3'-R-Spiro[cycloalkyl-1(2), (hetaryl-3(4), 6'-[1,2,4]triazino[2,3-c]quinazoline]-2'(7'H)-2-оnes as a perspective class of compounds with actoprotective activity

Abstract

Quinazolines and their derivatives are a perspective class of compounds with versatile biological activities. Their representatives are used in medical practice as sleeping, diuretic, antimicrobial and antitumor drugs. Continuing our search of perspective compounds with actprotective activity among azolo-(azino-)[c]quinazoline derivatives it was decided to combine the mentioned above heterocyclic system with carbocyclic or heterocyclic fragments in one molecule. Moreover, an affinity to melanocortin-4, nociceptin (NOP), adenosine, GABA and glutamine receptors among spiropiperidines, spiropiperidinoquinazolines, spiropiperidinotriazoloquinazolines, spiroindolinoquinazolines and others was found and as a rule they exhibit neuroprotective, neurotrophic, anti-inflammatory and other actions. Aim. The aim of the present work was the primary screening of actoprotective activity among novel 3'-R-spiro [cycloalkyl-1(2), (hetaryl-3(4), 6')-[1,2,4]triazino[2,3-c]quinazoline]-2'(7'H)-2-ones, estimating of antiradical activity as the possible mechanism of actoprotection and the evaluation of perspectivity of further profound researches for high-active compounds. Materials and methods. Actprotective activity of perspective and unknown 3´-R-spiro[cycloalkyl-1(2), (hetaryl-3(4), 6´-[1,2,4]triazino[2,3-c]quinazoline]-2´(7´H)-2-ones was studied using the swimming test at the temperature 24–26 °C (normothermia) with additional load (10 % from the weight of experimental animal). The experiment was carried out on white Wistar rats and “Mildronate” was used as a reference drug. Results and discussion. It was found, that most of the tested compounds being intragastrically administrated increased the duration of experimental animals swimming in dose of 50 mg/kg in conditions of normothermia. Also, we found a number of high active compounds (1.6, 1.11, 1.12, 1.18, 1,19, 1.25), that were superior to the reference drug “Mildronate” by the level of actoprotection on 13.2–47.8 %. It was shown that there is no reliable dependence between actoprotective and antiradical activities among 3´-R-spiro[cycloalkyl-1(2), (hetaryl-3(4), 6´-[1,2,4]triazino[2,3-c]quinazoline]-2´(7´H)-2-ones. The analysis of “structure–activity” correlation showed that critical factors in revealing of high actprotective action is not only the size and nature of spirocycle of position 6, but also a substituent in position 3 of triazino[2,3-c]quinazoline system. The most active compounds 1.6, 1.11, 1.12, 1.18, 1.19 and 1.25 were recommended for further pharmacological studies. 3'-R-spiro[cycloalkyl-1(2); (hetaryl-3(4); 6'-1,2,4]triazino[2,3-c]quinazoline]-2'(7'H)-2-оnes; swimming test; normothermia; actoprotective and antiradical activities

Keywords

• 3'-R-spiro[cycloalkyl-1(2)
• 3-c]quinazoline]-2'(7'H)-2-оnes
• swimming test
• normothermia
• actoprotective and antiradical activities