Chemoenzymatic synthesis, nanotization and anti- aspergillus activity of optically enriched fluconazole analogues

Despite recent advances in diagnostic and therapeutic advances 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 analogs. 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 microbroth dilution and disc diffusion assays, respectively. This compound is tolerated by mammalian erythrocytes and cell lines (A549 and U87) at concentrations of up to 1000 μg/mL. When incorporated into dextran nanoparticles, the novel, optically enriched fluconazole analog 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 nanotised counterparts, exhibiting anti-Aspergillus activity may have reduced toxicity

Biocatalytic acylation of Efavirenz intermediate: Unexpected novel product formation

1174-1177During attempted biocatalytic resolution of (R/S)-5-chloro--(cyclopropylethynyl)-2-amino--(trifluoromethyl) benzenemetha­nol containing a tertiary hydroxyl group, a novel, unexpected benzoxazine derivative (Efavirenz analogue) is formed during the lipase B from Candida antarctica (Novozyme -435) catalyzed reaction of Efavirenz intermediate (R/S)-5-chloro--(cyclo­pro­pylethynyl)-2-amino--(trifluoromethyl) benzenemethanol 1 using vinyl acetate