Background: (Quinazoline-4-ylidene)hydrazides are valued intermediates in modern organic chemistry, as they are commonly used for the synthesis of substituted [1,2,4]triazolo[1,5-c]quinazolines.
Objective: Unknown N-acyl-2-([1,2,4]triazolo[1,5-c]quinazoline-2-yl)-alkyl-(alkaryl-, aryl-) amines were synthesized and evaluated for anti-inflammatory potential.
Methods: The peculiarities of the synthesized compounds structures were studied by IR-, NMR spectroscopy and chromatography-mass spectrometry and were discussed in detail. Probable molecular mechanisms of activity (inhibition of COX-1 and COX-2) were predicted due to molecular docking. Anti-inflammatory activity of synthesized compounds was determined by their ability to reduce the formalin-induced paw edema in rats. Diclofenac sodium was used as reference drug.
Results: In this study, the synthesis of N-acetyl-(benzoyl)-2-([1,2,4]triazolo[1,5-c]quinazolinе- 2-yl)alkyl-(aralkyl-, aryl-)amines, using (3H-quinazoline-4-ylidene)hydrazides of Nprotected amino acids or 4-hydrazinoquinazoline and N-prorotected amino acids as starting compounds was developed. It was established that the reaction of (3H-quinazoline-4- ylidene)hydrazides of Boc-amino acids occurred with the formation of N-acetyl-substituted triazoloquinazolines. High anti-inflammatory activity was detected for unknown (3Hquinazoline- 4-ylidene)hydrazides Boc-amino acids (1.13-1.15) and N-acetyl-(benzoyl)-2- ([1,2,4]triazolo[1,5-c]quinazoline-2-yl-)aralkyl-(aryl-)amines (3.2, 3.3, 3.11, 3.12), using the experimental formalin test.
Conclusion: The conducted SAR-analysis allowed to detect critical fragments. Namely, the Boc-aminoaralkyl-(aryl-)acid residue in (3H-quinazoline-4-ylidene)hydrazides (1.13- 1.15), benzyl and phenyl linker groups in N-acetyl-(benzoyl)-2-([1,2,4]triazolo[1,5- c]quinazoline-2-yl-)aralkyl-(aryl-) amines (3.2, 3.3, 3.11, 3.12) are believed to be substantial for anti-inflammatory activity.
[http://dx.doi.org/10.3797/scipharm.1211-08] [PMID: 23833709]
[http://dx.doi.org/10.1021/jm00105a044] [PMID: 1846920]
[http://dx.doi.org/10.1021/jm980094b] [PMID: 9667972]
[http://dx.doi.org/10.1016/j.bmcl.2011.04.067] [PMID: 21602043]
[http://dx.doi.org/10.1016/j.ejmech.2011.10.018] [PMID: 22071254]
[http://dx.doi.org/10.1039/C7MD00209B] [PMID: 30108882]