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

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 muM, SI=167) and 5 e (IC(50)=0.11 muM, 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 muM, CC(50)=114.5 mum, 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.