Cardioprotective activity and screening of N-substituted of quinazolin-4(3Н)-ones

Abstract

Cardioprotection is a promising direction of therapy for myocardial infarction and the search for new substances with cardioprotective properties remains an urgent task in pharmacology. N-substituted quinazolin-4(3H)-ones, which are characterized by antihypoxic, antioxidant, angioprotective, anti-inflammatory, and others properties may have the cardioprotective activity. The purpose of the study is to detect the presence and the degree of cardioprotective effect in a number of N-substituted quinazolin-4(3H)-ones in the model of acute experimental myocardial infarction in different modes of administration, to determine a “structure – action” dependence, to identify a leader compound promising for in-depth study of its pharmacological properties. Materials and methods. 300 non-linear rats of both sexes, weighing 180–220 g, were used in this study. Myocardial infarction was modeled by diathermocoagulation of the coronary artery. In the 1st series of experiments, the studied substances and reference drugs amiodarone, mexidol and thiotriazoline were administered in the prophylactic, and in the 2nd series – in the therapeutic regimen. The cardioprotective effect size was estimated on the basis of the mortality rate of animals. Results. The cardioprotective activity of both the test compounds and reference drugs was evidenced by a decrease in the mortality rate of animals with a heart attack in the critical periods of the experiment relative to the control. The PC-66 has been found to be the most effective: the mortality rate was 20 % versus 54 % of the control in the critical period of the experiment, that is, it was 2.7 times less than in the control. The test substances by the degree of cardioprotective effect in the course of therapeutic introduction into the body can be arranged in the following order: PC-66 = amiodarone ≥ mexidol ≥ thiotriazoline> PC-32 = PC-51. Cardioprotection, the signs of which were found in the PC-66 compound, are well combined with the presence of central analgesic and cerebroprotective effects, which suggests the multifactorial effects of this substance. We can state the originality of the resulting substance and its potential properties. Conclusions. N-substituted quinazolin-4(3H)-ones exhibit cardioprotective activity. 4-(4-oxo-4H-quinazolin-3-yl) benzoic acid (compound PC-66) displays cardioprotective properties the most. The obtained data testify to the prospects of the pharmacological properties and safety of the PC-66 compound in-depth study.

Keywords

• myocardial infarction
• amiodarone
• mexidol
• thiotriazolin