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Parallel Solution-Phase and Microwave-Assisted Synthesis of New S-DABO Derivatives Endowed with Subnanomolar Anti-HIV-1 Activity

A simple and efficient methodology for the parallel solution-phase synthesis has been set up to obtain a series of thiouracils, in turn selectively S-benzylated under microwave irradiation to give new S-DABOs. Biological screening led to the identification of compounds with nanomolar activity toward...

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Published in:Journal of medicinal chemistry 2005-12, Vol.48 (25), p.8000-8008
Main Authors: Manetti, Fabrizio, Esté, José A, Clotet-Codina, Imma, Armand-Ugón, Mercedes, Maga, Giovanni, Crespan, Emmanuele, Cancio, Reynel, Mugnaini, Claudia, Bernardini, Cesare, Togninelli, Andrea, Carmi, Caterina, Alongi, Maddalena, Petricci, Elena, Massa, Silvio, Corelli, Federico, Botta, Maurizio
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Language:English
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Summary:A simple and efficient methodology for the parallel solution-phase synthesis has been set up to obtain a series of thiouracils, in turn selectively S-benzylated under microwave irradiation to give new S-DABOs. Biological screening led to the identification of compounds with nanomolar activity toward both the highly purified recombinant human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) enzyme (wild-type and mutants) and wild-type (wt) and mutant HIV-1 strains. In particular, 20 was found to be the most potent S-DABO reported so far (ID50 = 26 nM toward the isolated wt enzyme) with subnanomolar activity toward both the wt and the pluriresistant virus (IRLL98) HIV-1 strain (EC50 < 0.14 nM and EC50 = 0.22 nM, respectively). Molecular modeling calculations were also performed to investigate the binding mode of such compounds onto the non-nucleoside reverse transcriptase inhibitor binding site and to rationalize the relationships between their chemical structure and activity values toward wt RT.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm050744t