Design, Synthesis, SAR, and Molecular Modeling Studies of Acylthiocarbamates: A Novel Series of Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors Structurally Related to Phenethylthiazolylthiourea Derivatives
| Autor: | Tiziana Marceddu, Paolo La Colla, Alessandra Pani, O. Bruno, Silvia Schenone, Francesco Bondavalli, Andrea Spallarossa, Angelo Ranise, Massimo Mura, Laura Vargiu |
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| Rok vydání: | 2003 |
| Předmět: |
Models
Molecular Molecular model Stereochemistry HIV-1 non-nucleoside reverse transcriptase inhibitors Quantitative Structure-Activity Relationship Ligands Virus Replication Chemical synthesis Cell Line Thiocarbamates Drug Discovery medicine Humans chemistry.chemical_classification Reverse-transcriptase inhibitor biology Chemistry Thiourea virus diseases Nucleotidyltransferase HIV Reverse Transcriptase Reverse transcriptase Thiazoles Enzyme Enzyme inhibitor Mutation biology.protein Computer-Aided Design Reverse Transcriptase Inhibitors Molecular Medicine Nucleoside medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 46:768-781 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm0209984 |
| Popis: | A novel series of potent, selective HIV-1 N-acylthiocarbamate (ATC) nonnucleoside reverse transcriptase inhibitors (NNRTIs) is described. The title compounds were synthesized through a highly convergent, one-pot procedure. In cell-based assays, the lead compound (17c) prevented the HIV-1 multiplication with an EC(50) of 8 microM. The lead optimization strategy was developed by single or multiple modifications of the three molecular portions, in which 17c was notionally divided. Molecular modeling studies led to the synthesis of O-(2-phthalimidoethyl)-N-(p-substituted phenyl)-N-acylthiocarbamates, which showed in vitro activities against HIV-1 in the low nanomolar range. Nevertheless, the title compounds retained low potency against HIV-1 strains carrying mutations (K103R, Y181C, and K103N/Y181C) responsible for NNRTI resistance. The hypothetical docking model of RT/17c and RT/25c, derived from X-ray crystallographic structure of a PETT derivative in complex with HIV-1 RT, revealed that the model structures of ATCs do not approximate the NNRTI butterfly-like conformation. Analysis of these hypotetical complexes helps to rationalize some SARs and resistance data. |
| Databáze: | OpenAIRE |
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