In order to discover novel compounds with inhibitory activity against 3-phosphoglycerate dehydrogenase (PHGDH), a series of thiourea derivatives were designed and synthesized based on the structural modification of compound 5d. Compound 5d emerged from the visual database of ChemDiv of 200,000 small molecules by docking score ranking. Inhibition experiments on PHGDH activity of newly synthesized compounds were performed in vitro. Compounds with more than 30% inhibitory rate at 25 μM on PHGDH were screened for IC₅₀ measurement. Anti-proliferative activity of 4a, 5a, 6e, 6n against A2780, MDA-MB-468, MDA-MB-231 and HEK293T in vitro was evaluated. The results showed that the compound 4a displayed the best inhibitory activity on PHGDH among the newly synthesized compounds, and the compounds 4a, 5a, 6n had a better proliferation inhibition effect on human A2780 cell line than NCT-503 reported previously. In addition, 2D interaction diagrams revealed potential action modes of active compounds with PHGDH.

中文翻译：

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新型硫脲衍生物作为PHGDH抑制剂的合成与生物学评价

为了发现对3-磷酸甘油酸脱氢酶（PHGDH）具有抑制活性的新型化合物，基于化合物5d的结构修饰，设计并合成了一系列硫脲衍生物。化合物5d通过对接得分排名从200,000个小分子的ChemDiv可视化数据库中出现。在体外进行了对新合成化合物PHGDH活性的抑制实验。筛选了在25μM时对PHGDH抑制率超过30％的化合物以进行IC ₅₀测量。4a，5a，6e，6n的抗增殖活性针对A2780，MDA-MB-468，MDA-MB-231和HEK293T在体外进行了评估。结果表明，所述化合物4a中所显示的最佳抑制活性上PHGDH新合成的化合物中，和所述化合物4a中，图5a，6N对人类A2780细胞系更好增殖抑制效果比NCT - 503以前的报告。另外，二维相互作用图揭示了具有PHGDH的活性化合物的潜在作用方式。