Pharmacophore-fusing design of pyrimidine sulfonylacetanilides as potent non-nucleoside inhibitors of HIV-1 reverse transcriptase

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

doi:10.1016/j.bioorg.2020.103595

Pharmacophore-fusing design of pyrimidine sulfonylacetanilides as potent non-nucleoside inhibitors of HIV-1 reverse transcriptase

Bioorg Chem. 2020 Mar:96:103595. doi: 10.1016/j.bioorg.2020.103595. Epub 2020 Jan 22.

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; Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology, 18 Chao Wang Road, 310014 Hangzhou, People's Republic of China. Electronic address: rfchen@fudan.edu.cn.

PMID: 32006797
DOI: 10.1016/j.bioorg.2020.103595

Abstract

Twenty-seven derivatives (40-66) were generated by pharmacophore fusing of sulfonylacetanilide-diarylpyrimidine (1) with rilpivirine or biphenyl-diarylpyrimidines. They displayed up to single-digit nanomolar activity against wild-type (WT) virus and various drug-resistant mutant strains in HIV-1-infected MT-4 cells, thereby targeting the reverse transcriptase (RT) enzyme. Compound 51 displayed exceptionally potent activity against WT virus (EC₅₀ = 6 nM) and several mutant strains (L100I, EC₅₀ = 8 nM, K103N, EC₅₀ = 6 nM, Y181C, EC₅₀ = 26 nM, Y188L, EC₅₀ = 122 nM, E138K, EC₅₀ = 26 nM). The structure-activity relationships of the newly obtained pyrimidine sulfonylacetanilides were also elucidated. Molecular docking analysis explained the activity and provided a structural insight for follow-up research.

Keywords: Biphenyl; DAPYs; HIV-1; Reverse transcriptase; Rilpivirine; Sulfonylacetanilide.

Publication types

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

MeSH terms

Acetanilides / chemistry*
Acetanilides / pharmacology*
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology
Drug Design
HIV Infections / drug therapy
HIV Infections / virology
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV Reverse Transcriptase / metabolism
HIV-1 / drug effects
HIV-1 / enzymology
Humans
Molecular Docking Simulation
Pyrimidines / chemistry
Pyrimidines / pharmacology
Reverse Transcriptase Inhibitors / chemistry*
Reverse Transcriptase Inhibitors / pharmacology*

Substances

Acetanilides
Anti-HIV Agents
Pyrimidines
Reverse Transcriptase Inhibitors
reverse transcriptase, Human immunodeficiency virus 1
HIV Reverse Transcriptase
acetanilide