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Title: 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
Authors: Botta, Maurizio 
Maga, G
Alongi, M
Angeli, L
Samuele, A
Zanoli, S
Bellucci, L
Tafi, Andrea 
Casaluce, G
Giorgi, Gianluca 
Armand Ugon, M
Gonzalez, E
Esté, Ja
Baltzinger, M
Bec, G
Dumas, P
Ennifar, E
Botta, Maurizio 
Issue Date: 2009
Project: None 
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.
ISSN: 0022-2623
DOI: 10.1021/jm801330n
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