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首页> 外文期刊>Current topics in medicinal chemistry >Synthesis and evaluation of tricyclic dipyrido diazepinone derivatives as inhibitors of secretory phospholipase A2 with anti-inflammatory activity.
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Synthesis and evaluation of tricyclic dipyrido diazepinone derivatives as inhibitors of secretory phospholipase A2 with anti-inflammatory activity.

机译：三环二吡啶基二氮杂吡啶酮衍生物的合成和评估，该衍生物作为具有抗炎活性的分泌型磷脂酶A2的抑制剂。

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摘要

A series of tricyclic dipyrido diazepinone derivatives 6(a-f) bearing different substituents at the tenth position of diazepinone ring were designed and are characterized by 1H NMR, FTIR and X-Ray crystallography studies. The synthesised derivatives are tested in-vitro phospholipase A2 (PLA2) enzyme inhibitory activity and in-vivo anti-inflammatory activity against purified group I and group II PLA2 enzymes from the snake venom and human pleural fluid. Compounds bearing aromatic ring with different substituents at different positions shown varied specificity. The 6f derivative with strong electron withdrawing nitro (-NO2) and trifluoromethyl (-CF3) groups at ortho and para positions respectively shown greater inhibitory activity. Inhibitory effect of the compound appeared to be direct interaction with active site and likely competes with substrates as supported by substrate dependent and calcium independent assays. The IC50 value of potent PLA2 inhibitor 6f was 22.1 microM and showed similar potency inthe neutralization of in vivo PLA2 induced mouse paw edema and hemolytic activity.
机译：设计了一系列在二氮杂庚酮环的第十位带有不同取代基的三环二吡啶基二氮杂庚酮衍生物6（a-f），并通过1 H NMR，FTIR和X射线晶体学研究对其进行了表征。测试了合成的衍生物对蛇毒和人胸膜液中纯化的I和II类PLA2酶的体外磷脂酶A2（PLA2）酶的抑制活性和体内抗炎活性。在不同位置带有带有不同取代基的芳香环的化合物显示出不同的特异性。在邻位和对位分别具有较强的吸电子硝基（-NO2）和三氟甲基（-CF3）基团的6f衍生物显示出更大的抑制活性。该化合物的抑制作用似乎是与活性位点的直接相互作用，并且可能与底物依赖性和钙非依赖性测定所支持的底物竞争。有效的PLA2抑制剂6f的IC50值为22.1 microM，在中和体内PLA2诱导的小鼠爪水肿和溶血活性方面显示出相似的效力。

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