Design, synthesis and biological evaluation of 2, 4-disubstituted oxazole derivatives as potential PDE4 inhibitors. Issue 6 (15th March 2017)

• Record Type: Journal Article
• Authors: Li, Ya-Sheng; Hu, De-Kun; Zhao, Dong-Sheng; Liu, Xing-Yu; Jin, Hong-Wei; Song, Gao-Peng; Cui, Zi-Ning; Zhang, Lian-Hui
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 6(2017)
• Page Start: 1852
• Page End: 1859
• Publication Date: 2017-03-15
• Subjects: Synthesis -- 4-Phenyl-2-oxazole -- Pyrazole derivatives -- PDE4 inhibitor -- Molecular simulation; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.01.047
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: In this study, a series of pyrazole derivatives containing 4-phenyl-2-oxazole moiety were designed and synthesized in a concise way, some of which exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNF- α release. Compound4c displayed the strongest inhibition activity (IC50 = 1.6 ± 0.4 μM) and good selectivity against PDE4B. Meanwhile, compound4c showed good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary structure–activity relationship study showed the 3, 5-dimethylpyrazole residue was essential for the bioactivity, and the substituted group R1 at the benzene ring also affected the activity. Docking results showed that compound4c played a key role to form integral hydrogen bonds and a π-π stacking interaction, using hydrazide scaffold (CONN) and pyrazole ring respectively, 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. Compound4c would be great promise as a lead compound for further study based on the preliminary structure-activity relationship and molecular modeling studies.