Background: Computer-aided drug design is among the most effective methods of medicinal
chemistry. The above mentioned approach is used for the purposeful search of antiinflammatory
agents among quinazoline condensed derivatives.
Objective: The study aimed to conduct a purposeful synthesis of novel 3-R-2,8-dioxo-7,8-dihydro-
2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline-5a(6H)carboxylic acids and their salts as promising
anti-inflammatory agents, evaluate their structure by physicochemical methods and establish
their anti-inflammatory activity.
Methods: The structures of target compounds were proposed due to their structure similarity to existing
drugs and experimental agents with anti-inflammatory activities. The features of the synthesized
compounds structures were evaluated by IR-, NMR spectroscopy and chromatography-mass
spectrometry and discussed in detail. Probable molecular mechanisms of activity were predicted by
molecular docking. The anti-inflammatory activity was determined by their ability to reduce the
formalin- and carrageenan-induced paw edema in rats.
Results: It was found that the condensation of 3-(2-aminophenyl)-6-R-1,2,4-triazin-5(2H)ones with
2-oxoglutaric acid yielded 3-R-2,8-dioxo-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline-
5a(6H)carboxylic acids which may be considered as a promising anti-inflammatory agent.
An in silico study showed that the obtained compounds revealed affinity to the molecular targets
and corresponded to the drug-like criteria. Additionally docking study allowed to estimate the nature
of interactions between synthesized compounds and molecular targets. The in vivo experiments
showed that the obtained compounds demonstrated significant anti-inflammatory activity comparable
or higher than the activity of the reference drug Diclofenac.
Conclusion: The developed and implemented search strategy of the anti-inflammatory agents was
acids possessed the anti-inflammatory activity and additional introduction of fluorine atoms
in position 11 or 12 of the heterocyclic system led to amplification of this activity.