Study of the Impact of the New Methyltheophylline Derivative on the Kidneys Functional State of the Rats on the Background of Spontaneous Diuresis

Korniyenko, V. I.; Ladohubets, E. V.; Ponomarenko, O. V.; Harkusha, I. V.; Duchenko, E. A.

doi:10.31890/vttp.2018.02.12

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“…Нашу увагу привернули вперше синтезовані органічні речовини в ряду 7-заміщених-8-аміно-3метилксантинів (Korniyenko et al, 2018;Korniyenko et al, 2020). Прогнозування біологічної активності 7-заміщених-8-аміно-3-метилксантинів проведено з використанням єдиного опису хімічної структури і універсального математичного алгоритму встановлення залежностей «структура-активність» за програмою PASS (Prediction of Activity Spectra for Substances) за допомогою Java аплету сайту прогнозу спектра біологічної активності http://www.…”

Section: вступunclassified

Acute toxicity and diuretic activity of amino-3-methylxanthine derivates

Korniyenko¹,

Ladohubets²,

Harkusha³

et al. 2021

VSTFH

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A vital problem of the contemporary pharmacology lies in creation of safer and more efficient medicinal products. Regulation of sodium balance and water being one of the important homeostatic functions is essential for developing the methods of rational therapy through means of diuretics of renal function of kidneys.This work is aimed to study the dependence of acute toxicity and diuretic activity on chemical structure of the newly synthesized 7-substituted-8-amino-3-methylxanthines in experiments on rats.The acute toxicity of 7-(2-hydroxy-3-p-methoxyphenoxy) propyl-8-substituted theophylline has been studied on the intact white nonlinear mice weighing 20-24 LD50 and has been calculated according to the method of Körber. The study of the diuretic activity of the above-mentioned compounds has been carried out on white rats of Wistar line weighing 180-195g according to the method of Y.B. Berkhina.The gained outcome of research into the acute toxicity of 7-substituted-8-amino-3methylxanthines (compounds 1-11) has shown that LD50 of the synthesized compounds is in the range from 290 to 835 mg/kg. The most toxic (LD50=290 mg/kg) compound is the 6 th one: 3-methyl-7-(2-hydroxy-3-p-methoxyphenoxy-) propyl-8-n-butylaminoethyl. Substitution in the 8 th position of the molecule of 7-substituted-8-amino-3-methylxanthines n-butylamine (compound 6) of radical with 4-benzylpiperazine-1-ilne (compound 11), p-ethoxyphenylamic (compound 10) N,N-diethylaminoethylamine (compound 4), 4-methylpiperazine-1-ilne (compound 1), N,N-diethylaminoethylamine (compound 3), N-methyl-N-benzylamine (compound 2), (pyrrolidine-1-ilne (compound 7), m-tolylamine (compound 9), βhydroxyethylepiperazine-1-ilne (compound 8), (furil-2)methylamine (compound 5) causes a reduction of the acute toxicity of the aforesaid substances.Analysis of the diuretic activity research shows that derivatives of 7-substituted-8amino-3-methylxanthines (compounds 1-11) increases excretion of urine in the range from 25.1% to 201.4% (p<0.05).The most signifying diuretic activity has been shown by the compound 5: 3-methyl-7-(2-hydroxy-3-p-methoxyphenoxy-) propyl-8-(furil-2)methylaminoxanthine, which in the dose of 41.8 mg/kg enhances the water diuresis for 201. 4% (p<0.01).Introduction to the 8 th position of the molecule of 7-substituted-8-amino-3metylxanthines instead of furil-2-methylamine (compound 5) radical of m-tolylamine (compound 9), n-butylamine (compound 6) and p-ethoxyphenylamine (compound 10) fragments leads to a reduction in renal excretory function for 143.5%; 131.8% and 111%, accordingly. Hydrochlorothiazide in the dose of 25 mg/kg enhances the water diuresis for 90.1%.Thus, the most signifying diuretic effect is observed in the compound 5, which exceeds the effect of the hydrochlorothiazide for 111.3% (p<0.05) and has been selected for further study of the specific activity.

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Section: вступunclassified