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; Department of Applied Chemistry, College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China.
Eur J Med Chem. 2020 Dec 1;207:112795. doi: 10.1016/j.ejmech.2020.112795. Epub 2020 Sep 4.
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 IC 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.
在本研究中，设计并合成了一系列 5-苯基-2-呋喃和 4-苯基-2-恶唑衍生物，作为磷酸二酯酶 4 型（PDE4）抑制剂。体外实验结果表明，合成的化合物对 PDE4B 具有较强的抑制活性，并能阻断 LPS 诱导的 TNF-α释放。在所设计的化合物中，化合物 5j 在体外酶测定中对 PDE4 的抑制活性（IC50 值为 1.4 μM）优于母体罗利普兰（IC50 值为 2.0 μM），并且在 LPS 诱导的哮喘/COPD 动物模型和脓毒症动物模型中也显示出良好的体内活性。对接结果表明，苯环对位引入甲氧基，与 PDE4B 的金属结合口袋域表现出良好的相互作用，有助于增强抑制活性。
