Медицина/6. Экспериментальная и клиническая фармакология

Gotsulya A. S., Panasenko O. I., Knysh Ye. G., Gladskaya J. R.

Zaporizhzhia State Medical University, Ukraine

Acute toxicity of alkyl-, aryl- and heteryl derivatives 4-(2-methoxyphenyl)-5-methyl-1,2,4-triazoles-3-thione and 4-(2-methoxyphenyl)-5-phenyl-1,2,4-triazoles-3-thione

On the first stage of the obtained compounds biological research is explored primarily an acute toxicity, which can significantly reduce the number and intensity of the adverse reactions manifestations in terms of their clinical application.

Aim of the toxicological researches of compounds, derivatives of 1,2,4-triazoles, was detection of the nature and severity of their damaging effects towards an organism of the experimental animals and estimation of their safety.

Researches had been conducted on white rats of the Wistar line, by tabular express-method of V. B. Prozorovskiy.

Were used 4 groups of animals, 2 observations in each group with an additional use of a single previous and next dose. Water-soluble compounds were dissolved in 1,5 ml of purified water and injected, in compliance with the rules of asepsis and antisepsis, by means of syringe intraperitoneally. Water-insoluble compounds were stabilized by “Tween-80” and introduced through a metal tube into the stomach.

The observations had been conducted through 24 h.

By results of the acute toxicity research was found that the LD₅₀ of this class of chemical compounds is located in the range from 307 to 954 mg / kg, according to the classification of K. K. Sidorov they belong to the IV-th class of toxicity.

Synthesized by us 4-(2-methoxyphenyl)-5-methyl-1,2,4-triazoles-3-thione and 4-(2-methoxyphenyl)-5-phenyl-1,2,4-triazoles-3-thione possessing by low toxicity.

According to the classification of K. K. Sidorov, synthesized thiones related to low-toxic or practically non-toxic substances.

On the acute toxicity of these thiones largely affects as a presence of methyl or phenyl radical at the C₅ atom of 1,2,4-triazole cycle, as the nature of substituent at sulfur atom at the C₃ atom of 1,2,4-triazole cycle.

It should be noted that the replacement of the phenyl radical on methyl by fifth atom of 4-(2-methoxyphenyl)-5-R-1,2,4-triazoles-3-thione leads to a slight decrease in acute toxicity - up to 359 mg / kg.

At studying of the acute toxicity of alkyl -, aryl- and heteroderivatives of 4-(2-methoxyphenyl)-5-methyl-1,2,4-triazoles-3-thione and 4-(2-methoxyphenyl)-5-phenyl-1,2,4-triazoles-3-thione found that at the gradual increase of molecular weight of the alkyl residue firstly is observed a decrease on acute toxicity of 3-(methylthio)-4-(2-methoxyphenyl)-5-methyl-4H-1,2,4-triazoles, 3-(amylthio)-4-(2-methoxyphenyl)-5-methyl-4H-1,2,4-triazoles, 3-(cyclohexylthio)-4-(2-methoxyphenyl)-5-methyl-4H-methyl-1,2,4-triazole, as compared with 4-(2-methoxyphenyl)-5-methyl-1,2,4-triazoles-3-thione and 4-(2-methoxyphenyl)-5-phenyl-1,2,4-triazoles-3-thione. With the introduction of the nonyl radical is observed a significant increase of toxicity - up to 355 mg / kg. Further extension of the alkyl radical leads to the loss of the toxic properties at 3-(decylthio)-4-(2-methoxyphenyl)-5-methyl-4H-1,2,4-triazoles up to 954 mg / kg. Thus, the presence of decyle residues at the sulfur atom causes the lowest rates of the acute toxicity in a series of alkyl-, aryl- and heteryl derivatives of 4-(2-methoxyphenyl)-5-methyl-1,2,4-triazoles-3-thione and 4-(2-methoxyphenyl)-5-phenyl-1,2,4-triazoles-3- thione.

At the introduction of acylalkyl radicals is observed a decrease of the acute toxicity, mostly, in compounds, the structure of which includes the remains of aromatic ketone without substituents, at least - in connections with the remainder of the aromatic ketone with substituents on the aromatic nucleus. Thus, on the magnitude of these compounds toxicity affect substituents with a phenyl group of ketone residue. So, substitutions 4-methoxy- and 4-nitrosignificantly amplify the toxic properties of 2-[5-R-4-(2-methoxyphenyl)-1,2,4-triazoles-3-ylthio]-1-aryl-ethanons. It should be noted that the increase of acute toxicity is observed also at the restoration of 2-[5-R-4-(2-methoxyphenyl)-1,2,4-triazoles-3-ylthio]-1-aryl-ethanons up to 2-[5-R-4-(2-methoxyphenyl)-1,2,4-triazoles-3-ylthio]-1-arylethanons. Also found that a transition from 2-[5-methyl-4-(2-methoxyphenyl)-1,2,4-triazole-3-ylthio]-1-arylethanones to 2-[5-phenyl-4-(2-methoxyphenyle)-1,2,4-triazol-3-ylthio]-1-arylethanons does not allow to form a clear correlation dependence between the influence of radicals in the fifth position of 1,2,4-triazoles nucleus and a change of the acute toxicity.

References

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2. Raafat M. Shaker. The chemistry of mercapto- and thion-substituted 1,2,4-triazoles and their utility in heterocyclic synthesis / Raafat M. Shaker // ARKIVOC. – 2006. – Vol. IX. – P. 59 – 112.