Acute toxicity of 5-(furan-2-yl, 2-metylfuran-3-yl)-4-amino-1,2,4-triazole-3-thiol alkyl derivatives

Aim of our work was the further exploration of the new 5-(furan-2-yl, 2-metylfuran-3-yl)-4-amino-1,2,4-triazole-3-thiol alkyl derivatives’ acute toxicity, setting some patterns of alkyl substituents influence by the Sulfur atom on the acute toxicity. Research materials and methods. In this study we used first time synthesized 5-(furan-2-yl, 2-metylfuran-3-yl)-4-amino-4H-1,2,4-triazole3-thione derivatives. Acute toxicity was conducted on white rats weighing 160–250 g, which were injected once intraperitoneally with the investigated substances. The rats were received from the nursery of the Pharmacology and Toxicology Institute of Ukraine Medical Sciences Academy. The animals were kept on a standard diet with natural light mode “day-night”. Results and their discussion. After the acute toxicity studies in a group of 5-(furan-2-yl, 2-metylfuran-3-yl)-4-amino-4H-1,2,4-triazole 3-alkyl derivatives it was found that among all studied structures the most toxic was 2e, LD50 of which was 263 mg/kg, and the least toxic compound was 2a, LD50 of which was 1570 mg/kg, that belongs to the V toxicity class. After comparing the acute toxicity of well-known antimycotic agent fluconazole with the studied compounds it can be argued that most compounds are less toxic than the comparison drug fluconazole with the index of LD50 ˃320 mg/kg. It was found that the transition in a group from butyl to decyl, octyl, ventyl, propyl, nonyl and heptyl substituents in the molecule of 3-alkylthio 5-(furan-2-yl)-4-amino-4H-1,2,4-triazole is accompanied by the toxicity increasing. Speaking about the 5-(2-metylfuran-3-yl)-4-amino-4H1,2,4-triazole 3-alkylthio derivatives we can find that this dependence is observed in a number from propyl, pentyl, nonil, butyl, heksyl, octyl and heptyl hydrocarbon chains. Conclusions. The investigated 3-alkylthio 5-(furan-2-yl, 2-metylfuran-3-yl)-4-amino-4H-1,2,4-triazole derivatives belong to the IV-V toxicity class. The toxicity of 5-(furan-2-yl, 2-metylfuran-3-yl)-4-amino-4H-1,2,4-triazole alkyl derivatives varies depending on the hydrocarbon substituents, so the presence of 3-heptylthiol substituent in the С3 atom at 5-(furan-2-yl, 2-metylfuran-3-yl)-4-amino-4H-1,2,4-triazole leads to the toxicity increase. Introduction of 3-butylthiol to the molecule of 5-(furan-2-yl)-4-amino-4H-1,2,4-triazole, and the 3-propylthiol substituents in the 5-(2-metylfuran-3-yl)-4-amino-4H-1,2,4-triazole results the formation of lowest acute toxicity. Zaporozhye medical journal 2016; No5 (98): 101–104

Ключові слова: гостра токсичність, 1,2,активність,LD  I ntroduction.A significant contribution to the development of modern chemistry of heterocyclic compounds have scientific achievements of domestic scientists, who are engaged in the research of 1,2,4-triazole system for many years.The 1,2,4-triazole core is the study object of a wide scientists circle due to a number of unique properties.Modeling the 1,2,4-triazole heterocycle by attaching different functional substituents results the formation of promising compounds, new "libraries" for further chemical reactions, the study of biological properties, different patterns installation.Scientific publications demonstrate the relevance and perspective of 1,2,4-triazole derivatives study which contain the remains of furan heterocyclic system and amino groups as typical substituents.The authors convincingly demonstrated that an active "symbiosis" of 1,2,4-triazole, furan and amino groups in one molecule has positive effect on the new compounds' properties.
The vast experience of domestic scientists is an evidence of absolute necessity and obvious perspective for further research of these derivatives.The bright example of a typical functional substituents successful combination in one molecule is a new domestic drug "Tryfuzol", which is now widely used in veterinary practice.Previously was noted [1] that further testing of new 5-(furan-2-yl, 2-metylfuran-3-yl)-4-amino-1,2,4-triazole-3-thiol derivatives is important to have theoretical and practical significance.
Acute toxicity assessment was conducted on white rats weighing 160-250 g, which were injected once intraperitoneally with the investigated substances.The rats were received from the nursery of the Pharmacology and Toxicology Institute of Ukraine Medical Sciences Academy.The animals were kept on a standard diet with natural light mode "day -night" [2,3].
The study was conducted on the basis of "Pharmacological agents preclinical safety evaluation rules (GLP)" [4,6].
In the acute toxicity study each investigated compound was taken in the four doses range, each dose was tested in 2 animals [5].Follow-up term was 14 days, during which we studied the nature and duration of intoxication symptoms, death dates and the number of dead animals from each dose [6].
After comparing the acute toxicity of well-known antimycotic agent fluconazole with the studied compounds it can be argued that most of compounds are less toxic than the comparison drug fluconazole with the index of LD 50 ˃320 mg/kg.