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

Butts A, Martin JA, DiDone L, Bradley EK, Mutz M, Krysan DJ - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Rochester, Rochester, NY 14642, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Activity of commercially available SERM against C. neoformans and C. albicans.The structure, molecule number used in the text, name, minimum inhibitory concentration (MIC, μg/mL) against C.neoformans (first number) and MIC against C. albicans are provided.
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pone.0125927.g002: Activity of commercially available SERM against C. neoformans and C. albicans.The structure, molecule number used in the text, name, minimum inhibitory concentration (MIC, μg/mL) against C.neoformans (first number) and MIC against C. albicans are provided.

Mentions: We assembled a collection of commercially available, structurally-distinct estrogen receptor antagonists (Fig 1) and determined their activity against C. neoformans and C. albicans using standardized CLSI methods. We included previously reported [12, 18] data for tamoxifen, its metabolites endoxifen and hydroxy-tamoxifen, toremifene and idoxifen (Fig 2, molecules 1–5). Tamoxifen and toremifene are less active against C. albicans as compared to C. neoformans. We have also previously shown that the two major metabolites of tamoxifen, 4-hydroxy-tamoxifen (Afimoxifen, Fig 2, molecule 2) and endoxifen (Fig 2, molecule 3) are more active against C. neoformans than the parent drug [12]. Against C. albicans, the improved activity of the metabolites relative to the parent tamoxifen is more dramatic; the MIC for afimoxifen (molecule 2) and endoxifen (molecule 3) is 8-fold lower than tamoxifen. The improved activity of the afimoxifen and endoxifen metabolites may explain why tamoxifen is efficacious in a mouse model of disseminated candidiasis despite its relatively poor MIC [18]. The molecules with improved activity against C. albicans relative to tamoxifen (Fig 2, molecules 2, 3, 7, and 8) have hydroxyl- or alkoxyl- substituents at the 4-position of ring A (Fig 1), suggesting that this moiety is particularly important for anti-candidal activity.


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

Butts A, Martin JA, DiDone L, Bradley EK, Mutz M, Krysan DJ - PLoS ONE (2015)

Activity of commercially available SERM against C. neoformans and C. albicans.The structure, molecule number used in the text, name, minimum inhibitory concentration (MIC, μg/mL) against C.neoformans (first number) and MIC against C. albicans are provided.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4446328&req=5

pone.0125927.g002: Activity of commercially available SERM against C. neoformans and C. albicans.The structure, molecule number used in the text, name, minimum inhibitory concentration (MIC, μg/mL) against C.neoformans (first number) and MIC against C. albicans are provided.
Mentions: We assembled a collection of commercially available, structurally-distinct estrogen receptor antagonists (Fig 1) and determined their activity against C. neoformans and C. albicans using standardized CLSI methods. We included previously reported [12, 18] data for tamoxifen, its metabolites endoxifen and hydroxy-tamoxifen, toremifene and idoxifen (Fig 2, molecules 1–5). Tamoxifen and toremifene are less active against C. albicans as compared to C. neoformans. We have also previously shown that the two major metabolites of tamoxifen, 4-hydroxy-tamoxifen (Afimoxifen, Fig 2, molecule 2) and endoxifen (Fig 2, molecule 3) are more active against C. neoformans than the parent drug [12]. Against C. albicans, the improved activity of the metabolites relative to the parent tamoxifen is more dramatic; the MIC for afimoxifen (molecule 2) and endoxifen (molecule 3) is 8-fold lower than tamoxifen. The improved activity of the afimoxifen and endoxifen metabolites may explain why tamoxifen is efficacious in a mouse model of disseminated candidiasis despite its relatively poor MIC [18]. The molecules with improved activity against C. albicans relative to tamoxifen (Fig 2, molecules 2, 3, 7, and 8) have hydroxyl- or alkoxyl- substituents at the 4-position of ring A (Fig 1), suggesting that this moiety is particularly important for anti-candidal activity.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Rochester, Rochester, NY 14642, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus