Chemoenzymatic Synthesis, Nanotization, and Anti-Aspergillus Activity of Optically Enriched Fluconazole Analogues
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...
Published in: | Antimicrobial Agents and Chemotherapy |
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Online Access: | http://dx.doi.org/10.1128/aac.00273-17 https://journals.asm.org/doi/pdf/10.1128/AAC.00273-17 |
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crasmicro:10.1128/aac.00273-17 2024-09-15T17:44:44+00:00 Chemoenzymatic Synthesis, Nanotization, and Anti-Aspergillus Activity of Optically Enriched Fluconazole Analogues Malhotra, Shashwat Singh, Seema Rana, Neha Tomar, Shilpi Bhatnagar, Priyanka Gupta, Mohit Singh, Suraj K. Singh, Brajendra K. Chhillar, Anil K. Prasad, Ashok K. Len, Christophe Kumar, Pradeep Gupta, Kailash C. Varma, Anjani J. Kuhad, Ramesh C. Sharma, Gainda L. Parmar, Virinder S. Richards, Nigel G. J. 2017 http://dx.doi.org/10.1128/aac.00273-17 https://journals.asm.org/doi/pdf/10.1128/AAC.00273-17 en eng American Society for Microbiology https://journals.asm.org/non-commercial-tdm-license Antimicrobial Agents and Chemotherapy volume 61, issue 8 ISSN 0066-4804 1098-6596 journal-article 2017 crasmicro https://doi.org/10.1128/aac.00273-17 2024-07-22T04:08:52Z 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. Article in Journal/Newspaper Antarc* Antarctica ASM Journals (American Society for Microbiology) Antimicrobial Agents and Chemotherapy 61 8 |
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English |
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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. |
format |
Article in Journal/Newspaper |
author |
Malhotra, Shashwat Singh, Seema Rana, Neha Tomar, Shilpi Bhatnagar, Priyanka Gupta, Mohit Singh, Suraj K. Singh, Brajendra K. Chhillar, Anil K. Prasad, Ashok K. Len, Christophe Kumar, Pradeep Gupta, Kailash C. Varma, Anjani J. Kuhad, Ramesh C. Sharma, Gainda L. Parmar, Virinder S. Richards, Nigel G. J. |
spellingShingle |
Malhotra, Shashwat Singh, Seema Rana, Neha Tomar, Shilpi Bhatnagar, Priyanka Gupta, Mohit Singh, Suraj K. Singh, Brajendra K. Chhillar, Anil K. Prasad, Ashok K. Len, Christophe Kumar, Pradeep Gupta, Kailash C. Varma, Anjani J. Kuhad, Ramesh C. Sharma, Gainda L. Parmar, Virinder S. Richards, Nigel G. J. Chemoenzymatic Synthesis, Nanotization, and Anti-Aspergillus Activity of Optically Enriched Fluconazole Analogues |
author_facet |
Malhotra, Shashwat Singh, Seema Rana, Neha Tomar, Shilpi Bhatnagar, Priyanka Gupta, Mohit Singh, Suraj K. Singh, Brajendra K. Chhillar, Anil K. Prasad, Ashok K. Len, Christophe Kumar, Pradeep Gupta, Kailash C. Varma, Anjani J. Kuhad, Ramesh C. Sharma, Gainda L. Parmar, Virinder S. Richards, Nigel G. J. |
author_sort |
Malhotra, Shashwat |
title |
Chemoenzymatic Synthesis, Nanotization, and Anti-Aspergillus Activity of Optically Enriched Fluconazole Analogues |
title_short |
Chemoenzymatic Synthesis, Nanotization, and Anti-Aspergillus Activity of Optically Enriched Fluconazole Analogues |
title_full |
Chemoenzymatic Synthesis, Nanotization, and Anti-Aspergillus Activity of Optically Enriched Fluconazole Analogues |
title_fullStr |
Chemoenzymatic Synthesis, Nanotization, and Anti-Aspergillus Activity of Optically Enriched Fluconazole Analogues |
title_full_unstemmed |
Chemoenzymatic Synthesis, Nanotization, and Anti-Aspergillus Activity of Optically Enriched Fluconazole Analogues |
title_sort |
chemoenzymatic synthesis, nanotization, and anti-aspergillus activity of optically enriched fluconazole analogues |
publisher |
American Society for Microbiology |
publishDate |
2017 |
url |
http://dx.doi.org/10.1128/aac.00273-17 https://journals.asm.org/doi/pdf/10.1128/AAC.00273-17 |
genre |
Antarc* Antarctica |
genre_facet |
Antarc* Antarctica |
op_source |
Antimicrobial Agents and Chemotherapy volume 61, issue 8 ISSN 0066-4804 1098-6596 |
op_rights |
https://journals.asm.org/non-commercial-tdm-license |
op_doi |
https://doi.org/10.1128/aac.00273-17 |
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Antimicrobial Agents and Chemotherapy |
container_volume |
61 |
container_issue |
8 |
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1810492383853281280 |