Design and synthesis of 4-amino-2-phenylquinazolines as novel topoisomerase I inhibitors with molecular modeling

4-Amino-2-phenylquinazolines were designed as bioisosteres of 3-arylisoquinolinamines that were energy minimized to provide stable conformers. The 2-phenyl ring of 4-amino-2-phenylquinazolines was parallel to the quinazoline ring and improved their DNA intercalation ability in the DNA–topo I complex. 4-Amino-2-phenylquinazolines 7 were designed as bioisosteres of 3-arylisoquinolinamines 6 that were energy minimized to provide stable conformers. Interestingly, the 2-phenyl ring of 4-amino-2-phenylquinazolines was parallel to the quinazoline ring and improved their DNA intercalation ability in the DNA–topo I complex. Among the synthesized 4-amino group-substituted analogs, 4-cyclohexylamino-2-phenylquinazoline 7h exhibited potent topo I inhibitory activity and strong cytotoxicity. Interestingly, consistency was observed between the cytotoxicities and topo I activities in these quinazoline analogs, suggesting that the target of 4-amino-2-phenylquinazolines is limited to topo I. Molecular docking studies were performed with the Surflex–Dock program to afford the ideal interaction mode of the compound into the binding site of the DNA–topo I complex in order to clarify the topo I activity of 7h.