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

[ Vol. 19 , Issue. 1 ]

Author(s):

Yulya Martynenko*, Oleksii Antypenko , Inna Nosulenko, Galina Berest and Sergii Kovalenko   Pages 61 - 73 ( 13 )

Abstract:


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]quinazolinŠµ- 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.

Keywords:

(3H-quinazoline-4-ylidene)hydrazides N-protected amino acids, [1, 2, 4]triazolo[1, 5-c]quinazolines, anti-inflammatory activity, molecular docking, SAR-analysis, heterocyclization products.

Affiliation:

Department of Organic and Bioorganic Chemistry, Pharmaceutical Faculty No. 2, Zaporizhzhia State Medical University, Zaporizhzhia, Department of Organic and Bioorganic Chemistry, Pharmaceutical Faculty No. 2, Zaporizhzhia State Medical University, Zaporizhzhia, Department of Pharmacognosy with the Course of Botany, Pharmaceutical Faculty No. 2, Zaporizhzhia State Medical University, Zaporizhzhia, Department of Pharmacognosy, Pharmaceutical Chemistry and Medicinal Preparations Technology, Faculty of Post-graduate Education, Zaporizhzhia State Medical University, Zaporizhzhia, Department of Organic and Bioorganic Chemistry, Pharmaceutical Faculty No. 2, Zaporizhzhia State Medical University, Zaporizhzhia

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