Synthesis of new Thiazolidinedione derivate as TNF-α receptor type-1 inhibitor

Abstract

Introduction: Tumor necrosis factor (TNF-α) is a cytokine involved in various biological functions. However, TNF-α over-expression can result in serious pathological disorders such as rheumatoid arthritis and crohn’s disease. Therefore, TNF-α inhibition is of great importance to overcome the complexities caused by its aberrant production. Among various TNF-α inhibition strtategies, small molecule TNFR1 inhibitors have attracted much attention due to the high selectivity, low hypersensitivity reactions and production cost. Aim: Synthesis of a new thiazolidinedione derivative as a TNF-α type 1 receptor inhibitor Method: The desired compound was divided into smaller parts by disconnection approach. To produce Phenylpiperazine, aniline and bis(2-chloroethyl) amine were stirred under a nitrogen atmosphere in diethylene glycol monoethyl ether for 6 to 12 hours at 150 ° C. Phenylpiperazine was then reacted with chloroacetyl chloride along with TEA and chloroform to obtain 2-Chloro-1- (4-phenyl-1-piperazinyl) ethenone. To produce 5- (3- (furan-2-yl) allylidene) thiazolidine-2,4-dione, thiazolidinedione was refluxed overnight by mixing furyl acrolein in solvent and toluene / NH4OAc under the Dean-Stark system overnight. Then, the materials produced in the previous steps were mixed with K2CO3 and DMF for 1 hour at a temperature of 60 C to obtain the desired product. H1NMR, CNMR, CHN, FT-IR and mass spectroscopy were used for the characterization. For the biological evaluation, MTT assay was used where different concentrations of synthesized compound alone or along with TNF-α and actinomycin were prepared and its inhibitory effect on TNFR1 was measured. Results: The desired compound and the intermediate materials were characterized using H1NMR, CNMR, CHN, FT-IR and mass spectroscopy indicating the successful synthesis of the compound. MTT assay showed that not only the compound didn’t inhibit TNF-α activity through TNFR1 inhibition, it also exacerbated TNF-α cytotoxic effects. Discussion and Conclusion: It seems that the synthesized compound has agonisitic effects on TNF-α receptor rather than antagonistic