Abstract
Despite recent advances in diagnostic and therapeutic methods in antifungal research, aspergillosis still remains a leading cause of morbidity and mortality. One strategy to address this problem is to enhance the activity spectrum of known antifungals, and we now report the first successful application of Candida antarctica lipase (CAL) for the preparation of optically enriched fluconazole analogues. Anti-Aspergillus activity was observed for an optically enriched derivative, (-)-S-2-(2',4'-difluorophenyl)-1-hexyl-amino-3-(1‴,2‴,4‴)triazol-1‴-yl-propan-2-ol, which exhibits MIC values of 15.6 μg/ml and 7.8 μg/disc in broth microdilution and disc diffusion assays, respectively. This compound is tolerated by mammalian erythrocytes and cell lines (A549 and U87) at concentrations of up to 1,000 μg/ml. When incorporated into dextran nanoparticles, the novel, optically enriched fluconazole analogue exhibited improved antifungal activity against Aspergillus fumigatus (MIC, 1.63 μg/ml). These results not only demonstrate the ability of biocatalytic approaches to yield novel, optically enriched fluconazole derivatives but also suggest that enantiomerically pure fluconazole derivatives, and their nanotized counterparts, exhibiting anti-Aspergillus activity may have reduced toxicity.
Highlights
Despite recent advances in diagnostic and therapeutic methods in antifungal research, aspergillosis still remains a leading cause of morbidity and mortality
Three different immobilized lipases were evaluated for their ability to catalyze this reaction: Candida rugosa lipase (CRL), porcine pancreatic lipase (PPL), and Candida antarctica lipase (CAL)-B
The ring-opening reactions catalyzed by CRL and PPL were of no practical utility, when the reaction was performed in the presence of CAL-B in tetrahydrofuran (THF) as solvent, the desired products (3a to -j, 5a, and 5b) were obtained with good yields in optically enriched forms (Fig. 1; see Tables S1 and S2 in the supplemental material)
Summary
Despite recent advances in diagnostic and therapeutic methods in antifungal research, aspergillosis still remains a leading cause of morbidity and mortality. One strategy to address this problem is to enhance the activity spectrum of known antifungals, and we report the first successful application of Candida antarctica lipase (CAL) for the preparation of optically enriched fluconazole analogues. AntiAspergillus activity was observed for an optically enriched derivative, (Ϫ)-S-2-(2=,4=difluorophenyl)-1-hexyl-amino-3-(1ٞ,2ٞ,4ٞ)triazol-1ٞ-yl-propan-2-ol, which exhibits MIC values of 15.6 g/ml and 7.8 g/disc in broth microdilution and disc diffusion assays, respectively. When incorporated into dextran nanoparticles, the novel, optically enriched fluconazole analogue exhibited improved antifungal activity against Aspergillus fumigatus (MIC, 1.63 g/ml). In vitro assays show that the optically enriched analogues exhibit more potent antifungal activity than the corresponding racemic mixtures This bioactivity can be enhanced by their encapsulation in dextran-based nanoparticles [19]
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