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A Multidisciplinary Approach for the Identification of Novel HIV‐1 Non‐Nucleoside Reverse Transcriptase Inhibitors: S‐DABOCs and DAVPs
Author(s) -
Radi Marco,
Falciani Chiara,
Contemori Lorenzo,
Petricci Elena,
Maga Giovanni,
Samuele Alberta,
Zanoli Samantha,
Terrazas Montserrat,
Castria Marinunzia,
Togninelli Andrea,
Esté José A.,
ClotetCodina Imma,
ArmandUgón Mercedes,
Botta Maurizio
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200700198
Subject(s) - reverse transcriptase , nucleoside , human immunodeficiency virus (hiv) , nucleoside reverse transcriptase inhibitor , computational biology , biology , drug discovery , stereochemistry , chemistry , virology , biochemistry , rna , gene
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).