A Chemotype That Inhibits Three Unrelated Pathogenic Targets: The Botulinum Neurotoxin Serotype A Light Chain, P. falciparum Malaria, and the Ebola Filovirus
2011
Аутори
Opsenica, IgorBurnett, James C.
Gussio, Rick
Opsenica, Dejan
Todorović, Nina
Lanteri, Charlotte A.
Sciotti, Richard J.
Gettayacamin, Montip
Basilico, Nicoletta
Taramelli, Donatella
Nuss, Jonathan E.
Wanner, Laura
Panchal, Rekha G.
Šolaja, Bogdan
Bavari, Sina
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
A 1,7-bis(alkylamino)diazachrysene-based small molecule was previously identified as an inhibitor of the botulinum neurotoxin serotype A light chain metalloprotease. Subsequently, a variety of derivatives of this chemotype were synthesized to develop structure activity relationships, and all are inhibitors of the BoNT/A LC. Three-dimensional analyses indicated that half of the originally discovered 1,7-DAAC structure superimposed well with 4-amino-7-chloroquinolinebased antimalarial agents. This observation led to the discovery that several of the 1,7-DAAC derivatives are potent in vitro inhibitors of Plasmodium falciparum and, in general, are more efficacious against CQ-resistant strains than against CQ-susceptible strains. In addition, by inhibiting beta-hematin formation, the most efficacious 1,7-DAAC-based antimalarials employ a mechanism of action analogous to that of 4,7-ACQ-based antimalarials and are well tolerated by normal cells. One candidate was also effective when administ...ered orally in a rodent-based malaria model. Finally, the 1,7-DAAC-based derivatives were examined for Ebola filovirus inhibition in an assay employing Vero76 cells, and three provided promising antiviral activities and acceptably low toxicities.
Извор:
Journal of Medicinal Chemistry, 2011, 54, 5, 1157-1169Издавач:
- American Chemical Society (ACS)
Финансирање / пројекти:
- Синтеза аминохинолина и њихових деривата као антималарика и инхибитора ботулинум неуротоксина А (RS-172008)
- National Cancer Institute, National Institutes of Health [HHSN261200800001E]
- Serbian Academy of Sciences and Arts
- Defense Threat Reduction Agency [3.10084_09_RD_B, Y3CM 100505]
- NATOs Public Diplomacy Division [SfP983638]
DOI: 10.1021/jm100938u
ISSN: 0022-2623
PubMed: 21265542
WoS: 000287833300004
Scopus: 2-s2.0-79952265619
Институција/група
IHTMTY - JOUR AU - Opsenica, Igor AU - Burnett, James C. AU - Gussio, Rick AU - Opsenica, Dejan AU - Todorović, Nina AU - Lanteri, Charlotte A. AU - Sciotti, Richard J. AU - Gettayacamin, Montip AU - Basilico, Nicoletta AU - Taramelli, Donatella AU - Nuss, Jonathan E. AU - Wanner, Laura AU - Panchal, Rekha G. AU - Šolaja, Bogdan AU - Bavari, Sina PY - 2011 UR - https://cer.ihtm.bg.ac.rs/handle/123456789/901 AB - A 1,7-bis(alkylamino)diazachrysene-based small molecule was previously identified as an inhibitor of the botulinum neurotoxin serotype A light chain metalloprotease. Subsequently, a variety of derivatives of this chemotype were synthesized to develop structure activity relationships, and all are inhibitors of the BoNT/A LC. Three-dimensional analyses indicated that half of the originally discovered 1,7-DAAC structure superimposed well with 4-amino-7-chloroquinolinebased antimalarial agents. This observation led to the discovery that several of the 1,7-DAAC derivatives are potent in vitro inhibitors of Plasmodium falciparum and, in general, are more efficacious against CQ-resistant strains than against CQ-susceptible strains. In addition, by inhibiting beta-hematin formation, the most efficacious 1,7-DAAC-based antimalarials employ a mechanism of action analogous to that of 4,7-ACQ-based antimalarials and are well tolerated by normal cells. One candidate was also effective when administered orally in a rodent-based malaria model. Finally, the 1,7-DAAC-based derivatives were examined for Ebola filovirus inhibition in an assay employing Vero76 cells, and three provided promising antiviral activities and acceptably low toxicities. PB - American Chemical Society (ACS) T2 - Journal of Medicinal Chemistry T1 - A Chemotype That Inhibits Three Unrelated Pathogenic Targets: The Botulinum Neurotoxin Serotype A Light Chain, P. falciparum Malaria, and the Ebola Filovirus VL - 54 IS - 5 SP - 1157 EP - 1169 DO - 10.1021/jm100938u ER -
@article{ author = "Opsenica, Igor and Burnett, James C. and Gussio, Rick and Opsenica, Dejan and Todorović, Nina and Lanteri, Charlotte A. and Sciotti, Richard J. and Gettayacamin, Montip and Basilico, Nicoletta and Taramelli, Donatella and Nuss, Jonathan E. and Wanner, Laura and Panchal, Rekha G. and Šolaja, Bogdan and Bavari, Sina", year = "2011", abstract = "A 1,7-bis(alkylamino)diazachrysene-based small molecule was previously identified as an inhibitor of the botulinum neurotoxin serotype A light chain metalloprotease. Subsequently, a variety of derivatives of this chemotype were synthesized to develop structure activity relationships, and all are inhibitors of the BoNT/A LC. Three-dimensional analyses indicated that half of the originally discovered 1,7-DAAC structure superimposed well with 4-amino-7-chloroquinolinebased antimalarial agents. This observation led to the discovery that several of the 1,7-DAAC derivatives are potent in vitro inhibitors of Plasmodium falciparum and, in general, are more efficacious against CQ-resistant strains than against CQ-susceptible strains. In addition, by inhibiting beta-hematin formation, the most efficacious 1,7-DAAC-based antimalarials employ a mechanism of action analogous to that of 4,7-ACQ-based antimalarials and are well tolerated by normal cells. One candidate was also effective when administered orally in a rodent-based malaria model. Finally, the 1,7-DAAC-based derivatives were examined for Ebola filovirus inhibition in an assay employing Vero76 cells, and three provided promising antiviral activities and acceptably low toxicities.", publisher = "American Chemical Society (ACS)", journal = "Journal of Medicinal Chemistry", title = "A Chemotype That Inhibits Three Unrelated Pathogenic Targets: The Botulinum Neurotoxin Serotype A Light Chain, P. falciparum Malaria, and the Ebola Filovirus", volume = "54", number = "5", pages = "1157-1169", doi = "10.1021/jm100938u" }
Opsenica, I., Burnett, J. C., Gussio, R., Opsenica, D., Todorović, N., Lanteri, C. A., Sciotti, R. J., Gettayacamin, M., Basilico, N., Taramelli, D., Nuss, J. E., Wanner, L., Panchal, R. G., Šolaja, B.,& Bavari, S.. (2011). A Chemotype That Inhibits Three Unrelated Pathogenic Targets: The Botulinum Neurotoxin Serotype A Light Chain, P. falciparum Malaria, and the Ebola Filovirus. in Journal of Medicinal Chemistry American Chemical Society (ACS)., 54(5), 1157-1169. https://doi.org/10.1021/jm100938u
Opsenica I, Burnett JC, Gussio R, Opsenica D, Todorović N, Lanteri CA, Sciotti RJ, Gettayacamin M, Basilico N, Taramelli D, Nuss JE, Wanner L, Panchal RG, Šolaja B, Bavari S. A Chemotype That Inhibits Three Unrelated Pathogenic Targets: The Botulinum Neurotoxin Serotype A Light Chain, P. falciparum Malaria, and the Ebola Filovirus. in Journal of Medicinal Chemistry. 2011;54(5):1157-1169. doi:10.1021/jm100938u .
Opsenica, Igor, Burnett, James C., Gussio, Rick, Opsenica, Dejan, Todorović, Nina, Lanteri, Charlotte A., Sciotti, Richard J., Gettayacamin, Montip, Basilico, Nicoletta, Taramelli, Donatella, Nuss, Jonathan E., Wanner, Laura, Panchal, Rekha G., Šolaja, Bogdan, Bavari, Sina, "A Chemotype That Inhibits Three Unrelated Pathogenic Targets: The Botulinum Neurotoxin Serotype A Light Chain, P. falciparum Malaria, and the Ebola Filovirus" in Journal of Medicinal Chemistry, 54, no. 5 (2011):1157-1169, https://doi.org/10.1021/jm100938u . .