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

• Published in: Journal of medicinal chemistry 2009-02, Vol.52 (3), p.840-851
• Main Authors: Radi, Marco, Maga, Giovanni, Alongi, Maddalena, Angeli, Lucilla, Samuele, Alberta, Zanoli, Samantha, Bellucci, Luca, Tafi, Andrea, Casaluce, Gianni, Giorgi, Gianluca, Armand-Ugon, Mercedes, Gonzalez, Emmanuel, Esté, José A, Baltzinger, Mireille, Bec, Guillaume, Dumas, Philippe, Ennifar, Eric, Botta, Maurizio
• Format: Article
• Language: English
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biochemistry, Molecular Biology; Biological and medical sciences; Cell Line, Tumor; Cellular Biology; Computer Simulation; Drug Design; Drug Resistance, Viral; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - metabolism; Humans; Kinetics; Life Sciences; Medical sciences; Models, Molecular; Mutation; Pharmacology. Drug treatments; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidinones - chemical synthesis; Pyrimidinones - pharmacology; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - pharmacology; Stereoisomerism; Sulfides - chemical synthesis; Sulfides - pharmacology; Surface Plasmon Resonance
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm801330n

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.