V. Stavytskyi, I. Nosulenko, K. I. Kandybey
Mar 5, 2020
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Journal
Journal of Organic and Pharmaceutical Chemistry
Abstract
bonded to or moieties a of the “pharmacophore” frag- ment in most NSAID molecules. the carboxyl group may cause the appearance of toxic effects and is characterized by unsatisfactory pharmacokinetic properties. The structural modification of the carboxyl group, including its bioisosteric replacement, is among the most widely used approaches in medicinal chemistry to improve pharmacodynamic, pharmacokinetic and technological characteristics. Aim. To develop the synthetic procedures for functional derivatives of 3-R-2,8-dioxo-7,8-dihydro-2 Н -pyrrolo[1,2- а ]- [1,2,4]triazino[2,3- с ]quinazoline-5 а (6 Н )-carboxylic(-propanoic) acids, study the effect of the carboxyl group chemical modification on the LOX-inhibiting and antiradical activity as a possible mechanism of the pharmaco - logical activity. Results and discussion. The synthesis of esters of 3-(2,8-dioxo-3-R 1 -7,8-dihydro-2 H -pyrrolo[1,2- a ][1,2,4]- triazino[2,3- c ]quinazolin-5 a (6 H )-yl)carboxylic(propanoic) acids was conducted by esterification of the corresponding acids and tandem heterocyclization of 2-(6-R 1 -2,5-dihydro-5-оxo-1,2,4-triazino-3-yl)anilines with diethyl 4-oxo - heptanedioate. The synthesis of amides was conducted by aminolysis of N- acylimidazolides generated in situ . The of approach for the synthesis of the target esters via condensation of 2-(6-R 1 -2,5-dihydro-5-oxo-1,2,4-triazino-3-yl)anilines with diethyl 4-oxoheptanedioate has been proposed. It has been found that the highest radical scavenging and LOX-inhibiting activities are characteristic for hetarylpropa noic acids that contain electron withdrawing substituents in position 3, as well as fluorine atoms in positions 11 and 12. The chemical modification of the carboxylic group in most cases results in a decrease or the loss of the activity.