Discovery of cytotoxic indolo[1,2-<i>c</i>]quinazoline derivatives through scaffold-based design

Indolo[1,2-<i>c</i>]quinazoline derivatives have emerged as promising chemotype in drug discovery due to their versatile biological activities, including antimicrobial and antiviral properties. In this study, we report the design, synthesis, and biological evaluation of novel indolo[1,2-<i>c</i>]quinazoline derivatives, with a particular focus on their antiproliferative potential against human cancer cells. We introduced structural modifications at positions 5, 6, and 12 of the indolo[1,2-<i>c</i>]quinazoline core to explore the structure-activity relationships and enhance cytotoxicity. Our results highlight that 12-aminomethyl derivatives exhibited notable cytotoxicity against tumor cell lines, with the highest activity observed for compound <b>9c</b>, which showed significant selectivity toward tumor cells. In contrast, while the compounds demonstrated planar polycyclic structures, DNA was not the primary target for their antiproliferative effects, as confirmed by FID assay and fluorescence titration studies. This study represents the first comprehensive evaluation of indolo[1,2-<i>c</i>]quinazolines as potential scaffold for the development of antitumor agents, offering valuable insights into their SAR and paving the way for a future evaluation of these compounds as anticancer therapeutics.