1,2,4‐Triazole‐conjugated 1,3,4‐thiadiazole hybrid scaffolds: A potent ameliorant of carrageenan‐induced inflammation by lessening proinflammatory mediators,Archiv der Pharmazie

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1,2,4‐Triazole‐conjugated 1,3,4‐thiadiazole hybrid scaffolds: A potent ameliorant of carrageenan‐induced inflammation by lessening proinflammatory mediators
Archiv der Pharmazie ( IF 4.3 ) Pub Date : 2019-11-07 , DOI: 10.1002/ardp.201900233
Prateek Pathak ₁ , Parjanya K Shukla _{2,

3} , Vladislav Naumovich ₁ , Maria Grishina ₁ , Amita Verma ₂ , Vladimir Potemkin ₁

Affiliation

Inflammation acts as an alarming signal for the progression of various biological complications. Various reports in the literature have revealed that heterocycle‐containing synthetic compounds have a restorative capability against acute and chronic inflammatory stages. In the current study, we synthesized a series of 1,2,4‐triazole‐conjugated 1,3,4‐thiadiazole hybrid scaffolds and evaluated their impacts against carrageenan‐induced paw edema and proinflammatory markers in Wistar rats. Further, 3D QSAR study (three‐dimensional quantitative structure–activity relationships), ADMET (absorption, distribution, metabolism, and excretion) profiling, and docking studies were performed to determine the possible mechanism of the action of the derivatives. The study shows that the most active derivatives, 13f and 13g, have optimal logP, a higher anti‐inflammatory activity score, and poor metabolism at various sites of cytochrome P450. The docking studies recommended that the synthesized compounds have a similar affinity as the ligands A307, 63X, and S58 to interact with tumor necrosis factor‐α, COX‐1, and COX‐2. So, these molecules will definitely hold a promise for the future drug development initiative.

中文翻译：

1,2,4-三唑偶联的 1,3,4-噻二唑杂化支架：通过减少促炎介质有效改善角叉菜胶诱导的炎症

炎症是各种生物并发症进展的警报信号。文献中的各种报道表明，含杂环的合成化合物具有针对急性和慢性炎症阶段的修复能力。在目前的研究中，我们合成了一系列 1,2,4-三唑偶联的 1,3,4-噻二唑杂化支架，并评估了它们对 Wistar 大鼠角叉菜胶诱导的爪水肿和促炎标志物的影响。此外，还进行了 3D QSAR 研究（三维定量结构-活性关系）、ADMET（吸收、分布、代谢和排泄）分析和对接研究，以确定衍生物作用的可能机制。研究表明，最活跃的衍生物 13f 和 13g 具有最佳的 logP，较高的抗炎活性评分，以及细胞色素 P450 各个位点的代谢不良。对接研究表明，合成的化合物与配体 A307、63X 和 S58 具有相似的亲和力，可与肿瘤坏死因子-α、COX-1 和 COX-2 相互作用。因此，这些分子肯定会为未来的药物开发计划带来希望。

更新日期：2019-11-07

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