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

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

Author information

1
Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi, India.
2
Kirori Mal College, Department of Chemistry, University of Delhi, Delhi, India.
3
CSIR-Institute of Genomics and Integrative Biology, Delhi, India.
4
Centre for Biotechnology, Maharishi Dayanand University, Rohtak, Haryana, India.
5
Sorbonne Universités, Université de Technologie de Compiègne, Ecole Supérieure de Chimie Organique et Minérale, Compiègne, France.
6
School of Chemical Sciences, Central University of Haryana, Mahendragarh, Haryana, India.
7
CSIR-Institute of Genomics and Integrative Biology, Delhi, India drglsharma@hotmail.com virparmar@gmail.com RichardsN14@cardiff.ac.uk.
8
Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi, India drglsharma@hotmail.com virparmar@gmail.com RichardsN14@cardiff.ac.uk.
9
Institute of Advanced Sciences, Dartmouth, Massachusetts, USA.
10
School of Chemistry, Cardiff University, Park Place, Cardiff, United Kingdom drglsharma@hotmail.com virparmar@gmail.com RichardsN14@cardiff.ac.uk.

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

PMID:
28607028
PMCID:
PMC5527590
DOI:
10.1128/AAC.00273-17
[Indexed for MEDLINE]
Free PMC Article

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