Martynenko Yulya, Antypenko Oleksii, Nosulenko Inna, Berest Galina, Kovalenko Sergii
Department of Organic and Bioorganic Chemistry, Pharmaceutical Faculty No. 2, Zaporizhzhia State Medical University, Zaporizhzhia, Ukraine.
Department of Pharmacognosy with the Course of Botany, Pharmaceutical Faculty No. 2, Zaporizhzhia State Medical University, Zaporizhzhia, Ukraine.
Antiinflamm Antiallergy Agents Med Chem. 2020;19(1):61-73. doi: 10.2174/1871523018666190115092215.
(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.
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.
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.
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.
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.
（喹唑啉-4-亚基）酰肼是现代有机化学中有价值的中间体，因为它们常用于合成取代的[1,2,4]三唑并[1,5-c]喹唑啉。
合成未知的N-酰基-2-（[1,2,4]三唑并[1,5-c]喹唑啉-2-基）-烷基-（烷芳基、芳基）胺，并评估其抗炎潜力。
通过红外光谱、核磁共振光谱和色谱-质谱研究了合成化合物结构的特点，并进行了详细讨论。通过分子对接预测了可能的活性分子机制（COX-1和COX-2的抑制）。通过合成化合物减少大鼠福尔马林诱导的爪肿胀的能力来测定其抗炎活性。双氯芬酸钠用作参考药物。
在本研究中，开发了以N-保护氨基酸的（3H-喹唑啉-4-亚基）酰肼或4-肼基喹唑啉和N-保护氨基酸为起始化合物合成N-乙酰基-（苯甲酰基）-2-（[1,2,4]三唑并[1,5-c]喹唑啉-2-基）-烷基-（芳烷基、芳基）胺的方法。确定了Boc-氨基酸的（3H-喹唑啉-4-亚基）酰肼反应生成N-乙酰基取代的三唑并喹唑啉。使用实验性福尔马林试验检测到未知的Boc-氨基酸（3H-喹唑啉-4-亚基）酰肼（1.13-1.15）和N-乙酰基-（苯甲酰基）-2-（[1,2,4]三唑并[1,5-c]喹唑啉-2-基）-芳烷基-（芳基）胺（3.2、3.3、3.11、3.12）具有高抗炎活性。
进行的构效关系分析允许检测关键片段。即，（3H-喹唑啉-4-亚基）酰肼中的Boc-氨基芳烷基-（芳基）酸残基（1.13-1.15），N-乙酰基-（苯甲酰基）-2-（[1,2,4]三唑并[1,5-c]喹唑啉-2-基）-芳烷基-（芳基）胺中的苄基和苯基连接基团（3.2、3.3、3.11、3.12）被认为对抗炎活性至关重要。
