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Studies on Cycloheptathiophene‐3‐carboxamide Derivatives as Allosteric HIV‐1 Ribonuclease H Inhibitors
Author(s) -
Corona Angela,
Desantis Jenny,
Massari Serena,
Distinto Simona,
Masaoka Takashi,
Sabatini Stefano,
Esposito Francesca,
Manfroni Giuseppe,
Maccioni Elias,
Cecchetti Violetta,
Pannecouque Christophe,
Le Grice Stuart F. J.,
Tramontano Enzo,
Tabarrini Oriana
Publication year - 2016
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.201600015
Subject(s) - allosteric regulation , rnase h , context (archaeology) , carboxamide , ribonuclease , reverse transcriptase , chemistry , human immunodeficiency virus (hiv) , enzyme , rnase p , biology , biochemistry , stereochemistry , virology , rna , paleontology , gene
Despite the significant progress achieved with combination antiretroviral therapy in the fight against human immunodeficiency virus (HIV) infection, the difficulty to eradicate the virus together with the rapid emergence of multidrug‐resistant strains clearly underline a pressing need for innovative agents, possibly endowed with novel mechanisms of action. In this context, owing to its essential role in HIV genome replication, the reverse transcriptase associated ribonuclease H (RNase H) has proven to be an appealing target. To identify new RNase H inhibitors, an in‐house cycloheptathiophene‐3‐carboxamide library was screened; this led to compounds endowed with inhibitory activity, the structural optimization of which led to the catechol derivative 2‐(3,4‐dihydroxybenzamido)‐ N ‐(pyridin‐2‐yl)‐5,6,7,8‐tetrahydro‐4 H ‐cyclohepta[ b ]thiophene‐3‐carboxamide (compound 33 ) with an IC 50 value on the RNase H activity in the nanomolar range. Mechanistic studies suggested selective inhibition of the RNase H through binding to an innovative allosteric site, which could be further exploited to enrich this class of inhibitors.