ABSTRACT The present study aimed at the design and synthesis of a series of triazole‐linked coumarin‐thiobarbituric acid derivatives, inspired by the anti‐breast cancer efficacy of thiobarbituric acid derivatives, the anti‐tubulin efficacy of the coumarin scaffold, and outcomes of previously developed barbituric acid derivatives. Synthesized derivatives were effective against breast cancer cells, and compound PKB6 was most effective against hormone‐positive (MCF‐7) breast cancer cells with an IC 50 value of 1.266 µM. PKB6 competitively binds at the colchicine binding site of tubulin and inhibits tubulin polymerization (IC 50 = 2.196 µM) and induces apoptosis by cell cycle arrest at the G2/M phase. PKB6 demonstrated a higher selectivity for MCF‐7 cells (Selectivity Index: 5.815) over normal skin fibroblasts (L929), supporting its selective cytotoxicity against breast cancer cells. Morphological examination further confirmed the apoptotic cell death by PKB6 . Molecular docking and molecular dynamics simulations further indicated the favorable interactions and stability of PKB6 in the colchicine binding site of tubulin. This investigation established the anti‐breast cancer efficacy of PKB6 mediated via tubulin polymerization inhibition, and acts as an effective hit lead for further development of anti‐tubulin scaffolds for targeting breast cancer.
Kaur et al. (Fri,) studied this question.