Synthesis, biological evaluation and molecular modeling studies of quinazolin-4(3H)-one and benzenesulfonamide hybrids as potential anticancer agents

Cancer is a life-threatening disease that affects millions globally; however, a sufficient number of potent and selective chemotherapeutic drugs are still unavailable. For this reason, researchers are conducting studies to develop new selective compounds with anticancer activity. Some of these studies have focused on quinazolin-4(3H)-one core compounds designed by molecular hybridization. Inspired by this, a series of quinazolin-4(3H)-one and benzenesulfonamide hybrids were synthesized and evaluated for their antiproliferative and cytotoxic activities using human non-small cell lung (A549), human liver (HepG2), and human breast (MCF-7) cancer cell lines, as well as a normal human lung fibroblast (CCD-34) cell line in this study. Additionally, molecular modeling studies were performed to determine the interaction mode against epidermal growth factor receptors (EGFRs) as a plausible mechanism of anticancer activity of quinazoline and some quinazolin-4(3H)-one compounds. According to the biological activity results, a significant number of compounds with strong antiproliferative activity against various cancer cell lines, along with an acceptable selectivity rate, were identified. In particular, compound 3, which bears a 2-phenylethyl group on the sulfonamide nitrogen, exhibited more potent and selective antiproliferative activity against the human liver cancer cell line (IC₅₀ < 12.5 μM, SI > 16) compared to the reference drug doxorubicin (IC₅₀ = 25.37 μM, SI > 1.57). The molecular modeling study indicated that the relatively active compounds have the potential to interact with EGFR target. These results suggest that quinazolin-4(3H)-one and benzenesulfonamide hybrids may serve as lead compounds in the discovery of novel anticancer agents for the treatment of various malignancies.