Ibuprofen-furo[2,3-d]pyrimidine-based hybrid bearing triazole, hydrazide and oxadiazole as potent antitumor agents: Design and synthesis and activity evaluation

In this study, building upon the ibuprofen lead compound and previous research on antitumor agents, 33 novel ibuprofen-furo[2,3-d]pyrimidine bearing triazole, hydrazide and oxadiazole hybrid derivatives were synthesized. The all compounds were confirmed structurally using H-1 NMR, C-13 NMR, and HR-MS. Subsequently, the antitumor activities of these compounds were evaluated on HepG2 and A549 cell lines in vitro. The findings indicated that all target compounds exhibited potent antitumor activity. A preliminary comparison among different pharmacophores of 3a-3h, 6a-6g, 9a-9m, and 10a-10e revealed a general trend: triazole > hydrazide/bishydrazide > oxadiazole in terms of activity. Additionally, for compounds 9a-9m, substituents at the C-4 position of the pyrimidine ring demonstrated significant effects on activity, with the order of potency being piperidin-1-yl > morpholin-1-yl > diethylamino > di-n-propyl amino. Furthermore, the representative compound 9b was selected to explore its impact on HepG2 and A549 cell apoptosis, and the results indicated that 9b typically caused cell apoptosis in a dose-dependent manner. Further target prediction results displayed that 9b may be a G protein-coupled receptors CCR3 inhibitor. Ultimately, compound 9b showed excellent antitumor activity against HepG2 and A549 cell lines with IC50 values of 0.144 mu mol/L and 0.068 mu mol/L, respectively, making it a promising antitumor candidate for further study.