Synthesis and bioactivity of phenyl substituted furan and oxazole carboxylic acid derivatives as potential PDE4 inhibitors

Yinuo Lin; Wasim Ahmed; Min He; Xuwen Xiang; Riyuan Tang; Zi-Ning Cui

doi:10.1016/j.ejmech.2020.112795

Synthesis and bioactivity of phenyl substituted furan and oxazole carboxylic acid derivatives as potential PDE4 inhibitors

Eur J Med Chem. 2020 Dec 1:207:112795. doi: 10.1016/j.ejmech.2020.112795. Epub 2020 Sep 4.

Authors

Yinuo Lin¹, Wasim Ahmed¹, Min He¹, Xuwen Xiang¹, Riyuan Tang², Zi-Ning Cui³

Affiliations

¹ State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou, 510642, China.
² Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, China; Department of Applied Chemistry, College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China. Electronic address: rytang@scau.edu.cn.
³ State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou, 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, China. Electronic address: ziningcui@scau.edu.cn.

PMID: 33002845
DOI: 10.1016/j.ejmech.2020.112795

Abstract

In this present study, a series of 5-phenyl-2-furan and 4-phenyl-2-oxazole derivatives were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. In vitro results showed that the synthesized compounds exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNF-α release. Among the designed compounds, Compound 5j exhibited lower IC₅₀ value (1.4 μM) against PDE4 than parent rolipram (2.0 μM) in in vitro enzyme assay, which also displayed good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. Docking results suggested that introduction of methoxy group at para-position of phenyl ring, demonstrated good interaction with metal binding pocket domain of PDE4B, which was helpful to enhance inhibitory activity.

Keywords: 2-cyanoimino-1,3-thiazolidine; 4-phenyl-2-oxazole; 5-phenyl-2-furan; Molecular simulation; PDE4 inhibitors; Synthesis.

MeSH terms

Animals
Carboxylic Acids / chemical synthesis*
Carboxylic Acids / chemistry
Carboxylic Acids / metabolism
Carboxylic Acids / pharmacology*
Chemistry Techniques, Synthetic
Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry
Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
Drug Design*
Female
Fura-2 / chemistry*
Humans
Inhibitory Concentration 50
Male
Mice
Molecular Docking Simulation
Oxazoles / chemistry*
Phosphodiesterase 4 Inhibitors / chemical synthesis*
Phosphodiesterase 4 Inhibitors / chemistry
Phosphodiesterase 4 Inhibitors / metabolism
Phosphodiesterase 4 Inhibitors / pharmacology*
Protein Conformation
Rats
Structure-Activity Relationship

Substances

Carboxylic Acids
Oxazoles
Phosphodiesterase 4 Inhibitors
Cyclic Nucleotide Phosphodiesterases, Type 4
Fura-2