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

Marcin Mączyński,Maja Kocięba,Sylwia Borska,Iwona Kochanowska,Michał Zimecki,Katarzyna Mieszała,Ewa Zaczyńska

doi:10.3390/molecules23071545

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 N′-substituted derivatives of 5-amino-N,3-dimethyl-1,2-oxazole-4-carbohydrazide (MM1–MM10) was synthesized in reaction of 5-amino-N,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-N′-(2,4-dihydroxyphenyl)methylidene-N,3-dimethyl-1,2-oxazole-4-carbohydrazide (MM3) 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, MM3 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.

Highlights

Isoxazoles are an important class of heterocyclic compound, displaying a broad spectrum of biological activities
A series of N 0 -substituted derivatives of 5-amino-N,3-dimethyl-1,2-oxazole-4-carbohydrazideMM1–10 was synthesized according to the synthetic pathway presented in Scheme 1
In pilot experiments (Supplementary Materials, Figure S3), we found that compounds MM2, MM3, MM5, MM6, and MM7 inhibited to various degrees concanavalin A-induced proliferation of mouse splenocytes

Summary

Introduction

Isoxazoles are an important class of heterocyclic compound, displaying a broad spectrum of biological activities. Modification in their structures has offered a high degree of diversity that has proved useful for the development of new therapeutic agents with improved potency and lower toxicity. The pharmacological profits of employing the isoxazole ring are due to the fact that this structure acts as a key pharmacophore for the biological activity of such drugs as Valdecoxib (COX-2 inhibitor) [9] and Leflunomide (antirheumatic drug) [10]. The compounds containing the isoxazole ring are promising therapeutic agents in neurodegenerative diseases because of their similarity to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, which is a specific agonist for the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) receptor [11].

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