A Multidisciplinary Approach for the Identification of Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: S-DABOCs and DAVPs

• Published in: ChemMedChem Vol. 3; no. 4; pp. 573 - 593
• Main Authors: Radi, Marco, Falciani, Chiara, Contemori, Lorenzo, Petricci, Elena, Maga, Giovanni, Samuele, Alberta, Zanoli, Samantha, Terrazas, Montserrat, Castria, Marinunzia, Togninelli, Andrea, Esté, José A., Clotet-Codina, Imma, Armand-Ugón, Mercedes, Botta, Maurizio
• Format: Journal Article
• Language: English; German
• Published: Weinheim WILEY-VCH Verlag 14.04.2008; WILEY‐VCH Verlag
• Subjects: 3,4‐dihydro‐2‐alkoxy‐6‐benzyl‐4‐oxypyrimidines (DABOs); 4-dihydro-2-alkoxy-6-benzyl-4-oxypyrimidines (DABOs); Drug Design; HIV Reverse Transcriptase - genetics; HIV-1; HIV-1 - drug effects; HIV-1 - genetics; Human immunodeficiency virus 1; Humans; lead discovery; Mutation; non-nucleoside reverse transcriptase inhibitors (NNRTIs); reverse transcriptase (RT); Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Structure-Activity Relationship
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.200700198

Among the FDA approved drugs for the treatment of AIDS, non‐nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of first‐line anti‐HIV‐1 therapy because of the less‐severe adverse effects associated with NNRTIs administration in comparison to therapies based on other anti‐HIV‐1 agents. In this contest, 3,4‐dihydro‐2‐alkoxy‐6‐benzyl‐4‐oxypyrimidines (DABOs) have been the object of many studies aimed at identifying novel analogues endowed with potent inhibitory activity towards HIV‐1 wild type and especially drug‐resistant mutants. Accordingly, based on the encouraging results obtained from the biological screening of our internal collection of S‐DABO derivatives, we started with the systematic functionalization of the pyrimidine scaffold to identify the minimal required structural features for RT inhibition. Herein, we describe how the combination of synthetic, biological, and molecular modeling studies led to the identification of two novel subclasses of S‐DABO analogues: S‐DABO cytosine analogues (S‐DABOCs) and 4‐dimethyamino‐6‐vinylpyrimidines (DAVPs). Targeting HIV. A systematic functionalization of the pyrimidine scaffold has been conducted to identify the minimal required structural features for RT inhibition. Herein, we describe how the combination of synthetic, biological, and molecular modeling studies allowed the identification of two novel classes of S‐DABO analogues: S‐DABO cytosine analogues (S‐DABOCs) and 4‐dimethyamino‐6‐vinylpyrimidines (DAVPs).