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Arylthiopyrrole (AThP) Derivatives as Non‐Nucleoside HIV‐1 Reverse Transcriptase Inhibitors: Synthesis, Structure–Activity Relationships, and Docking Studies (Part 2)
Author(s) -
Lavecchia Antonio,
Costi Roberta,
Artico Marino,
Miele Gaetano,
Novellino Ettore,
Bergamini Alberto,
Crespan Emmanuele,
Maga Giovanni,
Di Santo Roberto
Publication year - 2006
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.200600122
Subject(s) - docking (animal) , reverse transcriptase , isopropyl , stereochemistry , chemistry , enzyme , structure–activity relationship , nucleoside , biochemistry , in vitro , rna , medicine , nursing , organic chemistry , gene
Arylthio isopropyl pyridinylmethylpyrrolemethanols (AThPs) have been recently reported as a new class of human immunodeficiency virus type 1 (HIV‐1) reverse transcriptase (RT) inhibitors acting at the non‐nucleoside binding site (NNBS) of this enzyme. Docking experiments of the potent inhibitors 4 k (IC 50 =0.24 μ M , SI=167) and 5 e (IC 50 =0.11 μ M , SI>1667) of wild‐type RT prompted the synthesis and biological evaluation of novel AThP derivatives featuring a number of polar groups in position 3 of the pyrrole ring and larger and more hydrophobic alicyclic substituents in place of the isopropyl group at position 4. Among the compounds synthesized and tested in cell‐based assays against HIV‐1 infected cells, 19 b was the most active, with EC 50 =0.007 μ M , CC 50 =114.5 μ m, and SI=16357. This compound and its precursor 18 b retained interesting activities against clinically relevant drug‐resistant RT forms carrying K103N, Y181I, and L100I mutations. Docking calculations of 10 , 14 , 18 b , and 19 b were also performed to investigate their binding mode into the RT NNBS and to rationalize both structure–activity relationship and resistance data.