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.
Jadavpur University, Kolkata 700032, India.
Eur J Med Chem. 2014 May 6;78:294-303. doi: 10.1016/j.ejmech.2014.03.063. Epub 2014 Mar 21.
In our drug discovery program, a series of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones were designed, synthesized and evaluated for their TP inhibitory potential. All the synthesized analogues conferred a varying degree of TP inhibitory activity, comparable or better than positive control, 7-deazaxanthine (7-DX, 2) (IC50 value = 42.63 μM). A systematic approach to the lead optimization identified compounds 3c and 4a as the most promising TP inhibitors, exhibiting mixed mode of enzyme inhibition. Moreover, selected compounds demonstrated the ability to attenuate the expression of the angiogenic markers (viz. MMP-9 and VEGF) in MDA-MB-231 cells at sublethal concentrations. In addition, molecular docking studies revealed the plausible binding orientation of these inhibitors towards TP, which was in accordance with the experimental results. Taken as a whole, these compounds would constitute a new direction for the design of novel TP inhibitors with promising antiangiogenic properties.
在我们的药物发现计划中，设计、合成并评估了一系列 2-硫代-吡唑并[1,5-a][1,3,5]三嗪-4-酮，以评估它们对 TP 抑制潜力。所有合成的类似物都具有不同程度的 TP 抑制活性，与阳性对照物 7-脱氮黄嘌呤（7-DX，2）（IC50 值= 42.63 μM）相当或更好。对先导化合物的优化确定了化合物 3c 和 4a 作为最有前途的 TP 抑制剂，具有混合的酶抑制模式。此外，在亚致死浓度下，选定的化合物表现出降低 MDA-MB-231 细胞中血管生成标记物（即 MMP-9 和 VEGF）表达的能力。此外，分子对接研究揭示了这些抑制剂与 TP 的可能结合方向，这与实验结果一致。总的来说，这些化合物将为设计具有潜在抗血管生成特性的新型 TP 抑制剂提供新的方向。
