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

• Published in: ChemMedChem 2011-08, Vol.6 (8), p.1371-1389
• Main Authors: Maga, Giovanni, Falchi, Federico, Radi, Marco, Botta, Lorenzo, Casaluce, Gianni, Bernardini, Martina, Irannejad, Hamid, Manetti, Fabrizio, Garbelli, Anna, Samuele, Alberta, Zanoli, Samantha, Esté, José A., Gonzalez, Emmanuel, Zucca, Elisa, Paolucci, Stefania, Baldanti, Fausto, De Rijck, Jan, Debyser, Zeger, Botta, Maurizio
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - toxicity; antiviral agents; Cell Line, Tumor; Computer Simulation; DDX3; DEAD-box RNA Helicases - antagonists & inhibitors; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Drug Design; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - toxicity; Gene Knockdown Techniques; helicase; HIV-1; HIV-1 - drug effects; HIV-1 - enzymology; host cofactors; Humans; inhibitors; MicroRNAs - metabolism; Rhodanine - chemical synthesis; Rhodanine - chemistry; Rhodanine - toxicity; Structure-Activity Relationship; Triazines - chemical synthesis; Triazines - chemistry; Triazines - toxicity; Virus Replication - drug effects
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201100166

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. Targeting DEAD‐box helicase: We report the rational design of second‐generation DDX3 inhibitors endowed with nanomolar antienzymatic activity in vitro and low‐micromolar anti‐HIV activity in infected cells. We also conducted a thorough analysis to confirm DDX3 as a valid anti‐HIV target. The compounds described herein represent a significant advance in the quest for new drugs that target HIV‐1 host cofactors.