Design, synthesis, and in vitro and in vivo biological evaluation of triazolopyrimidine hybrids as multitarget directed anticancer agents

Abstract

In response to the urgent need for new anti-proliferative agents, four novel series of triazolopyrimidine compounds (7a–e, 9a–d, 11a–f, and 13a–e) were synthesized and evaluated for in vitro anticancer efficacy against HCT116, HeLa, and MCF-7 cell lines. Compound 13c emerged as the most potent, with IC₅₀ values of 6.10, 10.33, and 2.42 μM respectively, while 11e and 7c also showed strong activity. In multi-target suppression tests, 13c exhibited the highest inhibition against EGFR, TOP-II, HER-2, and ARO (IC₅₀: 0.087, 31.56, 0.078, and 0.156 μM, respectively). Flow cytometry revealed 13c's ability to suppress the S-phase cell population in MCF-7 cells. In vivo studies of 13c demonstrated significant tumor growth inhibition, comparable to the positive control. Molecular docking studies supported the experimental findings, confirming the binding of the novel motifs to the target enzymes' active sites. This comprehensive evaluation highlights the potential of these triazolopyrimidine compounds, particularly 13c, as promising anticancer agents, warranting further investigation.