Open AccessSynthesis, Biological Activity, Pharmacokinetic Properties and Molecular Modelling Studies of Novel 1H,3H-Oxazolo[3,4-a]Benzimidazoles: Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors
Author(s) -
Alba Chimirri,
Pierre Monforte,
Angela Rao,
Maria Zappalà,
AM Monforte,
Giovambattista De Sarro,
Christophe Pannecouque,
Myriam Witvrouw,
Jan Balzarini,
Erik De Clercq
Publication year - 2001
Publication title -
antiviral chemistry and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.919
H-Index - 51
eISSN - 2040-2066
pISSN - 0956-3202
DOI - 10.1177/095632020101200304
Subject(s) - reverse transcriptase , reverse transcriptase inhibitor , nucleoside reverse transcriptase inhibitor , human immunodeficiency virus (hiv) , pharmacokinetics , nucleoside , biological activity , molecular model , nucleotidyltransferase , biology , chemistry , stereochemistry , pharmacology , virology , sida , biochemistry , in vitro , viral disease , rna , gene
New 1H,3H-oxazolo[3,4-a]benzimidazoles (OBZs) were synthesized as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) to extend the structure-activity relationships observed for an early series of related 1H,3H-thiazolo[3,4-a]benzimidazole derivatives (TBZs). The new compounds showed inhibitory activity against the replication of various HIV-1 strains, including NNRTI-resistant strains. Testing of a representative OBZ derivative in an HPLC assay on biological fluids, indicated that the sulphur substitution appreciably improved the metabolic stability of the TBZ compound. In addition, molecular modelling studies demonstrated that OBZs, TBZs and other NNRTIs have similar structural properties, that is a butterfly-like conformation, which is a key structural requirement for reverse transcriptase inhibition.
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