Synthesis and antimicrobial activity of new 3-(1-R-3(5)-methyl-4-nitroso-1H-5(3)-pyrazolyl)-5-methylisoxazoles

A number of new 3-(1-R-3(5)-methyl-4-nitroso- 1 H-5(3)- pyrazolyl)-5-methyl isoxazoles 6a-g (7b-f) were synthesized and tested for antibacterial and an tifungal activity. Some of these compounds displayed antifungal activity at non-cytotoxic concentrations. Derivative 6c was 9 times more potent in vit ro than miconazole and 20 times more selective against C. neoformans. 6c wa s also 8- and 125-fold more potent than amphotericin B and fluconazole, res pectively. None of the compounds was active against bacteria. Preliminary s tructure-activity relationship (SAR) studies showed that the NO group at po sition 4 of the pyrazole ring is essential for the activity. Lipophilicity of the pyrazole moiety, N-alkyl chain length and planarity of the two heter ocyclic rings appear to play a decisive role in modulating cytotoxicity and antifungal activity. (C) 2000 Elsevier Science Ltd. All rights reserved.