Structure-based linker optimization of 6-(2-cyclohexyl-1-alkyl)-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors
| Autor: | Chun-Sheng Zhang, Le Yu, Wei Ding, Fen-Er Chen, Yiming Li, Da-Xiong Li, Wen-Kai Pan, Si-Ming Huang, Yueping Wang, Yan-Ping He, Nan Lu, Erik De Clercq, Christophe Pannecouque, Hongbing Zhang |
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| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
Molecular model Chemistry Stereochemistry Human immunodeficiency virus (HIV) Rational design Wild type virus diseases 02 engineering and technology General Chemistry 010402 general chemistry 021001 nanoscience & nanotechnology medicine.disease_cause 01 natural sciences Reverse transcriptase 0104 chemical sciences medicine 0210 nano-technology Linker Nucleoside Alkyl |
| Zdroj: | Chinese Chemical Letters. 32:1020-1024 |
| ISSN: | 1001-8417 |
| DOI: | 10.1016/j.cclet.2020.09.035 |
| Popis: | In continuation of our efforts toward the discovery of potent HIV-1 NNRTIs with diverse structures, a series of novel S-DACO analogues of 6-(2-cyclohexyl-1-alkyl)-2-(2-oxo-2-phenyl-ethylsulfanyl)pyrimidin-4(3H)-ones were designed, synthesized and evaluated for their antiviral activities in MT-4 cells. Most of these new compounds showed moderate to good activities against wild type HIV-1 with IC50 values ranging from 7.55 μmol/L to 0.018 μmol/L. Among them, compound 5c was identified as the most promising inhibitor against HIV-1 replication with an IC50 = 0.018 μmol/L, CC50 = 194 μmol/L, and SI = 12791, which was much more potent than the reference drugs NVP and DLV and comparable to AZT and EFV. In addition, 5c also exhibited improved activity against double mutant HIV-1 strain RES056 compared to that of the reference drugs NVP/DLV and DB02. The preliminary structure-activity relationship (SAR) and molecular modeling studies were also discussed, which provides some useful indications for guiding the further rational design of new S-DACO analogues. keywords: NNRTIs, -DABOs, -DACOs, Anti HIV-1 activity, SAR ispartof: Chinese Chemical Letters vol:32 issue:3 pages:1020-1024 status: published |
| Databáze: | OpenAIRE |
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