Design, Synthesis, and Selective Antiproliferative Activity of Indolizine Derivatives as Microtubule Destabilizers

The development of selective anticancer agents with minimal off‐target toxicity remains a major therapeutic goal. In this study, we synthesized and evaluated a series of 32 indolizine derivatives for antiproliferative activity against oral (CAL‐27), breast (BT‐20), and gastric (HGC‐27) cancer cell lines, as well as non‐tumoral fibroblasts (OHMF). Compounds 8e and 8h emerged as potent and selective candidates, exhibiting nanomolar IC₅₀ values (47–117 nM) and negligible cytotoxicity toward healthy cells. These compounds induced G2/M cell‐cycle arrest, inhibited tubulin polymerization, and modulated proteins related to apoptosis and proliferation, including p‐AKT, cyclin D1, Bcl‐2, and p21. Docking studies confirmed their interaction with the colchicine‐binding site of tubulin. Together, the results support further investigation of these compounds as microtubule‐interacting agents with selective antiproliferative activity.