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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Synthesis, characterization and anti-inflammatory activity evaluation of 1,2,4-triazole and its derivatives as a potential scaffold for the synthesis of drugs against prostaglandin-endoperoxide synthase
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Synthesis, characterization and anti-inflammatory activity evaluation of 1,2,4-triazole and its derivatives as a potential scaffold for the synthesis of drugs against prostaglandin-endoperoxide synthase

机译：1,2,4-三唑的合成，表征和抗炎活性评价为1,2,4-三唑及其衍生物作为潜在支架，用于合成前列腺素 - 内驱糖氧化物合酶的药物

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Substituted 1,2,4-triazole nucleus is common in several drugs used in a variety of clinical conditions including infections, hypoglycemia, hypertension and cancer. In this study, we synthesized 1,2,4-triazole and its 16 hydrazone derivatives (B1-B16), characterized them by IR, NMR and Mass spectroscopy, and evaluated their radical scavenging and anti-inflammatory activities in vitro and in vivo. Out of 16 derivatives, five (B1, B5, B6, B9, and B13) demonstrated a significant radical scavenging and anti-inflammatory activity in vitro. B6, which possessed two electron-donating hydroxyl groups, was most active among all. Molecular docking and MD simulation of the complex of B6 with prostaglandin-endoperoxide synthase (PTGS) or cyclooxygenase (COX) showed that B6 occupied celecoxib binding site in COX with high affinity (the binding free energy of the complex with COX-1 was -10.5, and -11.2 kcal/mol with COX-2). Maximum anti-inflammatory activity was also shown by the B6 derivative in vivo, in the rat model of carrageenan-induced inflammation. B6, along with four other derivatives (B1, B5, B9 and B13) exhibited 80-90% free radical scavenging activity. The IC50 values of these compounds were >= 40 mu M. Griess nitrite and dichloro-dihydro-fluorescein-diacetate assays suggested a significant inhibition of nitric oxide and reactive oxygen species, especially by B6 and B9. Taken together, out of 16 derivatives, B6 is reported to have highest anti-inflammatory and antioxidant activity at a low dose level, which may be attributed to its two electron-donating hydroxyls. B6 is proposed to be an important scaffold for the synthesis of new drugs against PTGS for use in a myriad of inflammatory and infectious diseases. Communicated by Ramaswamy H. Sarma
机译：取代的1,2,4-三唑核仁在用于各种临床条件的几种药物中很常见，包括感染、低血糖、高血压和癌症。在本研究中，我们合成了1,2,4-三唑及其16个腙衍生物（B1-B16），通过IR、NMR和质谱对其进行了表征，并对其在体内外的自由基清除和抗炎活性进行了评价。在16种衍生物中，5种（B1、B5、B6、B9和B13）在体外表现出显著的自由基清除和抗炎活性。B6具有两个供电子羟基，是所有化合物中最活跃的。B6与前列腺素内过氧化物合酶（PTGS）或环氧化酶（COX）复合物的分子对接和MD模拟显示，B6以高亲和力占据COX中塞来昔布结合位点（与COX-1的复合物的结合自由能为-10.5，与COX-2的结合自由能为-11.2 kcal/mol）。在卡拉胶诱导的大鼠炎症模型中，B6衍生物在体内也显示出最大的抗炎活性。B6以及其他四种衍生物（B1、B5、B9和B13）表现出80-90%的自由基清除活性。这些化合物的IC50值大于等于40μM。格里斯亚硝酸盐和二氯二氢荧光素二乙酸酯分析表明，对一氧化氮和活性氧有显著抑制作用，尤其是B6和B9。综上所述，在16种衍生物中，据报道B6在低剂量水平下具有最高的抗炎和抗氧化活性，这可能归因于其两种供电子羟基。B6被认为是合成抗PTGS新药的重要支架，用于治疗各种炎症和传染病。由拉玛斯瓦米·H·萨尔玛传达

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