Synthesis and antituberculosis activity of N'-(2-(5-((theophylline-7'-yl)methyl)-4-R-4Н-1,2,4-triazole-3-ylthio)acetyl)isonicotinohydrazides

Abstract

The paper shows the results of clinical, pathological and histological studies of tuberculosis inflammation and non-specific changes in guinea pigs organs in the experimental model of tuberculosis during the comparative isoniazid and GKP-305 (N'-(2-(5-((theophylline-7'-yl)methyl)-4-ethyl-4Н-1,2,4-triazole-3-ylthio)acetyl)-isonicotinohydrazide) treatment. The optimum location for the GKP-305 injection is found.

The aim of the study was to study the tuberculostatic activity of GKP-305 in vivo experiment and to evaluate its possible application in the treatment of experimental tuberculosis infection caused by Mycobacterium bovis (M. bovis).

Materials and methods. We used first time synthesized N'-(2-(5-((theophylline-7'-yl)methyl)-4-ethyl-4Н-1,2,4-triazole-3-ylthio)acetyl)isonicotino-hydrazide. 18 small guinea pigs with an average weight of 250 g were used for the experiment. Six groups of 3 animals were formed in each. The test substances were administered as follows: the 1st group ‒ isoniazid at a dose of 10 mg/kg of animal weight per os; the 2nd group is isoniazid at a dose of 10 mg/kg of animal weight sub cutem; the 3rd group ‒ GKP-305 at a dose of 10 mg/kg of animal weight per os; the 4th group ‒ GKP-305 at a dose of 10 mg/kg of animal weight sub cutem; the 5-th and 6-th groups are control. The duration of treatment was 90 days. Infection of animals was carried out by subcutaneous administration of M. bovis 100 passage at a dose of 0.01 mg wet weight in a volume of 0.5 cm³ physiological saline solution of sodium chloride. When performing the autopsy, macroscopic tuberculosis lesions were assessed in conventional units (c. u.) for each individual Cavia porcellus. For histological examination, the lymph nodes, pieces of spleen, liver, lungs, as well as the kidney, were taken from each mumps in regional guinea pigs and placed in 10% formalin solution. Pathoanatomical dissection was performed by the method of complete evisceration according to G. V. Shor. Pathohistological studies were performed by staining with hematoxylin and eosin. The study of blood biochemical parameters was carried out with the help of the photometers.

Results. Positive results were obtained using the agent GKP-305 as only 1 % solution used internally affects tuberculostatically.

Conclusions. It has been established that subcutaneous administration of GKP-305 at a dose of 10 mg/kg of animal weight leads to the absence of specific and nonspecific manifestations of inflammation in the lungs, liver, kidneys and spleen.