Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC), Dokki, Giza 12622, Egypt.
Center for Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu 02792, Republic of Korea; University of Science & Technology (UST), Daejeon, Yuseong-gu 34113, Republic of Korea; Department of Biomolecular Science, University of Science & Technology (UST), Daejeon, Yuseong-gu 34113, Republic of Korea; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza 12566, Egypt.
Bioorg Med Chem. 2019 May 15;27(10):2041-2051. doi: 10.1016/j.bmc.2019.03.062. Epub 2019 Apr 2.
In this work, a new series of imidazo[2,1-b]thiazole was designed and synthesized. The new compounds are having 3-fluorophenyl at position 6 of imidazo[2,1-b]thiazole and pyrimidine ring at position 5. The pyrimidine ring containing either amide or sulphonamide moiety attached to a linker (ethyl or propyl) at position 2 of the pyrimidine ring. The final compounds were selected by NCI for in vitro cytotoxicity screening. Most derivatives showed cytotoxic activity against colon cancer and melanoma cell lines. In addition, ICs of the target compounds were determined over A375 and SK-MEL-28 cell lines using sorafenib as positive control. Compounds12b, 12c, 12e, 12f, 15a, 15d, 15f, 14g and 15h exhibited superior activity when compared to sorafenib. The most potent compounds were tested against wild type BRAF, v600e BRAF, and CRAF. Compound 15h exhibited a potential inhibitory effect againstBRAF (IC = 9.3 nM).
在这项工作中，设计并合成了一系列新的咪唑并[2,1-b]噻唑。这些新化合物在咪唑并[2,1-b]噻唑的 6 位具有 3-氟苯基，在 5 位具有嘧啶环。嘧啶环的 2 位连接一个（乙基或丙基） linker，其上连接酰胺或磺酰胺部分。最终的化合物由 NCI 选择进行体外细胞毒性筛选。大多数衍生物对结肠癌和黑色素瘤细胞系表现出细胞毒性。此外，用索拉非尼作为阳性对照，在 A375 和 SK-MEL-28 细胞系上测定了目标化合物的 IC。与索拉非尼相比，化合物 12b、12c、12e、12f、15a、15d、15f、14g 和 15h 表现出更好的活性。对最有效的化合物进行了野生型 BRAF、v600e BRAF 和 CRAF 的测试。化合物 15h 对 BRAF 具有潜在的抑制作用（IC=9.3nM）。
