragment of the heterosystem.

The dynamics of antioxidant activity on the model of inhibition of adrenaline oxidation confirms the opinion about the lowest toxicity and the highest ability to inhibit the formation of reactive oxygen species of compounds 4b and 4c (40.16 and 38.82% relative to ionol).

So, with the use of preclinical diagnostic methods, we proved the presence of physicochemical activity in a number of investigated compounds. 2-amino-[1,2,4]triazolo[1,5a]pyridine derivatives with a bromine atom as a substitute in the pyridine fragment of the molecule should be considered as potential antioxidants in the future, and the studied condensed system can be considered a promising heterocyclic framework for creating potential antioxidant agents.