Gudala Satish, Sharma Archi, Lankada Aruna, Liu Ruotong, Jha Anubhuti, Penta Santhosh, Dar Owias Iqbal, Yang Jianxin
Department of Chemistry, National Institute of Technology, Raipur, Chhattisgarh 492010, India.
Key Laboratory of Green Catalysis and Reaction Engineering of Haikou, College of Chemistry and Chemical Engineering, Hainan University, Haikou 570228, People's Republic of China.
ACS Omega. 2024 Aug 29;9(36):38262-38271. doi: 10.1021/acsomega.4c05587. eCollection 2024 Sep 10.
A facile, green, one-pot multicomponent synthesis strategy was employed to fabricate novel thiazole scaffolds incorporating phthalazine, pyridazine, and pyrido-pyridazine derivatives (-). This synthetic route entailed the reaction of an α-halo carbonyl compound () with thiosemicarbazide () and various anhydrides (-), utilizing NiFeO nanoparticles as a reusable catalyst in an ethanol:water (1:1) solvent system. The cytotoxicity of the synthesized compounds was meticulously assessed against three cancer cell lines, A375, HeLa, and MCF-7, employing IC values (μM) as the benchmark, and compared to the reference drug erlotinib. Compound displayed remarkable efficacy against A375 (0.87 ± 0.31 μM), HeLa (1.38 ± 1.24 μM), and MCF-7 (1.13 ± 0.96 μM) cell lines, significantly surpassing erlotinib's IC values. Additionally, compounds , , , and demonstrated notable cytotoxicity across all tested cell lines, indicating their potential as effective anticancer agents. docking studies against Hsp82 and Hsp90 proteins indicated that ligands , , , , , and had superior binding affinities compared to erlotinib. ADME analysis showed that compounds , , , , and had favorable pharmacokinetic profiles, including nontoxicity, high human intestinal absorption, and low CYP inhibitory promiscuity. Structure-activity relationship analysis revealed that cyano and benzylidene substitutions significantly enhanced anticancer activity. Overall, the synthesized compounds, particularly , demonstrated high efficacy, favorable binding interactions, and promising pharmacokinetic profiles, making them strong candidates for further development as anticancer agents.
采用一种简便、绿色的一锅多组分合成策略，制备了包含酞嗪、哒嗪和吡啶并哒嗪衍生物（-）的新型噻唑支架。该合成路线涉及α-卤代羰基化合物（）与硫代氨基脲（）和各种酸酐（-）的反应，在乙醇：水（1:1）溶剂体系中使用NiFeO纳米颗粒作为可重复使用的催化剂。以IC值（μM）为基准，对合成化合物对三种癌细胞系A375、HeLa和MCF-7的细胞毒性进行了细致评估，并与参考药物厄洛替尼进行了比较。化合物对A375（0.87±0.31μM）、HeLa（1.38±1.24μM）和MCF-7（1.13±0.96μM）细胞系显示出显著疗效，明显超过厄洛替尼的IC值。此外，化合物、、和在所有测试细胞系中均表现出显著的细胞毒性，表明它们作为有效抗癌剂的潜力。针对Hsp82和Hsp90蛋白的对接研究表明，与厄洛替尼相比，配体、、、、和具有更高的结合亲和力。ADME分析表明，化合物、、、和具有良好的药代动力学特征，包括无毒性、高人体肠道吸收和低CYP抑制混杂性。构效关系分析表明，氰基和亚苄基取代显著增强了抗癌活性。总体而言，合成的化合物，特别是，显示出高效、良好的结合相互作用和有前景的药代动力学特征，使其成为进一步开发为抗癌剂的有力候选物。
