Khellin-Derived Benzofuran–Pyrazoline Hybrids as Kinase-Targeted Anticancer Agents

Khellin, a naturally occurring furochromone, represents a valuable natural scaffold for the design of hybrid anticancer agents. In the present study, two series of khellin-derived hybrids─benzofuran–pyrazoline and benzofuran–pyrazoline–4-thiazolidinone derivatives─were rationally designed and synthesized through selective functionalization at the 5-position of the benzofuran core. The synthesized compounds were evaluated for their in vitro cytotoxic activity against human breast (MCF-7) and colon (HCT116) cancer cell lines, where several derivatives exhibited moderate antiproliferative activity in the micromolar range. Selected active compounds were further examined for their effects on EGFR and B-RAF protein expression levels as well as their kinase inhibitory activity, providing mechanistic insight into their potential mode of anticancer action. To assess therapeutic selectivity, the most active compounds were evaluated against normal human breast epithelial (MCF-12A) and normal colon (CCD-33Co) cell lines, revealing differential selectivity profiles among the tested derivatives. Molecular docking studies were performed on representative active compounds to rationalize observed biological activity and characterize key interactions within the ATP-binding sites of EGFR and B-RAF kinases. Collectively, these findings identify khellin-derived benzofuran–pyrazoline hybrid systems as promising candidates for targeting kinases and as potential anticancer agents, providing a rational basis for further structural optimization and mechanistic investigation.