Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria
2014
Аутори
Videnović, MilicaOpsenica, Dejan M.
Burnett, James C.
Gomba, Laura
Nuss, Jonathan E.
Selaković, Života
Konstantinović, Jelena M.
Krstić-Ristivojević, Maja
Šegan, Sandra B.
Zlatović, Mario
Sciotti, Richard J.
Bavari, Sina
Šolaja, Bogdan A.
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
Significantly more potent second generation 4-amino-7-chloroquinoline (4,7-ACQ) based inhibitors of the botulinum neurotoxin serotype A (BoNT/A) light chain were synthesized. Introducing an amino group at the C(3) position of the cholate component markedly increased potency (IC50 values for such derivatives ranged from 0.81 to 2.27 mu M). Two additional subclasses were prepared: bis(steroidal)-4,7-ACQ derivatives and bis(4,7-ACQ)cholate derivatives; both classes provided inhibitors with nanomolar-range potencies (e.g., the K-i of compound 67 is 0.10 mu M). During BoNT/A challenge using primary neurons, select derivatives protected SNAP-25 by up to 89%. Docking simulations were performed to rationalize the compounds' in vitro potencies. In addition to specific residue contacts, coordination of the enzyme's catalytic zinc and expulsion of the enzyme's catalytic water were a consistent theme. With respect to antimalarial activity, the compounds provided better IC90 activities against chlo...roquine resistant (CQR) malaria than CQ, and seven compounds were more active than mefloquine against CQR strain W2.
Извор:
Journal of Medicinal Chemistry, 2014, 57, 10, 4134-4153Издавач:
- Amer Chemical Soc, Washington
Финансирање / пројекти:
- Синтеза аминохинолина и њихових деривата као антималарика и инхибитора ботулинум неуротоксина А (RS-172008)
- National Cancer Institute, National Institutes of Health (U.S.) [HHSN261200800001E]
- National Institute of Allergy and Infectious Diseases (U.S.) [5-U01AI082051-02]
DOI: 10.1021/jm500033r
ISSN: 0022-2623
PubMed: 24742203
WoS: 000336510100017
Scopus: 2-s2.0-84901253130
Институција/група
Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Videnović, Milica AU - Opsenica, Dejan M. AU - Burnett, James C. AU - Gomba, Laura AU - Nuss, Jonathan E. AU - Selaković, Života AU - Konstantinović, Jelena M. AU - Krstić-Ristivojević, Maja AU - Šegan, Sandra B. AU - Zlatović, Mario AU - Sciotti, Richard J. AU - Bavari, Sina AU - Šolaja, Bogdan A. PY - 2014 UR - https://cherry.chem.bg.ac.rs/handle/123456789/1781 AB - Significantly more potent second generation 4-amino-7-chloroquinoline (4,7-ACQ) based inhibitors of the botulinum neurotoxin serotype A (BoNT/A) light chain were synthesized. Introducing an amino group at the C(3) position of the cholate component markedly increased potency (IC50 values for such derivatives ranged from 0.81 to 2.27 mu M). Two additional subclasses were prepared: bis(steroidal)-4,7-ACQ derivatives and bis(4,7-ACQ)cholate derivatives; both classes provided inhibitors with nanomolar-range potencies (e.g., the K-i of compound 67 is 0.10 mu M). During BoNT/A challenge using primary neurons, select derivatives protected SNAP-25 by up to 89%. Docking simulations were performed to rationalize the compounds' in vitro potencies. In addition to specific residue contacts, coordination of the enzyme's catalytic zinc and expulsion of the enzyme's catalytic water were a consistent theme. With respect to antimalarial activity, the compounds provided better IC90 activities against chloroquine resistant (CQR) malaria than CQ, and seven compounds were more active than mefloquine against CQR strain W2. PB - Amer Chemical Soc, Washington T2 - Journal of Medicinal Chemistry T1 - Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria VL - 57 IS - 10 SP - 4134 EP - 4153 DO - 10.1021/jm500033r ER -
@article{ author = "Videnović, Milica and Opsenica, Dejan M. and Burnett, James C. and Gomba, Laura and Nuss, Jonathan E. and Selaković, Života and Konstantinović, Jelena M. and Krstić-Ristivojević, Maja and Šegan, Sandra B. and Zlatović, Mario and Sciotti, Richard J. and Bavari, Sina and Šolaja, Bogdan A.", year = "2014", abstract = "Significantly more potent second generation 4-amino-7-chloroquinoline (4,7-ACQ) based inhibitors of the botulinum neurotoxin serotype A (BoNT/A) light chain were synthesized. Introducing an amino group at the C(3) position of the cholate component markedly increased potency (IC50 values for such derivatives ranged from 0.81 to 2.27 mu M). Two additional subclasses were prepared: bis(steroidal)-4,7-ACQ derivatives and bis(4,7-ACQ)cholate derivatives; both classes provided inhibitors with nanomolar-range potencies (e.g., the K-i of compound 67 is 0.10 mu M). During BoNT/A challenge using primary neurons, select derivatives protected SNAP-25 by up to 89%. Docking simulations were performed to rationalize the compounds' in vitro potencies. In addition to specific residue contacts, coordination of the enzyme's catalytic zinc and expulsion of the enzyme's catalytic water were a consistent theme. With respect to antimalarial activity, the compounds provided better IC90 activities against chloroquine resistant (CQR) malaria than CQ, and seven compounds were more active than mefloquine against CQR strain W2.", publisher = "Amer Chemical Soc, Washington", journal = "Journal of Medicinal Chemistry", title = "Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria", volume = "57", number = "10", pages = "4134-4153", doi = "10.1021/jm500033r" }
Videnović, M., Opsenica, D. M., Burnett, J. C., Gomba, L., Nuss, J. E., Selaković, Ž., Konstantinović, J. M., Krstić-Ristivojević, M., Šegan, S. B., Zlatović, M., Sciotti, R. J., Bavari, S.,& Šolaja, B. A.. (2014). Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria. in Journal of Medicinal Chemistry Amer Chemical Soc, Washington., 57(10), 4134-4153. https://doi.org/10.1021/jm500033r
Videnović M, Opsenica DM, Burnett JC, Gomba L, Nuss JE, Selaković Ž, Konstantinović JM, Krstić-Ristivojević M, Šegan SB, Zlatović M, Sciotti RJ, Bavari S, Šolaja BA. Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria. in Journal of Medicinal Chemistry. 2014;57(10):4134-4153. doi:10.1021/jm500033r .
Videnović, Milica, Opsenica, Dejan M., Burnett, James C., Gomba, Laura, Nuss, Jonathan E., Selaković, Života, Konstantinović, Jelena M., Krstić-Ristivojević, Maja, Šegan, Sandra B., Zlatović, Mario, Sciotti, Richard J., Bavari, Sina, Šolaja, Bogdan A., "Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria" in Journal of Medicinal Chemistry, 57, no. 10 (2014):4134-4153, https://doi.org/10.1021/jm500033r . .