Arylthiopyrrole (AThP) Derivatives as Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors: Synthesis, Structure–Activity Relationships, and Docking Studies (Part 2)

✍ Scribed by Antonio Lavecchia; Roberta Costi; Marino Artico; Gaetano Miele; Ettore Novellino; Alberto Bergamini; Emmanuele Crespan; Giovanni Maga; Roberto Di Santo

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 381 KB
• Volume: 1
• Category: Article
• ISSN: 1860-7179
• DOI: 10.1002/cmdc.200600122

✦ Synopsis

Abstract

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~=0.24μM__,__ SI=167) and 5 e (IC~50~=0.11 μM__,__ 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 μM, CC~50~=114.5 μm, 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.