Searching for derivatives with immunomodulatory properties we synthesized new series: MZ, MZO and MZA isoxazole derivatives. The described derivatives were synthesized by reaction of cyclization of 5-amino-3-methyl-4-isoxazolecarboxylic acid benzylamides with orthoesters or sodium nitrite. The derivatives showed significant immunological activity in several assays in mice and humans blood cells. The compounds were non-toxic and exhibited differential, dose-dependent property to suppress phytohemagglutinin A (PHA) - induced proliferation of human peripheral blood mononuclear cells (PBMC) and a weak ability to suppress lipopolysaccharide (LPS) – induced production of tumor necrosis factor alpha (TNFα  ) in whole blood cultures. The compounds were virtually devoid of toxicity against PBMC in 24h culture with exception of MZA-1 and MZO-1 which were moderately toxic at 100μg/ml. All compounds showed differential, dose-dependent, suppressive effects on PHA-induced proliferation. Among them MZO-2 was most active (statistically significant suppression already at 1μg/ml). The effects of the compounds on LPS-induced TNFα production were weak. The best inhibitory action was observed in the case of MZA-1 (25ug/ml). MZO-2, which demonstrated strong antiproliferative action, did not inhibit TNFα production. The differences in the observed immunosuppressive properties of the studied derivatives of isoxazole are a good reason for the theoretical investigations. The performed ab initio calculations provided useful information on the electron charge distribution in described molecules. The isoxazole ring is common part of all studied compound and can be considered as the reference molecular subunit. The charge distribution of the isoxazole ring should be related with the electronic structure of whole molecule.

The study was supported by grant of Polish National Science Centre nr N N405 682840.

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