title: Design, synthesis and biological evaluation of 2,4-disubstituted oxazole derivatives as potential PDE4 inhibitors.
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. Compound 4c displayed the strongest inhibition activity (IC50=1.6±0.4μM) and good selectivity against PDE4B. Meanwhile, compound 4c 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 R1at the benzene ring also affected the activity. Docking results showed that compound 4c 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. Compound 4c would be great promise as a lead compound for further study based on the preliminary structure-activity relationship and molecular modeling studies.
authors.affiliation: 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.
authors.forename: Ya-Sheng
authors.initials: YS
authors.lastname: Li
authors.affiliation: 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.
authors.forename: De-Kun
authors.initials: DK
authors.lastname: Hu
authors.affiliation: Department of Pharmacy, Quanzhou Medical College, Quanzhou 362100, China.
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Xing-Yu
authors.initials: XY
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Jin
authors.affiliation: College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China. Electronic address: vinsin1021@126.com.
authors.forename: Gao-Peng
authors.initials: GP
authors.lastname: Song
authors.affiliation: 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; Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang 550025, China. Electronic address: ziningcui@scau.edu.cn.
authors.forename: Zi-Ning
authors.initials: ZN
authors.lastname: Cui
authors.affiliation: 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.
authors.forename: Lian-Hui
authors.initials: LH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D004195:Disease Models, Animal; D015195:Drug Design; D005260:Female; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D010080:Oxazoles / Q000737:chemistry*; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D066244:Proton Magnetic Resonance Spectroscopy; D011720:Pyrazoles / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D010080:Oxazoles; D058988:Phosphodiesterase 4 Inhibitors; D011720:Pyrazoles; C027635:3,5-dimethylpyrazole
keywords: 4-Phenyl-2-oxazole; Molecular simulation; PDE4 inhibitor; Pyrazole derivatives; Synthesis