N,N′-diaryl-bishydrazones in a biphenyl platform: Broad spectrum antifungal agents

Nishad Thamban Chandrika; Emily K. Dennis; Sanjib K. Shrestha; Huy X. Ngo; Keith D. Green; Stefan Kwiatkowski; Agripina Gabriela Deaciuc; Linda P. Dwoskin; David S. Watt; Sylvie Garneau-Tsodikova

doi:10.1016/j.ejmech.2018.12.042

N,N′-diaryl-bishydrazones in a biphenyl platform: Broad spectrum antifungal agents

Nishad Thamban Chandrika, Emily K. Dennis, Sanjib K. Shrestha, Huy X. Ngo, Keith D. Green, Stefan Kwiatkowski, Agripina Gabriela Deaciuc, Linda P. Dwoskin, David S. Watt, Sylvie Garneau-Tsodikova

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12 Scopus citations

Abstract

N,N′-Diaryl-bishydrazones of [1,1′-biphenyl]-3,4′-dicarboxaldehyde, [1,1′-biphenyl]-4,4′-dicarboxaldehyde, and 4,4′-bisacetyl-1,1-biphenyl exhibited excellent antifungal activity against a broad spectrum of filamentous and non-filamentous fungi. These N,N′-diaryl-bishydrazones displayed no antibacterial activity in contrast to previously reported N,N′-diamidino-bishydrazones and N-amidino-N′-aryl-bishydrazones. The leading candidate, 4,4′-bis((E)-1-(2-(4-fluorophenyl)hydrazono)ethyl)-1,1′-biphenyl, displayed less hemolysis of murine red blood cells at concentrations at or below that of a control antifungal agent (voriconazole), was fungistatic in a time-kill study, and possessed no mammalian cytotoxicity and no toxicity with respect to hERG inhibition.

Original language	English
Pages (from-to)	273-281
Number of pages	9
Journal	European Journal of Medicinal Chemistry
Volume	164
DOIs	https://doi.org/10.1016/j.ejmech.2018.12.042
State	Published - Feb 15 2019

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Masson SAS

Funding

This work was supported by startup funds from the College of Pharmacy at the University of Kentucky (to S.G.-T.). D.S.W. was supported by CA172379 from the NIH . D.S.W. was also supported by the Office of the Dean of the College of Medicine , by the Center for Pharmaceutical Research and Innovation in the College of Pharmacy , and by NIH Grant Number P30 GM110787 from the National Institute of General Medical Sciences to L. Hersh, PI. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the NIGMS. D.S.W. was also supported by the Office of the Assistant Secretary of Defense for Health Affairs , through the Prostate Cancer Research Program under Award No. W81XWH-16-1-0635 . Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense.

Funders	Funder number
Center for Pharmaceutical Research and Innovation in the College of Pharmacy
Office of the Assistant Secretary of Defense for Health Affairs
National Institutes of Health (NIH)	CA172379
National Institute of General Medical Sciences	P30GM110787
University of Kentucky
DOD Prostate Cancer Research Program	W81XWH-16-1-0635

Keywords

Aspergillus sp.
Candida albicans
Cytotoxicity
Hemolysis
Non-albicans Candida
hERG channel

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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title = "N,N′-diaryl-bishydrazones in a biphenyl platform: Broad spectrum antifungal agents",

abstract = "N,N′-Diaryl-bishydrazones of [1,1′-biphenyl]-3,4′-dicarboxaldehyde, [1,1′-biphenyl]-4,4′-dicarboxaldehyde, and 4,4′-bisacetyl-1,1-biphenyl exhibited excellent antifungal activity against a broad spectrum of filamentous and non-filamentous fungi. These N,N′-diaryl-bishydrazones displayed no antibacterial activity in contrast to previously reported N,N′-diamidino-bishydrazones and N-amidino-N′-aryl-bishydrazones. The leading candidate, 4,4′-bis((E)-1-(2-(4-fluorophenyl)hydrazono)ethyl)-1,1′-biphenyl, displayed less hemolysis of murine red blood cells at concentrations at or below that of a control antifungal agent (voriconazole), was fungistatic in a time-kill study, and possessed no mammalian cytotoxicity and no toxicity with respect to hERG inhibition.",

keywords = "Aspergillus sp., Candida albicans, Cytotoxicity, Hemolysis, Non-albicans Candida, hERG channel",

author = "{Thamban Chandrika}, Nishad and Dennis, {Emily K.} and Shrestha, {Sanjib K.} and Ngo, {Huy X.} and Green, {Keith D.} and Stefan Kwiatkowski and Deaciuc, {Agripina Gabriela} and Dwoskin, {Linda P.} and Watt, {David S.} and Sylvie Garneau-Tsodikova",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Masson SAS",

year = "2019",

month = feb,

day = "15",

doi = "10.1016/j.ejmech.2018.12.042",

language = "English",

volume = "164",

pages = "273--281",

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T2 - Broad spectrum antifungal agents

AU - Thamban Chandrika, Nishad

AU - Dennis, Emily K.

AU - Shrestha, Sanjib K.

AU - Ngo, Huy X.

AU - Green, Keith D.

AU - Kwiatkowski, Stefan

AU - Deaciuc, Agripina Gabriela

AU - Dwoskin, Linda P.

AU - Watt, David S.

AU - Garneau-Tsodikova, Sylvie

PY - 2019/2/15

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N2 - N,N′-Diaryl-bishydrazones of [1,1′-biphenyl]-3,4′-dicarboxaldehyde, [1,1′-biphenyl]-4,4′-dicarboxaldehyde, and 4,4′-bisacetyl-1,1-biphenyl exhibited excellent antifungal activity against a broad spectrum of filamentous and non-filamentous fungi. These N,N′-diaryl-bishydrazones displayed no antibacterial activity in contrast to previously reported N,N′-diamidino-bishydrazones and N-amidino-N′-aryl-bishydrazones. The leading candidate, 4,4′-bis((E)-1-(2-(4-fluorophenyl)hydrazono)ethyl)-1,1′-biphenyl, displayed less hemolysis of murine red blood cells at concentrations at or below that of a control antifungal agent (voriconazole), was fungistatic in a time-kill study, and possessed no mammalian cytotoxicity and no toxicity with respect to hERG inhibition.

AB - N,N′-Diaryl-bishydrazones of [1,1′-biphenyl]-3,4′-dicarboxaldehyde, [1,1′-biphenyl]-4,4′-dicarboxaldehyde, and 4,4′-bisacetyl-1,1-biphenyl exhibited excellent antifungal activity against a broad spectrum of filamentous and non-filamentous fungi. These N,N′-diaryl-bishydrazones displayed no antibacterial activity in contrast to previously reported N,N′-diamidino-bishydrazones and N-amidino-N′-aryl-bishydrazones. The leading candidate, 4,4′-bis((E)-1-(2-(4-fluorophenyl)hydrazono)ethyl)-1,1′-biphenyl, displayed less hemolysis of murine red blood cells at concentrations at or below that of a control antifungal agent (voriconazole), was fungistatic in a time-kill study, and possessed no mammalian cytotoxicity and no toxicity with respect to hERG inhibition.

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KW - Candida albicans

KW - Cytotoxicity

KW - Hemolysis

KW - Non-albicans Candida

KW - hERG channel

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ER -

N,N′-diaryl-bishydrazones in a biphenyl platform: Broad spectrum antifungal agents

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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