title: Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen.
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.
authors.affiliation: Department of Chemistry, University of Rochester, Rochester, NY 14642, United States of America.
authors.forename: Arielle
authors.initials: A
authors.lastname: Butts
authors.affiliation: Department of Pediatrics, University of Rochester, Rochester, NY 14642, United States of America.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Martin
authors.affiliation: Department of Pediatrics, University of Rochester, Rochester, NY 14642, United States of America.
authors.forename: Louis
authors.initials: L
authors.lastname: DiDone
authors.affiliation: LigDCipher, San Diego, CA 92121, United States of America.
authors.forename: Erin K
authors.initials: EK
authors.lastname: Bradley
authors.affiliation: Amplyx Pharmaceutical, San Diego, CA 92121, United States of America.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Mutz
authors.affiliation: 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.
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Krysan
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D003453:Cryptococcosis / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000187:drug effects; D065171:Estrogen Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D020845:Selective Estrogen Receptor Modulators; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D065171:Estrogen Receptor Antagonists; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen