Synthesis, antiproliferative activity, and <i>in silico</i> studies of quinoline-based pyrimidinedione and thiazolidinedione derivatives

Cancer affects millions of people worldwide. PDK1 enzyme (co-crystallized with BIM-1) controls the proliferation of breast cancer cells. Aiming to resemble BIM-1’s binding, quinoline-based pyrimidinediones and thiazolidinediones were synthesized starting from 2-chloro-3-formylquinoline. Compared with doxorubicin (reference), in vitro antiproliferative activity against MCF7 and HCT116 cancer cell lines showed the most potency of thiobarbiturate 3 and thiazolidinedione 4. In silico molecular docking, DFT, and pharmacokinetics simulations supported the findings. The docking analysis toward PDK1 enzyme showed that most amino acids interacting with co-crystallized ligand (BIM-1) were successfully bonded to our docked substances, especially thiobarbiturate 3 with highest S-score closer to BIM-1. In DFT calculations, this compound exhibited the lowest energy gap and highest softness leading to more response to radical surface interactions. The compounds with significant antiproliferative activity exhibited high electrophilicity values. ADME analysis showed its desirable drug-likeness and oral bioavailability. This work may contribute to developing new potent antiproliferative agents.癌症在全球范围内影响数百万人的健康。3-磷酸肌醇依赖蛋白激酶1（PDK1）酶（与BIM-1共结晶）可调控乳腺癌细胞的增殖过程。为模拟BIM-1的结合模式，本研究以2-氯-3-甲酰基喹啉为起始原料，合成了一系列喹啉基嘧啶二酮与噻唑烷二酮类化合物。以多柔比星（doxorubicin，阳性对照）为参照，在针对MCF7与HCT116癌细胞系的体外抗增殖活性实验中，硫代巴比妥酸酯3与噻唑烷二酮4展现出最优的抗增殖活性。虚拟分子对接（in silico）、密度泛函理论（DFT）与药代动力学模拟验证了上述实验结果。针对PDK1酶的分子对接分析显示，与共结晶配体（BIM-1）相互作用的多数氨基酸残基，均可与本研究合成的受试化合物形成有效结合；其中硫代巴比妥酸酯3的S得分最高，且与BIM-1的结合亲和力最为接近。在DFT计算中，该化合物展现出最低的能隙与最高的分子柔软度，使其更易与自由基表面发生相互作用。具备显著抗增殖活性的化合物均表现出较高的亲电指数。ADME（吸收-分布-代谢-排泄）分析显示该类化合物具有良好的类药特性与口服生物利用度。本研究可为新型高效抗增殖制剂的开发提供有益参考。