Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen.
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...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0125927 |
| _version_ | 1819115227360264192 |
|---|---|
| author | Arielle Butts Jennifer A Martin Louis DiDone Erin K Bradley Mitchell Mutz Damian J Krysan |
| author_facet | Arielle Butts Jennifer A Martin Louis DiDone Erin K Bradley Mitchell Mutz Damian J Krysan |
| author_sort | Arielle Butts |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T04:57:50Z |
| format | Article |
| id | doaj.art-d788779a16c84687bcf4f7424a3d50c4 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T04:57:50Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-d788779a16c84687bcf4f7424a3d50c42022-12-21T18:38:20ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01105e012592710.1371/journal.pone.0125927Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen.Arielle ButtsJennifer A MartinLouis DiDoneErin K BradleyMitchell MutzDamian J KrysanCryptococcosis 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.https://doi.org/10.1371/journal.pone.0125927 |
| spellingShingle | Arielle Butts Jennifer A Martin Louis DiDone Erin K Bradley Mitchell Mutz Damian J Krysan Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen. PLoS ONE |
| title | Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen. |
| title_full | Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen. |
| title_fullStr | Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen. |
| title_full_unstemmed | Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen. |
| title_short | Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen. |
| title_sort | structure activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen |
| url | https://doi.org/10.1371/journal.pone.0125927 |
| work_keys_str_mv | AT ariellebutts structureactivityrelationshipsfortheantifungalactivityofselectiveestrogenreceptorantagonistsrelatedtotamoxifen AT jenniferamartin structureactivityrelationshipsfortheantifungalactivityofselectiveestrogenreceptorantagonistsrelatedtotamoxifen AT louisdidone structureactivityrelationshipsfortheantifungalactivityofselectiveestrogenreceptorantagonistsrelatedtotamoxifen AT erinkbradley structureactivityrelationshipsfortheantifungalactivityofselectiveestrogenreceptorantagonistsrelatedtotamoxifen AT mitchellmutz structureactivityrelationshipsfortheantifungalactivityofselectiveestrogenreceptorantagonistsrelatedtotamoxifen AT damianjkrysan structureactivityrelationshipsfortheantifungalactivityofselectiveestrogenreceptorantagonistsrelatedtotamoxifen |