Chemical space exploration of novel naphthyl-carboxamide-diarylpyrimidine derivatives with potent anti-HIV-1 activity

Yali Sang; Christophe Pannecouque; Erik De Clercq; Chunlin Zhuang; Fener Chen

doi:10.1016/j.bioorg.2021.104905

Chemical space exploration of novel naphthyl-carboxamide-diarylpyrimidine derivatives with potent anti-HIV-1 activity

Bioorg Chem. 2021 Jun:111:104905. doi: 10.1016/j.bioorg.2021.104905. Epub 2021 Apr 20.

Authors

Yali Sang¹, Christophe Pannecouque², Erik De Clercq², Chunlin Zhuang³, Fener Chen⁴

Affiliations

¹ Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, People's Republic of China.
² Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
³ Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, People's Republic of China. Electronic address: zclnathan@163.com.
⁴ Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, People's Republic of China. Electronic address: rfchen@fudan.edu.cn.

PMID: 33895602
DOI: 10.1016/j.bioorg.2021.104905

Abstract

Fifteen naphthyl-carboxamide-DAPYs were generated to explore chemical space in reverse transcriptase (RT) binding site via lead optimization strategy. They displayed up to single-digit nanomolar activity against wild-type (WT) and rilpivirine-associated resistant mutant E138K viruses, as well as potent inhibitory ability toward the RT enzyme. Compound a1 showed exceptionally inhibitory effects with an EC₅₀ value of 3.7 nM against HIV-1 wt strain, and an EC₅₀ of 11 nM targeting mutant E138K. The structure-activity relationships (SARs) of the newly obtained DAPYs were also investigated. Molecular docking analysis elucidated the biological activity and offered a structural insight for follow-up research.

Keywords: DAPYs; HIV-1; Naphthyl; Reverse transcriptase; SARs.

Publication types

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

MeSH terms

Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology*
Dose-Response Relationship, Drug
HIV / drug effects*
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Structure
Naphthalenes / chemical synthesis
Naphthalenes / chemistry
Naphthalenes / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

Anti-HIV Agents
Naphthalenes
Pyrimidines
pyrimidine