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INSIGHTS INTO MYCOBACTERIAL ACTIVITY AND CYTOTOXICITY OF SUBSTITUED ISOXAZOLE-4-CARBOHYDRAZIDE DERIVATIVES.

100%

Płoszaj P., Junka A., Szponar B., Mączyński M., Ryng S., Bartoszewicz M., Piwowar A.

Acta Poloniae Pharmaceutica - Drug Research

2018

vol. 75

issue 3

The purpose of this study was to evaluate the antimycobacterial activity of novel derivatives of 5-amino-3-methyl-4-isoxazolecarboxylic acid hydrazide 1, isoniazid (INH) structural analogue. A set of 5-amino-3-methyl-4-isoxazolecarboxylic acid hydrazide 1 derivatives 2a-j have been obtained by condensation reactions with aldehydes and further transformed by cyclization with corresponding orthoesters to 5-amino-3-methylisoxazole[5,4-d]pyrimidin-4-one derivatives 3a-j and 4a-j. From the structural and functional point of view, all these products proved to be biologically important and could be used as substrates for further synthesis. 21 out of 31 structures were newly developed. Described compounds were screened against Mycobacterium fortuitum in MABA test. The most active compound 2e, 2g revealed minimum inhibitory concentration at 16 μg/ml. In addition, these compounds revealed low cytotoxicity against lung (A549) and fibroblasts (L929) cell lines. The results demonstrated the potential and importance of further development of 5-amino-3-methyl-4-isoxazolecarboxylic acid hydrazide derivatives as a new class of antimycobacterial compounds.

Synthesis, immunosuppressive properties, mechanism of action and X-ray analysis of a new class of isoxazole derivatives

84%

Bąchor U., Ryng S., Mączyński M., Artym J., Kocięba M., Zaczyńska E., Kochanowska I., Tykarska E., Zimecki M.

Acta Poloniae Pharmaceutica - Drug Research

2019

vol. 76

issue 2

251-263

In the search for potential therapeutics, isoxazole derivatives are still objects of interest. Previously described immunoregulatory properties of 5-amino-3-methyl-4-isoxazolecarboxylic acid (AC) benzylamides prompted us to synthesize a new class of compounds of immunotropic activity. A series of new compounds containing the isoxazole moiety were synthesized using Passerini three-component reaction. The effects on phytohemagglutinin A (PHA)-induced proliferation of human peripheral blood mononuclear cells (PBMC), production of tumor necrosis factor alpha (TNF α) in human whole blood cultures stimulated with lipopolysaccharide (LPS) and two-way mixed lymphocyte reaction (MLR) of PBMC, were investigated. Also, the effect of 1-(cyclohexylcarbamoyl)cyclohexyl 5-amino-3-methylisoxazole-4-carboxylate (PUB1) on the expression of signaling molecules associated with cell apoptosis in Jurkat cells was also determined. The results showed that the compounds inhibited to various degree mitogen-induced PBMC proliferation in a dose-dependent manner and TNF α production at 10 μg/ml. PUB1 compound, selected on the basis of its strongest antiproliferative activity, was also shown to inhibit MLR. The molecular data suggest that immunosuppressive action of PUB1 depended on induction of Fas and elevation of caspase 8 expression. In summary, we revealed immunosuppressive properties of a new class of isoxazoles and established the mechanism of action of a representative PUB1 compound.

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2 Acta Poloniae Pharmaceutica - Drug Research

1 2019

1 2018

2 Mączyński M.

2 Ryng S.

1 Artym J.

1 Bartoszewicz M.

1 Bąchor U.

1 Junka A.

1 Kochanowska I.

1 Kocięba M.

1 Piwowar A.

1 Płoszaj P.

1 Szponar B.

1 Tykarska E.

1 Zaczyńska E.

1 Zimecki M.

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INSIGHTS INTO MYCOBACTERIAL ACTIVITY AND CYTOTOXICITY OF SUBSTITUED ISOXAZOLE-4-CARBOHYDRAZIDE DERIVATIVES.

Synthesis, immunosuppressive properties, mechanism of action and X-ray analysis of a new class of isoxazole derivatives