Structure-directed linker optimization of novel HEPTs as non-nucleoside inhibitors of HIV-1 reverse transcriptase

Qing-Qing Hao; Xiao-Mei Chen; Christophe Pannecouque; Erik De Clercq; Shuai Wang; Fen-Er Chen

doi:10.1016/j.bioorg.2023.106413

Structure-directed linker optimization of novel HEPTs as non-nucleoside inhibitors of HIV-1 reverse transcriptase

Bioorg Chem. 2023 Apr:133:106413. doi: 10.1016/j.bioorg.2023.106413. Epub 2023 Feb 9.

Authors

Qing-Qing Hao¹, Xiao-Mei Chen², Christophe Pannecouque³, Erik De Clercq³, Shuai Wang⁴, Fen-Er Chen⁵

Affiliations

¹ Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China; Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
² Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
³ Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
⁴ Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China. Electronic address: shuaiwang@fudan.edu.cn.
⁵ Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China; Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China. Electronic address: rfchen@fudan.edu.cn.

PMID: 36791619
DOI: 10.1016/j.bioorg.2023.106413

Abstract

1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymines (HEPTs) have been previously described as an important class of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). In our continuously pursuing HEPT optimization efforts, a series of novel HEPTs, featuring -C(OH)CH₂R, -CC, or -CHCH₂R linker at the benzylic α-methylene unit, were developed as NNRTIs. Among these new HEPTs, the compound C20 with -CHCH₃ group at the benzylic α-methylene unit conferred the highest potency toward WT HIV-1 and selectivity (EC₅₀ = 0.23 μM, SI = 150.20), which was better than the lead compound HEPT (EC₅₀ = 7 μM, SI = 106). Also, C20 was endowed with high efficacy against clinically relevant mutant strains (EC_50(L100I) = 1.07 μM; EC_50(K103N) = 4.33 μM; EC_50(Y181C) = 5.57 μM; EC_50(E138K) = 1.06 μM; EC_{50(F227L+V106A)} = 5.45 μM) and wild-type HIV-1 reverse transcriptase (RT) with an IC₅₀ value of 0.55 μM. Molecular docking and molecular dynamics simulations, as well as preliminary structure-activity relationship (SAR) analysis of these new compounds, provided a deeper insight into the key structural features of the interactions between HEPT analogs and HIV-1 RT and laid the foundation for further modification on HEPT scaffold.

Keywords: HEPTs; HIV-1; Linker Modification; NNRTIs; RT.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-HIV Agents* / chemistry
Anti-HIV Agents* / pharmacology
HIV Reverse Transcriptase
Molecular Docking Simulation
Reverse Transcriptase Inhibitors* / chemistry
Reverse Transcriptase Inhibitors* / pharmacology
Structure-Activity Relationship
Thymine

Substances

Anti-HIV Agents
HIV Reverse Transcriptase
Reverse Transcriptase Inhibitors
reverse transcriptase, Human immunodeficiency virus 1
Thymine
1-((2-hydroxyethoxy)methyl)-6-(phenylthio)thymine