Thiocarbamates as non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 1: Parallel synthesis, molecular modelling and structure–activity relationship studies on O-[2-(hetero)arylethyl]- N-phenylthiocarbamates

• Published in: Bioorganic & medicinal chemistry 2008-04, Vol.16 (7), p.4160-4172
• Main Authors: Cesarini, Sara, Spallarossa, Andrea, Ranise, Angelo, Fossa, Paola, Colla, Paolo La, Sanna, Giuseppina, Collu, Gabriella, Loddo, Roberta
• Format: Article
• Language: English
• Subjects: HIV-1; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 - genetics; Models, Molecular; Molecular Structure; Mutation - genetics; Non-nucleoside reverse transcriptase inhibitors; Nucleosides - chemistry; Parallel synthesis; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; RNA-Directed DNA Polymerase - genetics; RNA-Directed DNA Polymerase - metabolism; Structure-Activity Relationship; Thiocarbamates; Thiocarbamates - chemical synthesis; Thiocarbamates - chemistry; Thiocarbamates - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.12.050

In order to expand the structure–activity relationship (SAR) studies on Thiocarbamates (TCs), a recently discovered class of potent non-nucleoside HIV-1 reverse transcriptase inhibitors, 38 analogues of the lead O-[2-(2-pyridyl)ethyl]- N-phenylthiocarbamate 1 were prepared by parallel solution-phase synthesis. The SAR strategy was focused on the variation (mono- and disubstitution) of the N-phenyl ring and the replacement of the 2-pyridyl with 4-pyridyl, 2-thienyl and phenyl rings. The majority of the new TCs proved to prevent the wild-type HIV-1 multiplication in MT-4 cell culture and the most potent congeners displayed an EC 50 value of 100 nM. Two TCs were active also at micromolar concentrations against the Y181C- and/or K103N/Y181C-resistant mutants. Docking simulations helped to rationalize the SARs.