Structure-Activity Relationships for the Antifungal Activity of Selective Estrogen Receptor Antagonists Related to Tamoxifen

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

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 anticryptococcal 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 cellbased 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.

Original languageEnglish (US)
Article numbere0125927
JournalPloS one
Volume10
Issue number5
DOIs
StatePublished - May 1 2015

Fingerprint

tamoxifen
calmodulin
structure-activity relationships
Tamoxifen
Calmodulin
Structure-Activity Relationship
Scaffolds
Selective Estrogen Receptor Modulators
antagonists
aromatic compounds
Cryptococcosis
Molecules
ethylene
Assays
Acquired Immunodeficiency Syndrome
chemical derivatives
HIV
Derivatives
Mortality
assays

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Structure-Activity Relationships for the Antifungal Activity of Selective Estrogen Receptor Antagonists Related to Tamoxifen. / Butts, Arielle; Martin, Jennifer A.; DiDone, Louis; Bradley, Erin K.; Mutz, Mitchell; Krysan, Damian J.

In: PloS one, Vol. 10, No. 5, e0125927, 01.05.2015.

Research output: Contribution to journalArticle

Butts, Arielle ; Martin, Jennifer A. ; DiDone, Louis ; Bradley, Erin K. ; Mutz, Mitchell ; Krysan, Damian J. / Structure-Activity Relationships for the Antifungal Activity of Selective Estrogen Receptor Antagonists Related to Tamoxifen. In: PloS one. 2015 ; Vol. 10, No. 5.
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