Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen

Arielle Butts; Damian J Krysan; Jennifer A Martin; Louis DiDone; Erin K Bradley; Mitchell Mutz

doi:10.1371/journal.pone.0125927

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Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen

Journal article

Open access

Peer reviewed

Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen

Arielle Butts, Damian J Krysan, Jennifer A Martin, Louis DiDone, Erin K Bradley and Mitchell Mutz

PloS one, Vol.10(5), pp.e0125927-e0125927

2015

DOI: 10.1371/journal.pone.0125927

PMCID: PMC4446328

PMID: 26016941

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Abstract

Cryptococcosis is one of the most important invasive fungal infections and is a significant contributor to the mortality associated with HIV/AIDS. As part of our program to repurpose molecules related to the selective estrogen receptor modulator (SERM) tamoxifen as anti-cryptococcal agents, we have explored the structure-activity relationships of a set of structurally diverse SERMs and tamoxifen derivatives. Our data provide the first insights into the structural requirements for the antifungal activity of this scaffold. Three key molecular characteristics affecting anti-cryptococcal activity emerged from our studies: 1) the presence of an alkylamino group tethered to one of the aromatic rings of the triphenylethylene core; 2) an appropriately sized aliphatic substituent at the 2 position of the ethylene moiety; and 3) electronegative substituents on the aromatic rings modestly improved activity. Using a cell-based assay of calmodulin antagonism, we found that the anti-cryptococcal activity of the scaffold correlates with calmodulin inhibition. Finally, we developed a homology model of C. neoformans calmodulin and used it to rationalize the structural basis for the activity of these molecules. Taken together, these data and models provide a basis for the further optimization of this promising anti-cryptococcal scaffold.

Antifungal Agents - pharmacology

Microbial Sensitivity Tests

Estrogen Receptor Antagonists - pharmacology

Cryptococcosis - microbiology

Selective Estrogen Receptor Modulators

Tamoxifen - chemistry

Tamoxifen - pharmacology

Antifungal Agents - chemistry

Molecular Structure

Structure-Activity Relationship

Estrogen Receptor Antagonists - chemistry

Cryptococcus neoformans - drug effects

Details

Title: Subtitle: Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen
Creators: Arielle Butts - Department of Chemistry, University of Rochester, Rochester, NY 14642, United States of America
Damian J Krysan - Department of Pediatrics, University of Rochester, Rochester, NY 14642, United States of America; Department of Microbiology/Immunology, University of Rochester, Rochester, NY 14642, United States of America
Jennifer A Martin - Department of Pediatrics, University of Rochester, Rochester, NY 14642, United States of America
Louis DiDone - Department of Pediatrics, University of Rochester, Rochester, NY 14642, United States of America
Erin K Bradley - LigDCipher, San Diego, CA 92121, United States of America
Mitchell Mutz - Amplyx Pharmaceutical, San Diego, CA 92121, United States of America
Resource Type: Journal article
Publication Details: PloS one, Vol.10(5), pp.e0125927-e0125927
DOI: 10.1371/journal.pone.0125927
PMID: 26016941
PMCID: PMC4446328
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science
Grant note: 1R01AI091422 / NIAID NIH HHS R01 AI091422 / NIAID NIH HHS
Language: English
Date published: 2015
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
Record Identifier: 9984093224702771

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