Kamboj Payal, Alam Ozair, Patel Harun, Ahmad Iqrar, Ahmad Syed Sufian, Amir Mohd
Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.
Department of Pharmaceutical Chemistry, Division of Computer Aided Drug Design, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India.
Arch Pharm (Weinheim). 2024 Jan;357(1):e2300301. doi: 10.1002/ardp.202300301. Epub 2023 Oct 17.
A new series of quinoxaline derivatives possessing the hydrazone moiety were designed, synthesized, and screened for in-vitro anti-inflammatory activity by the bovine serum albumin (BSA) denaturation technique, and for antioxidant activity, by the (2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. The synthesized compounds were also tested for p38α mitogen-activated protein (MAP) kinase inhibition. The in-vivo anti-inflammatory activity was assessed by the carrageenan-induced rat paw edema inhibition method. All the compounds (4a-n) exhibited moderate to high in-vitro anti-inflammatory activity. Compound 4a displayed the highest inhibitory activity in the BSA assay (83.42%) in comparison to the standard drug diclofenac sodium (82.90%), while 4d exhibited comparable activity (81.87%). The DPPH assay revealed that compounds 4a and 4d have free radical scavenging potential (74.70% and 74.34%, respectively) comparable to the standard butylated hydroxyanisole (74.09%). Furthermore, the p38α MAP kinase inhibition assay demonstrated that compound 4a is highly selective against p38α MAP kinase (IC = 0.042) in comparison to the standard SB203580 (IC = 0.044). The five most active compounds (4a-4d and 4f) with good in-vitro profiles were selected for in-vivo anti-inflammatory studies. Compounds 4a and 4d were found to display the highest activity (83.61% and 82.92% inhibition, respectively) in comparison to the standard drug diclofenac sodium (82.65% inhibition). These compounds (4a and 4d) also exhibited better ulcerogenic and lipid peroxidation profiles than diclofenac sodium. The molecular docking and molecular dynamics simulation studies were also performed and found to be in agreement with the p38α MAP kinase inhibitory activity.
设计、合成了一系列含有腙部分的喹喔啉衍生物，并通过牛血清白蛋白（BSA）变性技术对其体外抗炎活性进行筛选，通过（2,2'-二苯基-1-苦基肼基（DPPH）自由基清除试验对其抗氧化活性进行筛选。还对合成的化合物进行了p38α丝裂原活化蛋白（MAP）激酶抑制测试。通过角叉菜胶诱导的大鼠足肿胀抑制法评估体内抗炎活性。所有化合物（4a - n）均表现出中度至高的体外抗炎活性。与标准药物双氯芬酸钠（82.90%）相比，化合物4a在BSA试验中显示出最高的抑制活性（83.42%），而4d表现出相当的活性（81.87%）。DPPH试验表明，化合物4a和4d具有与标准丁基羟基茴香醚（74.09%）相当的自由基清除潜力（分别为74.70%和74.34%）。此外，p38α MAP激酶抑制试验表明，与标准SB203580（IC = 0.044）相比，化合物4a对p38α MAP激酶具有高度选择性（IC = 0.042）。选择了五种具有良好体外特性的活性最高的化合物（4a - 4d和4f）进行体内抗炎研究。与标准药物双氯芬酸钠（82.65%抑制率）相比，发现化合物4a和4d表现出最高活性（分别为83.61%和82.92%抑制率）。这些化合物（4a和4d）还表现出比双氯芬酸钠更好的致溃疡和脂质过氧化特性。还进行了分子对接和分子动力学模拟研究，发现与p38α MAP激酶抑制活性一致。
