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Discovery of Chiral Cyclopropyl Dihydro-Alkylthio-Benzyl-Oxopyrimidine ( S -DABO) Derivatives as Potent HIV-1 Reverse Transcriptase Inhibitors with High Activity Against Clinically Relevant Mutants

2009; American Chemical Society; Volume: 52; Issue: 3 Linguagem: Inglês

10.1021/jm801330n

1520-4804

Marco Radi, Giovanni Maga, Maddalena Alongi, Lucilla Angeli, Alberta Samuele, Samantha Zanoli, Luca Bellucci, Andrea Tafi, Gianni Casaluce, Gianluca Giorgi, Mercedes Armand‐Ugón, Emmanuel González, José A. Esté, Mireille Baltzinger, Guillaume Bec, Philippe Dumas, Eric Ennifar, Maurizio Botta,

Biochemical and Molecular Research

The role played by stereochemistry in the C2-substituent (left part) on the S-DABO scaffold for anti-HIV-1 activity has been investigated for the first time. A series of S-DABO analogues, where the double bond in the C2-substituent is replaced by an enantiopure isosteric cyclopropyl moiety, has been synthesized, leading to the identification of a potent lead compound endowed with picomolar activity against RT (wt) and nanomolar activity against selected drug-resistant mutants. Molecular modeling calculation, enzymatic studies, and surface plasmon resonance experiments allowed us to rationalize the biological behavior of the synthesized compounds, which act as mixed-type inhibitors of HIV-1 RT K103N, with a preferential association to the enzyme−substrate complex. Taken together, our data show that the right combination of stereochemistry on the left and right parts (C6-substituent) of the S-DABO scaffold plays a key role in the inhibition of both wild-type and drug-resistant enzymes, especially the K103N mutant.