Mirghani Ahmed Hamdi, Pehlivanoglu Suray, Alici Hakan, Tahtaci Hakan, Uysal Saban
Department of Chemistry, Science Faculty, Karabuk University, Karabuk, Turkey.
Department of Molecular Biology and Genetic, Science Faculty, Necmettin Erbakan University, Konya, Turkey.
J Biochem Mol Toxicol. 2025 Feb;39(2):e70142. doi: 10.1002/jbt.70142.
In this study, four novels 2,5,6-trisubstituted imidazothiadiazole derivative ligands and their Ag(I) complexes were synthesized and characterized using various spectroscopic analysis techniques. First, imidazo[2,1-b][1,3,4]thiadiazole derivative (3) was obtained from the reaction of 5-amino-1,3,4-thiadiazole-2-thiol with benzyl bromide in the presence of KOH in an ethanolic medium. In the next step, the resultant compound reacted sequentially with four substituted phenacyl bromide derivatives (4a-4d) under refluxed ethanol for 24 h to obtain substituted 2-(benzylthio)-6-phenylimidazo[2,1-b][1,3,4]thiadiazole derivatives (5-8). Compounds (9-12) were obtained by attaching a carbonyl group to carbon number 5 of the imidazothiadiazole group in these compounds with the help of Vilsmeier-Haack reagent. The resultant compounds were reacted in an ethanolic medium to synthesize the novel (13-16) ligands by adding ethylenediamine in a 1:2 molar ratio. The Ag(I) complexes of the resultant ligands were synthesized by mixing silver acetate with the ligands in a dimethyl sulfoxide medium to obtain (17-20) complexes. All the synthesized compounds were analyzed using FTIR, H NMR, C NMR, mass spectroscopy, magnetic susceptibility, ICP-OES, and thermogravimetric analysis techniques. The study also investigates the in vitro cytotoxic effect of the ligands and complexes on A549 (nonsmall cell lung cancer) cells using the MTT assay and shows that the 13, 15, and 16 ligands, together with their complexes, exhibit potent cytotoxicity. In addition, in silico molecular docking simulations were conducted both to support the in vitro cytotoxicity experiments and to ascertain the active binding sites and interactions of the ligands and complexes on the EGFR receptor. The result indicates that ligands and complexes may serve as promising candidates for further investigation as anticancer agents.
在本研究中，合成了四种新型的2,5,6-三取代咪唑并噻二唑衍生物配体及其Ag(I)配合物，并使用各种光谱分析技术对其进行了表征。首先，在乙醇介质中，在KOH存在下，5-氨基-1,3,4-噻二唑-2-硫醇与苄基溴反应得到咪唑并[2,1-b][1,3,4]噻二唑衍生物(3)。下一步，所得化合物在回流乙醇中与四种取代苯甲酰溴衍生物(4a - 4d)依次反应24小时，得到取代的2-(苄硫基)-6-苯基咪唑并[2,1-b][1,3,4]噻二唑衍生物(5 - 8)。借助Vilsmeier - Haack试剂，通过在这些化合物的咪唑并噻二唑基团的5位碳原子上连接羰基，得到化合物(9 - 12)。所得化合物在乙醇介质中反应，通过以1:2的摩尔比加入乙二胺合成新型(13 - 16)配体。通过在二甲基亚砜介质中将乙酸银与配体混合，合成所得配体的Ag(I)配合物，得到(17 - 20)配合物。使用傅里叶变换红外光谱(FTIR)、氢核磁共振(H NMR)、碳核磁共振(C NMR)、质谱、磁化率、电感耦合等离子体发射光谱(ICP - OES)和热重分析技术对所有合成的化合物进行了分析。该研究还使用MTT法研究了配体和配合物对A549(非小细胞肺癌)细胞的体外细胞毒性作用，结果表明13、15和16号配体及其配合物表现出强大的细胞毒性。此外，进行了计算机模拟分子对接实验，以支持体外细胞毒性实验，并确定配体和配合物在表皮生长因子受体(EGFR)上的活性结合位点和相互作用。结果表明，配体和配合物有望作为抗癌药物进行进一步研究。
