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

Abstract

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. © 2011 Elsevier Ltd. All rights reserved.