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 <b>3</b> and thiazolidinedione <b>4</b>. <i>In silico</i> 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 <b>3</b> 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.癌症是全球范围内影响数百万人的重大疾病。3-磷酸肌醇依赖性蛋白激酶1（PDK1，与BIM-1共结晶）可调控乳腺癌细胞的增殖。为模拟BIM-1的结合模式，研究人员以2-氯-3-甲酰基喹啉为起始原料，合成了一系列喹啉类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，针对MCF7与HCT116癌细胞系的体外抗增殖活性实验显示，硫代巴比妥酸类化合物<b>3</b>与噻唑烷二酮类化合物<b>4</b>的活性最为显著。计算机模拟（In silico）分子对接、密度泛函理论（DFT）以及药代动力学模拟实验均验证了该研究结果。针对PDK1酶的对接分析结果显示，多数与共结晶配体BIM-1相互作用的氨基酸残基，均可与本研究中的待对接化合物形成有效结合，其中硫代巴比妥酸类化合物<b>3</b>的S评分最高，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柔软度，使其更易与自由基表面发生相互作用。具有显著抗增殖活性的化合物均表现出较高的亲电指数。吸收-分布-代谢-排泄（ADME）分析显示该类化合物具备良好的类药性质与口服生物利用度。本研究可为新型强效抗增殖药物的开发提供参考。