Novel aza-bicyclic 2-isoxazoline acylhydrazone hybrids and their synergistic potential with fluconazole against a drug-resistant Candida albicans strain

As the prevalence of drug-resistant Candida isolates continues to rise, the imperative for identifying novel compounds to enhance the arsenal of antifungal drugs becomes increasingly critical. Consequently, exploring new treatment strategies, including synthesizing molecular hybrids and applying combination therapy, is essential. For this reason, this study evaluated the efficacy of ten molecular hybrids of aza-bicyclic 2-isoxazoline-acylhydrazone belonging to two series 90 and 91 as possible anti- Candida agents. In addition, we also investigated the interaction between the hybrids and fluconazole, a commonly used antifungal drug. We evaluated the antifungal effect of aza-bicyclic 2-isoxazoline-acylhydrazone hybrid compounds against six Candida spp. strains that target planktonic cells. However, none of these new molecules were inhibitory active at the tested concentrations (2 to 1,024 µg/mL). Moreover, we analyzed the interaction between the ten new hybrid molecules and fluconazole using the checkerboard assay, employing two different methodologies for reading the plate. For this, one isolate fluconazole-resistant was selected. We observed that only one combination, 6-(4-tert-butylbenzoil)-4,5,6,6a-tetrahydro-3a-H-pirrole[3,2-d]isoxazole-3-carboxylic(furan-2-metilidene)-hydrazide (91e) and fluconazole, exhibited a synergistic interaction (FICI range 0.0781 to 0.4739). The combination successfully inhibited the growth of C. albicans CA2 fluconazole-resistant, and no interaction was observed in an isolate susceptible to fluconazole. Additionally, these results emphasize the continued need for research into new compounds and the importance of using combined approaches to increase their activity.