Directed Search of Anti-inflammatory Agents Among (3HQuinazoline- 4-ylidene)hydrazides of N-protected Amino acids and their Heterocyclization Products.

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.

Directed Search of Biologically Active Compounds among Hydrogenated Isoindolylalkyl(alkylaryl-,aryl-)carboxylic Acids with Quinazoline Fragment that Modify the Carbohydrate Metabolism: Design, Synthesis and Modification.

An effective synthesis of (3H-quinazoline-4-ylidene)hydrazides of N-carboxyalkyl-(arylalkyl-,aryl-)isoindoline-1,3-diones, using activated N-protected aminoacids and 4-hydrazinoquinazoline was proposed in the framework methodology of directed search of hypoglycemic agents (fragment-oriented design, molecular docking). These hydrazides prepared via cyclocondensation under acid catalysis were converted to the corresponding 2-([1,2,4]triazolo[1,5-c]quinazoline-2-yl-) alkyl-(alkylaryl-,aryl-)-hydroisoindole-1,3(2H)-diones. The structure of synthesized compounds was established using IR, 1H and 13C NMR spectroscopy and LC-MS and the features of spectral pattern were discussed. The results of pharmacological screening revealed a series of compounds, that are short-acting hypoglycemic agents like prandial regulators of glucose (Mitiglinide). The SAR analysis showed, that the introduction of a hydrogenated 1,3-dioxoisoindole moiety bonded through linker groups with 4-hydrazinoquinazoline and triazolo[1,5-c]quinazoline cycles is reasonable in the context of searching for short-acting hypoglycemic agents and requires further research.