Tetrahydroquinoline and tetrahydroisoquinoline derivatives as potential selective PDE4B inhibitors

Ya-Sheng Li; Xing-Yu Liu; Dong-Sheng Zhao; Yi-Xian Liao; Lian-Hui Zhang; Feng-Zhi Zhang; Gao-Peng Song; Zi-Ning Cui

doi:10.1016/j.bmcl.2018.04.068

Tetrahydroquinoline and tetrahydroisoquinoline derivatives as potential selective PDE4B inhibitors

Bioorg Med Chem Lett. 2018 Oct 15;28(19):3271-3275. doi: 10.1016/j.bmcl.2018.04.068. Epub 2018 May 3.

Authors

Ya-Sheng Li¹, Xing-Yu Liu², Dong-Sheng Zhao³, Yi-Xian Liao², Lian-Hui Zhang², Feng-Zhi Zhang⁴, Gao-Peng Song⁵, Zi-Ning Cui⁶

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; College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Zhejiang University of Technology, Hangzhou 310014, China.
² 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.
³ Department of Pharmacy, Quanzhou Medical College, Quanzhou 362100, China.
⁴ College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Zhejiang University of Technology, Hangzhou 310014, China.
⁵ College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China. Electronic address: vinsin1021@126.com.
⁶ 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. Electronic address: ziningcui@scau.edu.cn.

PMID: 30131242
DOI: 10.1016/j.bmcl.2018.04.068

Abstract

Tetrahydroquinoline and tetrahydroisoquinoline derivatives containing 2-phenyl-5-furan moiety were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. The bioassay results showed that title compounds showed good inhibitory activity against PDE4B and blockade of LPS (lipopolysaccharide) induced TNF-α release, which also exhibited considerable in vivo activity in animal models of asthma/COPD (chronic obstructive pulmonary disease) and sepsis induced by LPS. The bioactivity of compounds containing tetrahydroquinoline (series 4) was higher than that of tetrahydroisoquinoline derivatives (series 3). Compound 4 m with 4-methoxybenzene moiety exhibited the best potential selective activity against PDE4B. The primary structure-activity relationship study and docking results showed that the tetrahydroquinoline moiety of compound 4 m played a key role to form hydrogen bonds and π-π stacking interaction with PDE4B protein while the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4B. Based on LPS induced sepsis model for the measurement of TNF-α inhibition in Swiss Albino mice and neutrophilia inhibition for asthma and COPD in Sprague Dawley rats with the potential molecules, compound 4 m would be great promise as a hit inhibitor in the future study.

Keywords: Molecular simulation; PDE4B inhibitor; Synthesis; Tetrahydroisoquinoline; Tetrahydroquinoline.

Publication types

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

MeSH terms

Animals
Catalytic Domain
Mice
Phosphodiesterase 4 Inhibitors / metabolism
Phosphodiesterase 4 Inhibitors / pharmacology*
Quinolines / chemistry*
Quinolines / pharmacology*
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Tetrahydroisoquinolines / chemistry*
Tetrahydroisoquinolines / pharmacology*

Substances

Phosphodiesterase 4 Inhibitors
Quinolines
Tetrahydroisoquinolines
1,2,3,4-tetrahydroquinoline