A series of novel compounds bearing imidazo[2,1-b]thiazole scaffolds were designed and synthesized based on the optimization of the virtual screening hit compound N-(6-morpholinopyridin-3-yl)-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide (5a), and tested for their cytotoxicity against human cancer cell lines, including HepG2 and MDA-MB-231. The results indicated that the compound 2-(6-(4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl)-N-(6-(4-(4-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)acetamide (5l), with slightly higher inhibition on VEGFR2 than 5a (5.72% and 3.76% inhibitory rate at 20 μM, respectively), was a potential inhibitor against MDA-MB-231 (IC₅₀ = 1.4 μM) compared with sorafenib (IC₅₀ = 5.2 μM), and showed more selectivity against MDA-MB-231 than HepG2 cell line (IC₅₀ = 22.6 μM).

In order to overcome the drug resistance and enhance the membrane penetration ability of benzamide riboside [BR, (1-β-D-ribofuranosyl) benzene-3-carboxamide], which is a novel C-glycoside analogue of nicotinamide riboside and has excellent cytotoxic activity, we designed and synthesized two phosphordiamidates (1a and 1b) as prodrugs to deliver phosphorylated BR into cells. However, the bioactivity evaluation shows that 1a and 1b have lower biological activity (IC₅₀ > 200 μM and 173 μM, respectively) compared to BR. This might be due to the fact that 1a and 1b could only serve as the BR depot form and thus could not be metabolized to the phosporylatd benzamide riboside.