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. - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2009

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.

Marco Radi
Giovanni Maga
Maddalena Alongi
  • Fonction : Auteur
Lucilla Angeli
  • Fonction : Auteur
Alberta Samuele
  • Fonction : Auteur
Samantha Zanoli
  • Fonction : Auteur
Luca Bellucci
  • Fonction : Auteur
Andrea Tafi
  • Fonction : Auteur
Gianni Casaluce
  • Fonction : Auteur
Gianluca Giorgi
Mercedes Armand-Ugon
  • Fonction : Auteur
Emmanuel Gonzalez
  • Fonction : Auteur
Jose? A Este?
  • Fonction : Auteur
Mireille Baltzinger
  • Fonction : Auteur
Philippe Dumas
Eric Ennifar
Maurizio Botta
  • Fonction : Auteur

Résumé

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.
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Dates et versions

hal-00356518 , version 1 (27-01-2009)

Identifiants

Citer

Marco Radi, Giovanni Maga, Maddalena Alongi, Lucilla Angeli, Alberta Samuele, et al.. 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.. Journal of Medicinal Chemistry, 2009, epub ahead of print. ⟨10.1021/jm801330n⟩. ⟨hal-00356518⟩

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