Research of Dependence of Acute Toxicity and Diuretic Activity on Chemical Structure in the Row of 8-amino substituted of 7-(3-p-metoxyphenoxy)-propyl-3-methylxantines

A topical issue of the contemporary pharmacology and modern medicine remains the creation of new safer and more efficient medicines regulating the general haemodynamics and water and sodium balance in physiological and pathological conditions. Regulation of sodium and water balance being one of the important homeostatic functions is crucial for developing the new strategies for rational pharmacotherapy of excretory kidney function. Pathological processes in the kidneys develop in arterial hypertension, chronic heart failure, nephrotic syndrome, acute and chronic renal failure, diabetes, all type of shock and other diseases. Although progress in the prevention and treatment of many pathological conditions by diuretics is evident, many questions on this issue are topical and demand further active research. Along with a strong diuretic action, administration of diuretics may lead to the development of serious adverse effects such as hypokalemia, hypochloremic alkalosis, metabolic acidosis, hyperlipidemia, hyperglycemia, azotemia, disturbances of protein metabolism and others that limit their application in clinical practice. The purpose of this research was to study dependence of acute toxicity and diuretic activity on chemical structure of the newly synthesized compounds in the row of 8-amino substituted of 7-(3-p-metoxyphenoxy)-propyl-3-methylxantines in experiments on rats. The structure of the synthesized compounds has been confirmed by using modern physico-chemical methods of elemental analysis, UV-, IR-, PMR- and mass-spectrometry; counter synthesis. The purity of the synthesized substances was controlled by the method of thin-layer chromatography. Prediction of pharmacological activity of 8-amino substituted of 7-(3-p-metoxyphenoxy)-propyl-3-methylxantines was conducted with application of the universal description of the chemical structure and universal mathematical algorithm to predict pharmacological effects and biochemical mechanisms based on the structural formula of a substance by software product PASS (Prediction of Activity Spectra for Substances). The studies were carried out in accordance with EC Directive 86/609 EEC. The obtained results of acute toxicity of 8-amino substituted of 7-(3-p-metoxyphenoxy)-propyl-3-methylxantines (compounds 1-10) has shown that LD50 of the synthesized compounds is in the range from 340.0 to 985.0 mg/kg. According to the generally accepted classification of K.K. Sidorov, all the investigated compounds belong to the fourth class and they are low-toxic substances. Analysis of the diuretic activity research results showed that derivatives of 7-(3-p-metoxy-phenoxy)-propyl-8-amino-3-methylxantine (compounds 1-10) increased urine excretion in the range from 67.6% to 215.2% (p<0.01). It was found that the strongest diuretic activity among investigated compounds had the compound 5 – 3-methyl-7- (2-hydroxy-3-p- methoxyphenoxy-) propyl-8- (furil-2) methylaminoxanthine which at a dose of 41.8 mg/kg enhanced the water diuresis by 215.2% (p<0.01). Therefore, the derivatives of 7-(2-hydroxy-3-p-methoxyphenoxy)propyl-8-amino-3-methylxanthines are a promising group of low-toxic organic substances for further synthesis and research with the purpose of creation on their basis of highly effective agents that improve renal excretory function. The strongest diuretic effect has been shown by the compound 5, which exceeded the effect of the reference agent hydrochlorothiazide by 125.1% (p<0.05) and it may be selected for further study of the specific activity.