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. 2017 Jul 25;61(8):e00273-17.
doi: 10.1128/AAC.00273-17. Print 2017 Aug.

Chemoenzymatic Synthesis, Nanotization, and Anti-Aspergillus Activity of Optically Enriched Fluconazole Analogues

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Chemoenzymatic Synthesis, Nanotization, and Anti-Aspergillus Activity of Optically Enriched Fluconazole Analogues

Shashwat Malhotra et al. Antimicrob Agents Chemother. .
Free PMC article

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.

Keywords: Aspergillus; antifungal agents; chemoenzymatic synthesis; fluconazole.

Figures

FIG 1
FIG 1
CAL-B-catalyzed epoxide ring opening with open chain and cyclic aliphatic amines. Note that samples of each compound could also be prepared in racemic form by heating the epoxide and amine at 55°C in THF (see the supplemental material). The new stereogenic center is indicated by an asterisk.
FIG 2
FIG 2
In vitro release of (−)-S-3d from O-hexadecyl- (gray squares), O-decyl- (orange circles), and O-heptyl-derivatized (blue triangles) dextran nanoparticles.
FIG 3
FIG 3
In vitro antifungal activity of (−)-S-3d, amphotericin B, and their dextran nanoparticles. Lanes: a, negative control; b, empty O-alkyl dextran nanoparticles; c, amphotericin B; d, fluconazole; e, (−)-S-3d; f, O-heptyl nanoparticles containing (−)-S-3d; g, O-decyl nanoparticles containing (−)-S-3d; h, O-hexadecyl nanoparticles containing (−)-S-3d; i, O-heptyl nanoparticles containing amphotericin B; j, O-decyl nanoparticles containing amphotericin B; k, O-hexadecyl nanoparticles containing amphotericin B.
FIG 4
FIG 4
In vitro cytotoxicity assays for optically enriched (−)-S-3d and amphotericin B both in the free form and when encapsulated into dextran nanoparticles. (a) Hemolytic assay; (b and c) MTT-based assay using A459 (b) and U87 (c) cell lines.

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