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Online ISSN: 1860-7187
January 19, 2011
VIP: A Versatile and Practical Synthesis toward the Development of Novel HIV-1 Integrase Inhibitors
Marta Rinaldi, Cristina Tintori, Luigi Franchi, Giulia Vignaroli, Anna Innitzer, Silvio Massa, José A. Esté, Encarna Gonzalo, Frauke Christ, Zeger Debyser, and Maurizio Botta*
HIV-1 integrase (IN) is an essential enzyme for HIV-1 replication and represents an interesting target for the development of new drugs against AIDS. In 2007, the USFDA approved raltegravir (MK-0518), the first example of a drug active against HIV-1 IN, validating IN as a new target in the field of HIV. Viral strains that are resistant to this drug have already begun to emerge, thus necessitating the development of new IN inhibitors.
In this context, Maurizio Botta and colleagues report the design, synthesis, and evaluation of a novel series of HIV-1 IN inhibitors. The compounds, which were synthesized by three versatile and practical microwave-assisted synthetic strategies, are able to inhibit the replication of MT-4 cells at low micromolar concentrations, indicating their suitability as scaffolds for further optimization. The newly synthesized derivatives were also computationally investigated to analyze their binding mode within the DNA binding site of IN. The results of this study set the foundation for the development of a new generation of HIV-1 IN inhibitors.
Received November 25, 2010; published online January 18, 2011, DOI: 10.1002/cmdc.201000510.