Novel Fluconazole Derivatives with Promising Antifungal Activity

Authors

Nishad Thamban Chandrika, University of KentuckyFollow
Sanjib K. Shrestha, University of KentuckyFollow
Huy X. Ngo, University of KentuckyFollow
Kaitlind C. Howard, University of KentuckyFollow
Sylvie Garneau-Tsodikova, University of KentuckyFollow

Abstract

The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activities of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against mammalian cells. The best compounds from our study exhibited broad-spectrum activity against most of the fungal strains tested, with excellent MIC values against a number of clinical isolates. The most promising compounds were found to be less hemolytic than the least hemolytic FDA-approved azole antifungal agent voriconazole (VOR). Finally, we demonstrated that the synthetic alkyl-amino FLC analogues displayed chain-dependent fungal membrane disruption as well as inhibition of ergosterol biosynthesis as possible mechanisms of action.

Document Type

Article

Publication Date

2-1-2018

Notes/Citation Information

Published in Bioorganic & Medicinal Chemistry, v. 26, issue 3, p. 573-580.

© 2017 Elsevier Ltd. All rights reserved.

This manuscript version is made available under the CC‐BY‐NC‐ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/.

The document available for download is the author's post-peer-review final draft of the article.

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.bmc.2017.12.018

Funding Information

This work was supported by startup funds from the University of Kentucky (to S.G.-T.) and by NIH grant AI090048 (to S.G.-T.). H.X.N. was in part supported by a Pharmaceutical Sciences Excellence in Graduate Achievement Fellowship from the College of Pharmacy at the University of Kentucky.

Related Content

Refer to Web version on PubMed Central for supplementary material.

Repository Citation

Thamban Chandrika, Nishad; Shrestha, Sanjib K.; Ngo, Huy X.; Howard, Kaitlind C.; and Garneau-Tsodikova, Sylvie, "Novel Fluconazole Derivatives with Promising Antifungal Activity" (2018). Pharmaceutical Sciences Faculty Publications. 121.
https://uknowledge.uky.edu/ps_facpub/121