Structure-Based Design, Parallel Synthesis, Structure−Activity Relationship, and Molecular Modeling Studies of Thiocarbamates, New Potent Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitor Isosteres of Phenethylthiazolylthiourea Derivatives

• DOI: 10.1021/jm049252r
• Publication Date: 2005-05-26T04:20:32Z
• Authors: Angelo Ranise; Andrea Spallarossa; Sara Cesarini; Francesco Bondavalli; Silvia Schenone; Olga Bruno; Giulia Menozzi; Paola Fossa; Luisa Mosti; Massimiliano La C...; Giuseppina Sanna; Marta Murreddu; Gabriella Collu; Bernardetta Busonera; Maria Elena Marongiu; Alessandra Pani; Paolo La Colla; Roberta Loddo
• Keywords: Thiocarbamates; Molecular model; Docking (animal); Structure–activity relationship; Moiety; Efavirenz; Reverse-transcriptase inhibitor; Lead compound

In this paper we describe our structure-based ligand design, synthetic strategy, and structure−activity relationship (SAR) studies that led to the identification of thiocarbamates (TCs), a novel class non-nucleoside reverse transcriptase inhibitors (NNRTIs), isosteres phenethylthiazolylthiourea (PETT) derivatives. Assuming as lead compound O-[2-(phthalimido)ethyl]phenylthiocarbamate 12, one precursors previously described acylthiocarbamates (Ranise, A.; et al. J. Med. Chem. 2003, 46, 768−781), two targeted solution-phase TC libraries were prepared by parallel synthesis. The optimization strategy para-substituted TCs 31, 33, 34, 39, 40, 41, 44, 45, 50, which active against wild-type HIV-1 in MT-4-based assays at nanomolar concentrations (EC50 range: 0.04−0.01 μM). most potent congener 50 = 0.01 μM) bears methyl group position 4 phthalimide moiety nitro para N-phenyl ring. Most showed good selectivity indices, since no cytotoxic effect was detected high 100 μM. 37, 44 significantly reduced multiplication Y181C mutant, but they inactive K103R K103N + mutants. Nevertheless, fold increase resistance 41 not greater than efavirenz mutant enzyme assays. docking model predictions consistent with vitro biological anti-HIV-1 activity related compounds synthesized.