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.
Fiche publication
Date publication
février 2009
Journal
Journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ENNIFAR Eric
Tous les auteurs :
Radi M, Maga G, Alongi M, Angeli L, Samuele A, Zanoli S, Bellucci L, Tafi A, Casaluce G, Giorgi G, Armand-Ugon M, Gonzalez E, Esté JA, Baltzinger M, Bec G, Dumas P, Ennifar E, Botta M
Lien Pubmed
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.
Mots clés
Cell Line, Tumor, Computer Simulation, Drug Design, Drug Resistance, Viral, HIV Reverse Transcriptase, antagonists & inhibitors, Humans, Kinetics, Models, Molecular, Mutation, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Pyrimidinones, chemical synthesis, Reverse Transcriptase Inhibitors, chemical synthesis, Stereoisomerism, Sulfides, chemical synthesis, Surface Plasmon Resonance
Référence
J. Med. Chem.. 2009 Feb 12;52(3):840-51