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

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 <i>in vitro</i> and <i>in vivo</i>. Out of 16 derivatives, five (B1, B5, B6, B9, and B13) demonstrated a significant radical scavenging and anti-inflammatory activity <i>in vitro</i>. 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 <i>in vivo,</i> 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 µM. 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

取代1,2,4-三唑母核（substituted 1,2,4-triazole nucleus）广泛存在于用于多种临床病症的各类药物中，涉及感染、低血糖症、高血压及癌症等病症。本研究中，我们合成了1,2,4-三唑及其16种腙类衍生物（编号B1–B16），并通过红外光谱（IR）、核磁共振波谱（NMR）与质谱（Mass spectroscopy）对其进行结构表征，同时在体外（in vitro）与体内（in vivo）水平评估了其自由基清除活性与抗炎活性。在16种衍生物中，有5种（B1、B5、B6、B9及B13）在体外展现出显著的自由基清除与抗炎活性，其中带有两个供电子羟基的B6活性最强。对B6与前列腺素内过氧化物合酶（prostaglandin-endoperoxide synthase, PTGS，又称环氧化酶cyclooxygenase, COX）形成的复合物开展分子对接与分子动力学模拟，结果显示B6可高亲和力结合环氧化酶中的塞来昔布（celecoxib）结合位点：其与COX-1复合物的结合自由能为-10.5 kcal/mol，与COX-2复合物的结合自由能为-11.2 kcal/mol。在角叉菜胶诱导的大鼠炎症模型体内实验中，B6同样展现出最优的抗炎活性。B6与其余四种衍生物（B1、B5、B9及B13）的自由基清除率可达80%–90%，其半数抑制浓度（IC₅₀）值≥40 μM。格里斯亚硝酸盐（Griess nitrite）与二氯二氢荧光素二乙酸酯（dichloro-dihydro-fluorescein-diacetate）检测结果表明，这些衍生物可显著抑制一氧化氮与活性氧的生成，其中尤以B6与B9的抑制效果最为突出。综上，在16种衍生物中，B6被证实于低剂量下具备最优的抗炎与抗氧化活性，这一特性可归因于其含有的两个供电子羟基。研究认为，B6可作为重要的母核结构，用于合成靶向PTGS的新型药物，以应对各类炎症与感染性疾病。本文由Ramaswamy H. Sarma通讯。