Citation: Daxiong Li, Chunsheng Zhang, Wei Ding, Siming Huang, Le Yu, Nan Lu, Wenkai Pan, Yiming Li, Erik De Clercq, Christophe Pannecouque, Hongbing Zhang, Yueping Wang, Yanping He, Fener Chen. 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[J]. Chinese Chemical Letters, ;2021, 32(3): 1020-1024. doi: 10.1016/j.cclet.2020.09.035 shu

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

Daxiong Li ^{a, 1} ,
Chunsheng Zhang ^{a, e, 1} ,
Wei Ding ^a ,
Siming Huang ^a ,
Le Yu ^a ,
Nan Lu ^a ,
Wenkai Pan ^a ,
Yiming Li ^a ,
Erik De Clercq ^b ,
Christophe Pannecouque ^b ,
Hongbing Zhang ^a ,
Yueping Wang ^c ,
Yanping He ^{a, *,} ,
Fener Chen ^{d, *,}

a.
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
b.
Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000, Leuven, Belgium
c.
Department of Applied Chemistry, Faculty of Science, Kunming University of Science and Technology, Kunming 650500, China
d.
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China
e.
Office of Academic Affairs, Yunnan University of Finance and Economics, Kunming 650221, China

yphe@ynu.edu.cn

rfchen@fudan.edu.cn

Received Date: 5 August 2020
Revised Date: 3 September 2020
Accepted Date: 21 September 2020
Available Online: 3 October 2020

Figures(3)

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.
- NNRTIs,
- S-DABOs,
- S-DACOs,
- Anti HIV-1 activity,
- SAR
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