The present paper devoted to the purposeful search of the biologically active compounds among carboxyl-containing quinazolines, [1,2,4]triazolo[1,5-c]quinazolines and their functional derivatives using in silico, in vitro and in vivo methods, elaboration of their preparation methods, studying of their physicochemical properties and anti-inflammatory activity, estimation of “structurebiological activity” correlation, studying of the obtained compounds effects on the level of inflammation biomarkers, evaluation of the promising directions of further structural modification of lead-compounds and recommendation of the most active compounds for advanced studies.
Within the framework of present study 92 compounds were synthesized. For obtained compounds study of their anti-inflammatory activity was conducted at the Training Medical and Laboratory Center of ZSMU, department of pharmacology, pharmacognosy and pharmaceutical botany of ZSMU and department of pharmacology and medical formulation with the course of physiology of ZSMU.
The elaborated strategy for search of the novel anti-inflammatory agents among carboxyl-containing quinazolines, [1,2,4]triazolo[1,5-c]quinazolines and their derivatives allowed to estimate «structure-biological activity» correlations:
•it was found that presence of carboxyl and ethoxy carbonyl fragment is essential for manifestation of high anti-inflammatory activity of corresponding (quinazolin-4(3H)-yliden)hydrazides of mono-(di-)carboxylic acids. The prolongation of linker-group between hydrazide and carboxylic fragment per two or three homological units results decreasing of activity. At the same time introduction of methyl and cyclopropyl fragment to butylene moiety results the increasing of anti-inflammatory activity;
•the substitution of ethoxycarbonyl or carboxyalkyl fragment in molecule of corresponding (quinazoline-4(3H)-yliden)hydrazides by ethoxycarbonylphenyl or carboxyphenyl moiety does not lead to the increasing of activity. The anti-inflammatory activity in this group of compounds changes in the series para- > ortho- > meta-;
•the conversion to planar [1,2,4]triazolo[1,5-c]quinazolines results the loss of the anti-inflammatory activity independently the nature of substituents in positions 2 and 5 of heterocyclic system;
•the synthesis of non-planar dicarboxyl-containing 5,6-dihydro[1,2,4]-triazolo[1,5-c]quinazolines is reasonable approach for synthesis of new anti-inflammatory agents. The increasing of activity was observed in case of introduction of carboxyphenyl group to the position 5 and thoxycarbonyl or 4-ethoxycarbonylphenyl fragment to the position 2;
• annellation of pyrrolidine cycle with carboxy-group or carboxyethyl moiety at the angular (position 4a) carbon atom to a-side of 5,6-dihydro[1,2,4]triazolo[1,5-c]quinazolines results the loss of biological activity independently on the nature of substituents in position 2;
•the modification of carboxylic group in the molecules of corresponding ([1,2,4]triazolo[1,5-с]quinazolin-2-yl)alkyl-(aryl-)carboxylic acids via introduction of moieties of benzyl-(aryl-)amines with «pharmacophore» groups (methoxygroups, halogens) leads to the improvement of anti-inflammatory activity;
•the «small molecules», namely 3-R-2-(5-(2-aminophenyl)-1H-1,2,4-triazoles reveal significant anti-exudative activity. The presence of ethoxycarbonyl or carboxyethyl groups in position 3 is essential for presence of biological activity. The substitution of abovementioned fragments by carboxyphenyl or ethoxycarbonylphenyl moieties leads to the decreasing of activity.
The conducted studies for anti-inflammatory activity allowed to detect the series of the promising compounds that by the level of pharmacological effect competes with reference drug Sodium Diclophenac and require the advanced studies on other experimental models. The analysis of “structure-biological activity” correlations that was conducted for carboxyl-containing quinazolines and their condensed derivatives proved the essential role of carboxylic group for manifestation of anti-inflammatory activity and allowed to determine the promising directions of structural modification.
