A hit optimization protocol applied to the first nonnucleoside inhibitor of the ATPase activity of human DEAD-box RNA helicase DDX3 led to the design and synthesis of second-generation rhodanine derivatives with better inhibitory activity toward cellular DDX3 and HIV-1 replication. Additional DDX3 inhibitors were identified among triazine compounds. Biological data were rationalized in terms of structure-activity relationships and docking simulations. Antiviral activity and cytotoxicity of selected DDX3 inhibitors are reported and discussed. A thorough analysis confirmed human DDX3 as a valid anti-HIV target. The compounds described herein represent a significant advance in the pursuit of novel drugs that target HIV-1 host cofactors.
Toward the Discovery of Novel Anti-HIV Drugs. Second-Generation Inhibitors of the Cellular ATPase DDX3 with Improved Anti-HIV Activity: Synthesis, Structure-Activity Relationship Analysis, Cytotoxicity Studies, and Target Validation / Giovanni Maga;Federico Falchi;Marco Radi;Lorenzo Botta;Gianni Casaluce;Martina Bernardini;Hamid Irannejad;Fabrizio Manetti;Anna Garbelli;Alberta Samuele;Samantha Zanoli;José A. Esté;Emmanuel Gonzalez;Elisa Zucca;Stefania Paolucci;Fausto Baldanti;Jan De Rijck;Zeger Debyser;Maurizio Botta. - In: CHEMMEDCHEM. - ISSN 1860-7179. - 6(2011), pp. 1371-1389. [10.1002/cmdc.201100166]