New series of thiazole and imidazo[2,1-b]thiazole derivatives were synthesized and tested for their in vitro anticancer activity. Compounds 27, 34, 39 and 42–44 showed the best anticancer activity against the tested cancer cell lines with high safety profile and selectivity indices, especially MCF-7 breast cancer, compared to sorafenib. As an attempt to reveal their mode of cytotoxicity, EGFR, HER2 kinase and DHFR inhibition assays were performed. Compounds 39 and 43 were the most potent dual EGFR/HER2 kinase inhibitors, with IC₅₀ values of 0.153 (EGFR), 0.108 (HER2) and 0.122 (EGFR), 0.078 (HER2) μM, respectively. 39 and 42 were the best DHFR inhibitors showing IC₅₀ 0.291 and 0.123 μM, respectively. 39 and 43 induced their cytotoxicity via cell cycle arrest at G1/S and G1 phases, respectively, and apoptosis rather than necrosis in the MCF-7 breast cancer cell line. In vivo anti-breast cancer assay of 39 and 43 showed significant tumor volume reduction with recovered caspase-3 immunoexpression. Modeling study results proved the importance of the 5-(4-substituted phenyl)-imidazo[2,1-b]thiazole moiety and the hydrazide side chain for the anticancer activity. The most potent compounds showed good drug-likeness features and could be used as prototypes for further optimization. 39 could be an example of a multi-targeting anticancer agent that acts by inhibiting EGFR/HER2 kinase, DHFR enzymes and cellular apoptosis.

合成了新系列的噻唑和咪唑并[2,1- b ]噻唑衍生物，并对其体外抗癌活性进行了测试。与索拉非尼相比，化合物27、34、39和42-44对测试的癌细胞系显示出最佳的抗癌活性，具有高安全性和选择性指数，尤其是 MCF-7 乳腺癌。作为揭示其细胞毒性模式的尝试，进行了EGFR、HER2激酶和DHFR抑制测定。化合物39和43是最有效的双重 EGFR/HER2 激酶抑制剂，IC ₅₀值分别为 0.153 (EGFR)、0.108 (HER2) 和 0.122 (EGFR)、0.078 (HER2) μM。39和42是最好的 DHFR 抑制剂，IC ₅₀分别为 0.291 和 0.123 μM。39和43分别通过G1/S 和 G1 期的细胞周期停滞和 MCF-7 乳腺癌细胞系中的细胞凋亡而不是坏死来诱导它们的细胞毒性。39和43的体内抗乳腺癌试验显示，随着 caspase-3 免疫表达的恢复，肿瘤体积显着减小。建模研究结果证明了5-(4-取代苯基)-咪唑[2,1- b]噻唑部分和酰肼侧链具有抗癌活性。最有效的化合物显示出良好的药物相似特征，可用作进一步优化的原型。39可能是通过抑制 EGFR/HER2 激酶、DHFR 酶和细胞凋亡起作用的多靶向抗癌剂的一个例子。