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Synthesis, Antiviral Activity, and Structure–Activity Relationship of 1,3‐Benzodioxolyl Pyrrole‐Based Entry Inhibitors Targeting the Phe43 Cavity in HIV‐1 gp120
Author(s) -
Curreli Francesca,
Belov Dmitry S.,
Ahmed Shahad,
Ramesh Ranjith R.,
Kurkin Alexander V.,
Altieri Andrea,
Debnath Asim K.
Publication year - 2018
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.201800534
Subject(s) - entry inhibitor , bioisostere , stereochemistry , chemistry , moiety , viral entry , viral life cycle , structure–activity relationship , cytotoxicity , human immunodeficiency virus (hiv) , biochemistry , virus , in vitro , viral replication , chemical synthesis , biology , virology
The pathway by which HIV‐1 enters host cells is a prime target for novel drug discovery because of its critical role in the life cycle of HIV‐1. The HIV‐1 envelope glycoprotein gp120 plays an important role in initiating virus entry by targeting the primary cell receptor CD4. We explored the substitution of bulky molecular groups in region I in the NBD class of entry inhibitors. Previous attempts at bulky substituents in that region abolished antiviral activity, even though the binding site is hydrophobic. We synthesized a series of entry inhibitors containing the 1,3‐benzodioxolyl moiety or its bioisostere, 2,1,3‐benzothiadiazole. The introduction of the bulkier groups was well tolerated, and despite only minor improvements in antiviral activity, the selectivity index of these compounds improved significantly.