A series of imidazothiazole derivatives possessing potential activity against melanoma cells were investigated for molecular mechanism of action. The target compounds were tested against V600E-B-RAF and RAF1 kinases. Compound 1zb is the most potent against both kinases with IC₅₀ values 0.978 and 8.2 nM, respectively. It showed relative selectivity against V600E mutant B-RAF kinase. Compound 1zb was also tested against four melanoma cell lines and exerted superior potency (IC₅₀ 0.18-0.59 µM) compared to the reference standard drug, sorafenib (IC₅₀ 1.95-5.45 µM). Compound 1zb demonstrated also prominent selectivity towards melanoma cells than normal skin cells. It was further tested in whole-cell kinase assay and showed in-cell V600E-B-RAF kinase inhibition with IC₅₀ of 0.19 µM. Compound 1zb induces apoptosis not necrosis in the most sensitive melanoma cell line, UACC-62. Furthermore, molecular dynamic and 3D-QSAR studies were done to investigate the binding mode and understand the pharmacophoric features of this series of compounds.

研究了一系列对黑素瘤细胞具有潜在活性的咪唑并噻唑衍生物的分子作用机理。测试了目标化合物的V600E-B-RAF和RAF1激酶。化合物1zb对两种激酶最有效，IC ₅₀值分别为0.978和8.2 nM。它显示出对V600E突变B-RAF激酶的相对选择性。化合物1zb还针对四种黑色素瘤细胞系进行了测试，与参考标准药物索拉非尼（IC ₅₀ 1.95-5.45 µM）相比，具有更高的效价（IC ₅₀ 0.18-0.59 µM）。化合物1zb证明对黑素瘤细胞的选择性也比正常皮肤细胞高。它已在全细胞激酶测定中进一步测试，并显示出细胞内V600E-B-RAF激酶抑制作用，IC ₅₀为0.19 µM。化合物1zb在最敏感的黑色素瘤细胞系UACC-62中诱导凋亡而不是坏死。此外，进行了分子动力学和3D-QSAR研究以研究结合模式并了解该系列化合物的药效学特征。