这项研究的重点是合成和结构表征的新化合物,整合了噻唑烷-2,4-二酮,吖啶部分,还有一个乙酰胺接头,旨在利用这些药效团的协同作用来增强治疗潜力。新设计的分子通过多步过程有效合成,随后转化为其盐酸盐。全面的光谱技术,包括核磁共振(NMR),高分辨率质谱(HRMS),红外(IR)光谱,和元素分析,用于确定合成化合物的分子结构。进行生物学评价以评估新化合物的治疗潜力。评估了这些衍生物对各种癌细胞系代谢活性的影响,通过MTT测定确定IC50值。对结构-活性关系(SAR)的深入分析揭示了对其细胞毒性特征的有趣见解。具有吸电子基团的化合物通常表现出较低的IC50值,表明更高的效力。在连接的苯环上甲氧基的存在调节了化合物的效力和选择性。噻唑烷-2,4-二酮核心氮原子上吖啶核心的变化显着影响了对癌细胞系的活性,与吖啶-9-基取代基增强化合物的抗增殖活性。此外,与游离碱形式相比,盐酸盐形式的化合物对癌细胞系表现出更好的活性。化合物12c·2HCl(IC50=5.4±2.4μM),13d(IC50=4.9±2.9μM),12f·2HCl(IC50=4.98±2.9μM)对HCT116癌细胞系表现出优异的活性,和化合物7d·2HCl(IC50=4.55±0.35μM)对HeLa癌细胞系表现出优异的活性。值得注意的是,只有少数测试化合物,包括7e·2HCl(IC50=11.00±2.2μM),7f(IC50=11.54±2.06μM),和7f·2HCl(IC50=9.82±1.92μM),显示针对胰腺PATU细胞的活性。由于无症状的早期阶段,这种类型的癌症具有非常高的死亡率,转移的发生,和对化疗的频繁抵抗。四种衍生物,即,7e·2HCl,12d·2HCl,13c·HCl,13d,使用荧光光谱研究测试了它们与BSA的相互作用特性。猝灭常数(Ksv)的值在9.59×104至10.74×104M-1的范围内,表明对BSA蛋白具有良好的亲和力。
This study focuses on the synthesis and structural characterization of new compounds that integrate thiazolidine-2,4-dione, acridine moiety, and an acetamide linker, aiming to leverage the synergistic effects of these pharmacophores for enhanced therapeutic potential. The newly designed molecules were efficiently synthesized through a multi-step process and subsequently transformed into their hydrochloride salts. Comprehensive spectroscopic techniques, including nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HRMS), infrared (IR) spectroscopy, and elemental analysis, were employed to determine the molecular structures of the synthesized compounds. Biological evaluations were conducted to assess the therapeutic potential of the new compounds. The influence of these derivatives on the metabolic activity of various cancer cell lines was assessed, with IC50 values determined via MTT assays. An in-depth analysis of the structure-activity relationship (SAR) revealed intriguing insights into their cytotoxic profiles. Compounds with electron-withdrawing groups generally exhibited lower IC50 values, indicating higher potency. The presence of the methoxy group at the linking phenyl ring modulated both the potency and selectivity of the compounds. The variation in the acridine core at the nitrogen atom of the thiazolidine-2,4-dione core significantly affects the activity against cancer cell lines, with the acridin-9-yl substituent enhancing the compounds\' antiproliferative activity. Furthermore, compounds in their hydrochloride salt forms demonstrated better activity against cancer cell lines compared to their free base forms. Compounds 12c·2HCl (IC50 = 5.4 ± 2.4 μM), 13d (IC50 = 4.9 ± 2.9 μM), and 12f·2HCl (IC50 = 4.98 ± 2.9 μM) demonstrated excellent activity against the HCT116 cancer cell line, and compound 7d·2HCl (IC50 = 4.55 ± 0.35 μM) demonstrated excellent activity against the HeLa cancer cell line. Notably, only a few tested compounds, including 7e·2HCl (IC50 = 11.00 ± 2.2 μM), 7f (IC50 = 11.54 ± 2.06 μM), and 7f·2HCl (IC50 = 9.82 ± 1.92 μM), showed activity against pancreatic PATU cells. This type of cancer has a very high mortality due to asymptomatic early stages, the occurrence of metastases, and frequent resistance to chemotherapy. Four derivatives, namely, 7e·2HCl, 12d·2HCl, 13c·HCl, and 13d, were tested for their interaction properties with BSA using fluorescence spectroscopic studies. The values for the quenching constant (Ksv) ranged from 9.59 × 104 to 10.74 × 104 M-1, indicating a good affinity to the BSA protein.