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Design, Synthesis, and Biological Evaluation of 1,3‐Diarylpropenones as Dual Inhibitors of HIV‐1 Reverse Transcriptase
Author(s) -
Meleddu Rita,
Cannas Valeria,
Distinto Simona,
Sarais Giorgia,
Del Vecchio Claudia,
Esposito Francesca,
Bianco Giulia,
Corona Angela,
Cottiglia Filippo,
Alcaro Stefano,
Parolin Cristina,
Artese Anna,
Scalise Daniela,
Fresta Massimo,
Arridu Antonella,
Ortuso Francesco,
Maccioni Elias,
Tramontano Enzo
Publication year - 2014
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.201402015
Subject(s) - rnase h , reverse transcriptase , chemistry , enzyme , allosteric regulation , human immunodeficiency virus (hiv) , nucleoside reverse transcriptase inhibitor , dna polymerase , polymerase , biochemistry , stereochemistry , biology , rna , virology , gene
A small library of 1,3‐diarylpropenones was designed and synthesized as dual inhibitors of both HIV‐1 reverse transcriptase (RT) DNA polymerase (DP) and ribonuclease H (RNase H) associated functions. Compounds were assayed on these enzyme activities, which highlighted dual inhibition properties in the low‐micromolar range. Interestingly, mutations in the non‐nucleoside RT inhibitor binding pocket strongly affected RNase H inhibition by the propenone derivatives without decreasing their capacity to inhibit DP activity, which suggests long‐range RT structural effects. Biochemical and computational studies indicated that the propenone derivatives bind two different interdependent allosteric pockets.