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

• Published in: ChemMedChem Vol. 1; no. 12; pp. 1379 - 1390
• Main Authors: Lavecchia, Antonio, Costi, Roberta, Artico, Marino, Miele, Gaetano, Novellino, Ettore, Bergamini, Alberto, Crespan, Emmanuele, Maga, Giovanni, Di Santo, Roberto
• Format: Journal Article
• Language: English; German
• Published: Weinheim WILEY-VCH Verlag 11.12.2006; WILEY‐VCH Verlag
• Subjects: AIDS; antiviral agents; arylthiopyrroles; Binding Sites; Cell Line; Computer Simulation; Crystallography, X-Ray; Drug Design; HIV; HIV Reverse Transcriptase - antagonists & inhibitors; HIV-1 - drug effects; Human immunodeficiency virus 1; Humans; Ligands; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; NNRTI; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Stereoisomerism; Structure-Activity Relationship
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.200600122

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 (IC50=0.24  μM, SI=167) and 5 e (IC50=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 EC50=0.007 μM, CC50=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. AThPs are potent NNRTIs endowed with antiviral activities in cell‐based assays. The effect of substitution at positions 3 and 4 of the pyrrole ring (examples shown) toward biological properties was studied, and the most active derivatives showed interesting activities against clinically relevant, drug‐resistant RT forms (K103N, Y181I, and L100I). Docking simulations helped to explain some SAR and resistance data.