Abstract

Oxazolidinone hydroxamic acid derivatives were synthesised and evaluated for inhibitory activity against leukotriene (LT) biosynthesis in three in vitro cell-based test systems and on direct inhibition of recombinant human 5-lipoxygenase (5-LO). Thirteen of the 19 compounds synthesised were considered active ((50% inhibitory concentration (IC₅₀) ≤ 10 µM in two or more test systems)). Increasing alkyl chain length on the hydroxamic acid moiety enhanced activity and morpholinyl-containing derivatives were more active than N-acetyl-piperizinyl derivatives. The IC₅₀ values in cell-based assay systems were comparable to those obtained by direct inhibition of 5-LO activity, confirming that the compounds are direct inhibitors of 5-LO. Particularly, compounds PH-249 and PH-251 had outstanding potencies (IC₅₀ < 1 µM), comparable to that of the prototype 5-LO inhibitor, zileuton. Pronounced in vivo activity was demonstrated in zymosan-induced peritonitis in mice. These novel oxazolidinone hydroxamic acid derivatives are, therefore, potent 5-LO inhibitors with potential application as anti-allergic and anti-inflammatory agents.

摘要

合成了恶唑烷酮异羟肟酸衍生物，并在三个体外基于细胞的测试系统中评估了对白三烯（LT）生物合成的抑制活性，并直接抑制了重组人5-脂氧合酶（5-LO）。合成的19种化合物中有13种被认为具有活性（（在两个或多个测试系统中，50％抑制浓度（IC ₅₀）≤10 µM））。异羟肟酸部分上烷基链长度的增加增强了活性，并且含有吗啉基的衍生物比N-乙酰基-哌嗪基衍生物更具活性。IC ₅₀基于细胞的测定系统中的值与通过直接抑制5-LO活性获得的值相当，这证实了这些化合物是5-LO的直接抑制剂。尤其是，化合物PH-249和PH-251具有出色的效力（IC ₅₀ <1 µM），与原型5-LO抑制剂齐留通的效价相当。发音的体内活性证实在小鼠酵母聚糖诱导的腹膜炎。因此，这些新颖的恶唑烷酮异羟肟酸衍生物是有效的5-LO抑制剂，具有潜在的抗过敏和消炎作用。