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

•Drug repositioning development is a common and effective method for discovering new drug candidates.•Novel ibuprofen-furo[2,3-d]pyrimidine bearing triazole, hydrazide and oxadiazole hybrid derivatives were synthesized and evaluated for their antitumor activities.•All target compounds exhibited potent antitumor activity.•Target prediction results displayed that target compound 9b may be a G protein-coupled receptors CCR3 inhibitor. 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 1H NMR, 13C 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 0.144μmol/L and 0.068μmol/L, respectively, making it a promising antitumor candidate for further study. [Display omitted]