Fragment hopping-based discovery of novel sulfinylacetamide-diarylpyrimidines (DAPYs) as HIV-1 nonnucleoside reverse transcriptase inhibitors

Sheng Han; Yali Sang; Yan Wu; Yuan Tao; Christophe Pannecouque; Erik De Clercq; Chunlin Zhuang; Fen-Er Chen

doi:10.1016/j.ejmech.2019.111874

Fragment hopping-based discovery of novel sulfinylacetamide-diarylpyrimidines (DAPYs) as HIV-1 nonnucleoside reverse transcriptase inhibitors

Eur J Med Chem. 2020 Jan 1:185:111874. doi: 10.1016/j.ejmech.2019.111874. Epub 2019 Nov 10.

Authors

Sheng Han¹, Yali Sang¹, Yan Wu¹, Yuan Tao¹, Christophe Pannecouque², Erik De Clercq², Chunlin Zhuang³, Fen-Er 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: 31735575
DOI: 10.1016/j.ejmech.2019.111874

Abstract

The fragment hopping approach is widely applied in drug development. A series of diarylpyrimidines (DAPYs) were obtained by hopping the thioacetamide scaffold to novel human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitors (NNRTIs) to address the cytotoxicity issue of Etravirine and Rilpivirine. Although the new compounds (11a-l) in the first-round optimization possessed less potent anti-viral activity, they showed much lower cytotoxicity. Further optimization on the sulfur led to the sulfinylacetamide-DAPYs exhibiting improved anti-viral activity and a higher selectivity index especially toward the K103N mutant strain. The most potent compound 12a displayed EC₅₀ values of 0.0249 μM against WT and 0.0104 μM against the K103N mutant strain, low cytotoxicity (CC₅₀ > 221 μM) and a high selectivity index (SI _WT > 8873, SI _K103N > 21186). In addition, this compound showed a favorable in vitro microsomal stability across species. Computational study predicted the binding models of these potent compounds with HIV-1 reverse transcriptase thus providing further insights for new developments.

Keywords: Fragment hopping; HIV-1; NNRTIs; Sulfinylacetanilide-DAPYs; Thioacetanilide-DAPYs.

MeSH terms

Acetamides / chemical synthesis
Acetamides / chemistry
Acetamides / pharmacology*
Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV Reverse Transcriptase / metabolism
HIV-1 / drug effects*
HIV-1 / enzymology
Humans
Microbial Sensitivity Tests
Molecular Structure
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Reverse Transcriptase Inhibitors / chemical synthesis
Reverse Transcriptase Inhibitors / chemistry
Reverse Transcriptase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Acetamides
Anti-HIV Agents
Pyrimidines
Reverse Transcriptase Inhibitors
acetamide
reverse transcriptase, Human immunodeficiency virus 1
HIV Reverse Transcriptase