Gokaraju Rangaraju College of Pharmacy, Bachupally, Hyderabad 500090, India; Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
Bioorg Chem. 2013 Oct;50:34-40. doi: 10.1016/j.bioorg.2013.07.004. Epub 2013 Aug 2.
In our lead finding program, a series of 5-thioxo-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ones and their 5-thio-alkyl derivatives were designed and synthesized which contained different substituents at ortho-position of 2-phenyl ring attached to the fused ring structure. The preliminary pharmacological evaluation demonstrated that the synthesized compounds exhibited a varying degree of inhibitory activity towards thymidine phosphorylase (TP), comparable to reference compound, 7-Deazaxanthine (7-DX, 2) (IC50 value=42.63 μM). The study also inferred that the ortho-substituted group at the phenyl ring and 5-thio-alkyl moiety imparted steric hindrance effects in the binding site of the enzyme, leading to a reduced inhibitory response. In addition, compound 3a was identified as a mixed-type inhibitor of TP. Moreover, computational docking study was performed to illustrate the important structural information on the plausible ligand-enzyme binding interactions.
在我们的先导化合物发现计划中，设计并合成了一系列 5-硫代-[1,2,4]三唑并[1,5-a][1,3,5]三嗪-7-酮及其 5-硫代烷基衍生物，它们在连接到稠环结构的 2-苯基环的邻位具有不同的取代基。初步的药理学评价表明，合成的化合物对胸苷磷酸化酶（TP）表现出不同程度的抑制活性，与参考化合物 7-脱氮黄嘌呤（7-DX，2）（IC50 值=42.63 μM）相当。该研究还推断，苯环上的邻位取代基和 5-硫代烷基部分在酶的结合部位赋予了空间位阻效应，导致抑制反应降低。此外，化合物 3a 被鉴定为 TP 的混合类型抑制剂。此外，还进行了计算对接研究，以说明可能的配体-酶结合相互作用的重要结构信息。
