Synthesis, Biological Evaluation Of2,5-disubstituted-1,3,4-oxadiazole Derivatives As Potential Immunosuppressive Agents

Autoimmune diseases represent a major cause of morbidity and mortality. More than70autoimmune diseases have been described. The major autoimmune diseases include psoriasis, rheumatoid arthritis, Crohn’s disease, multiple sclerosis, and systemic lupus erythematosus. Although immunosuppressive drugs have been used for the treatment of autoimmune diseases in clinic, their side effects including liver toxicity, nephrotoxicity, infection, cardiovascular toxicity and others can not be neglected. Therefore, there is a clinical need for new and less toxic therapeutic agents with new mechanisms of action.Phosphoinositide3-kinases (PI3Ks) are a class of enzymes that catalyze phosphorylation of the3-hydroxyl position of phosphoinositides (PIs). The resulting second messengers, phosphatidylinositol3,4-bisphosphate (PIP2) and phosphatidylinositol3,4,5-trisphosphate (PIP3), can regulate a remarkably diverse array of physiological processes, including glucose homeostasis, cell growth, differentiation, and motility. IA PI3Ks include PI3Ka, PI3Kβ and PI3Kδ isoforms. Because of the isoforms’differential tissue distribution, they show distinct biological functions. PI3Kα and PI3Kβ are ubiquitously expressed and regulate functions such as cell proliferation and survival. Whereas PI3Kδ and PI3Kγ are mainly expressed in the hematopoietic system and mediate immune responses. It has been found that the PI3Ky isoform 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.As an fundamental class of heterocyclic compounds,1,3,4-oxadiazoles possess a variety of bioactivity. Especially, a few differently substituted1,3,4-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, Some salicylic acid derivatives were reported to show potent anti-inflammatory, antimicrobial, antiviral and anticancer activity, which could be widely used as drugs.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.26novel2,5-disubstituted-1,3,4-oxadiazole compounds derived from4-methoxysalicylic acid or4-methylsalicylic acid were designed and synthesized based the rationale of Computer-Aided Drug Design (CADD).The results of cytotoxicity test and immunosuppressive activity assay showed that most of the synthesized compounds displayed enhanced inhibitory activities and low toxicity. Among them, compound6z displayed the most potent biological activity against lymph node cells (inhibition=38.76%for lymph node cells and IC50=0.311μM for PI3Ky). The preliminary mechanism of compound6z inhibition effects was also detected by flow cytometry (FCM) and the compound exerted immunosuppressive activity via inducing the apoptosis of activated lymph node cells in a dose dependent manner. Docking simulation was performed to position compound6z into the PI3Ky structure active site to determine the probable binding model. All the results showed the great potential of compound6z as an immunosuppressant targeting PI3Ky.