Chemico-Biological Interactions ( IF 5.1 ) Pub Date : 2020-05-19 , DOI: 10.1016/j.cbi.2020.109137 Jelena Lazarević 1 , Andrija Šmelcerović 1 , Jelena Zvezdanović 2 , Denitsa Yancheva 3 , Silvana Casati 4 , Roberta Ottria 4 , Pierangela Ciuffreda 4
In the present study eighteen inhibitors of the hydrolytic enzymes of the endocannabinoid system were investigated for antioxidant activity using lipid peroxidation (LP) method. Among the assayed compounds ten belong to carbamates with phenyl [1,1′-biphenyl]-3-ylcarbamate (6), reported for the first time, and eight are retro-amide derivatives of palmitamine. Interestingly, results indicated that most of the tested compounds have good antioxidant properties. In particular, 1,3-di([1,1′-biphenyl]-3-yl)urea (3) shows IC50 = 26 ± 6 μM comparable toones obtained for standard antioxidants trolox and quercetin (IC50 = 22 ± 6 μM and 23 ± 6 μM, respectively). Compound 3 was investigated further by means of ab initio calculations, to clarify a possible mechanism of the antioxidant action. In order to estimate the capability of 3 to act as radical scavenger the structure was optimized at B3LYP/6–311++G⁄⁄ level and the respective bond dissociation enthalpies were calculated. The calculations in non-polar medium predicted as favorable mechanism a donation of a hydrogen atom to the free radical and formation of N-centered radical, while in polar solvents dominate mechanism of free radical scavenging by SPLET over HAT H-abstraction. The possible radical scavenging mechanisms of another compound with potent antioxidant properties (IC50 = 53 ± 12 μM), the retro-amide derivative of palmitamine, compound 18, was estimated computationally based on the reaction enthalpies of a model compound (structural analogue to 18). The computations indicated that the most favorable mechanisms are hydrogen atom transfer from the hydroxyl group in meta-position of the benzamide fragment in nonpolar medium, and proton transfer from the hydroxyl group in ortho-position of the benzamide fragment in nonpolar medium.
中文翻译:
脂质过氧化抑制研究:1,3-二([[1,1'-联苯] -3-基)脲的有前途的案例。
在本研究中,使用脂质过氧化(LP)方法研究了18种内源性大麻素系统水解酶抑制剂的抗氧化活性。在被测定的化合物中,有十种属于氨基甲酸酯,与苯基[1,1'-联苯] -3-基氨基甲酸酯(6)首次报道,而八种是棕榈胺的逆酰胺衍生物。有趣的是,结果表明大多数被测化合物具有良好的抗氧化性能。特别是,1,3-二([[1,1'-联苯] -3-基)脲(3)的IC 50 = 26±6μM,可与标准抗氧化剂trolox和槲皮素获得的酮相比较(IC 50 = 22±6) μM和23±6μM)。化合物3通过从头算来进一步研究,以阐明抗氧化作用的可能机理。为了估计3作为自由基清除剂的能力,在B3LYP / 6–311 ++ G⁄⁄水平上优化了结构,并计算了各自的键解离焓。在非极性介质中的计算预测了将氢原子赠予自由基并形成N中心自由基的有利机理,而在极性溶剂中的计算则是通过SPLET取代HAT H吸收清除自由基的机理。另一种具有强抗氧化剂性能的化合物(IC 50 = 53±12μM)的可能的自由基清除机理,棕榈胺的逆酰胺衍生物,化合物18根据模型化合物的反应焓(结构与18相似)进行计算估算。计算表明,最有利的机理是在非极性介质中氢原子从苯甲酰胺片段间位的羟基转移,以及在非极性介质中氢原子从苯酰胺片段邻位的质子转移。