Synthesis, Immunosuppressive Properties, and Mechanism of Action of a New Isoxazole Derivative

Abstract

This work describes the synthesis of a new series of isoxazole derivatives, their immunosuppressive properties, and the mechanism of action of a representative compound. A new series of <i>N</i>′-substituted derivatives of 5-amino-<i>N</i>,3-dimethyl-1,2-oxazole-4-carbohydrazide (<b>MM1</b>⁻<b>MM10</b>) was synthesized in reaction of 5-amino-<i>N</i>,3-dimethyl-1,2-oxazole-4-carbohydrazide with relevant carbonyl compounds. The isoxazole derivatives were tested in several in vitro models using human cells. The compounds inhibited phytohemagglutinin A (PHA)-induced proliferation of peripheral blood mononuclear cells (PBMCs) to various degrees. The toxicity of the compounds with regard to a reference A549 cell line was also differential. 5-amino-<i>N</i>′-(2,4-dihydroxyphenyl)methylidene-<i>N</i>,3-dimethyl-1,2-oxazole-4-carbohydrazide (<b>MM3</b>) compound was selected for further investigation because of its lack of toxicity and because it had the strongest antiproliferative activity. The compound was shown to inhibit lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF α) production in human whole blood cell cultures. In the model of Jurkat cells, <b>MM3</b> elicited strong increases in the expression of caspases, Fas, and NF-κB1, indicating that a proapoptotic action may account for its immunosuppressive action in the studied models.