Synthesis And Bioactive Evaluation Of 1,3,4-Oxadiazole Derivatives Containg 1,4-Benzodioxan Skeleton

1,3,4-oxadiazoles possess a variety of bioactivity. Especially, a few differently substituted 1,3,4-oxadiazoles have been found to exhibit anti-inflammatory activities which establishes this moiety as a member of the privileged structures class in pharmaceutical fields. In addition, compounds containing a 1,4-benzodioxan skeleton have received significant attention in chemical, medicinal and pharmaceutical research as this structural scaffold is found in a variety of drugs.Phosphoinositide 3-kinases (PI3Ks) are a class of enzymes that catalyze phosphorylation of the 3-hydroxyl position of phosphoinositides (PIs), which can be activated by many cytokines. Therefore, PI3K plays an important role in numerous cellular functions such as cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking. PI3Ks are grouped into three classes (Ⅰ, Ⅱ, and Ⅲ) according to their structure preference and substrate specificity. It has been found that the PI3Ky, the isoform of I PI3K, plays a pivotal role in inflammation and is involved in allergy, cardiovascular disorders, development of chronic inflammation, and autoimmune diseases. Therefore, the inhibition of PI3Ky might represent a promising therapy for autoimmune and inflammatory diseases.In this study, to obtain more potential and potent immunosuppressive compounds, we focused on PI3Kγ, a potential anti-inflammatory target, to design novel bioactive agents.19 novel 2,5-disubstituted-1,3,4-oxadiazole compounds containing a 1,4-benzodioxan skeleton were designed and synthesized based the rationale of Computer-Aided Drug Design (CADD).All the synthesized 1,3,4-oxadiazole derivatives 5a-5s were evaluated for their cytotoxicity and inhibitory activity on murine ymph node cells. The results showed that most of these synthesized compounds were proved to have potent immunosuppressive activity and low toxicity. Among them, compounds 5m-5r displayed the most potent biological activity against lymph node cells with the IC50 from 1.22-7.46μM. In order to study the preliminary anti-inflammatory mechanism of the compounds, flow cytometry (FCM) and western bloting were performed. The results showed that the compounds exerted immunosuppressive activity via inducing the apoptosis of activated lymph node cells in a dose dependent manner. Docking simulation was performed to position compound 5q into the PI3Kγ structure active site to determine the probable binding model.