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Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria

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2014
1578.pdf (4.498Mb)
Authors
Videnović, Milica
Opsenica, Dejan
Burnett, James C.
Gomba, Laura
Nuss, Jonathan E.
Selaković, Života
Konstantinović, Jelena M.
Krstic, Maja
Šegan, Sandra
Zlatović, Mario
Sciotti, Richard J.
Bavari, Sina
Šolaja, Bogdan
Article (Published version)
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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 chlo...roquine resistant (CQR) malaria than CQ, and seven compounds were more active than mefloquine against CQR strain W2.

Source:
Journal of Medicinal Chemistry, 2014, 57, 10, 4134-4153
Publisher:
  • American Chemical Society (ACS)
Funding / projects:
  • The synthesis of aminoquinoline-based antimalarials and botulinum neurotoxin A inhibitors (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
[ Google Scholar ]
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URI
https://cer.ihtm.bg.ac.rs/handle/123456789/1580
Collections
  • Radovi istraživača / Researchers' publications
Institution/Community
IHTM
TY  - JOUR
AU  - Videnović, Milica
AU  - Opsenica, Dejan
AU  - Burnett, James C.
AU  - Gomba, Laura
AU  - Nuss, Jonathan E.
AU  - Selaković, Života
AU  - Konstantinović, Jelena M.
AU  - Krstic, Maja
AU  - Šegan, Sandra
AU  - Zlatović, Mario
AU  - Sciotti, Richard J.
AU  - Bavari, Sina
AU  - Šolaja, Bogdan
PY  - 2014
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/1580
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  - American Chemical Society (ACS)
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 and Burnett, James C. and Gomba, Laura and Nuss, Jonathan E. and Selaković, Života and Konstantinović, Jelena M. and Krstic, Maja and Šegan, Sandra and Zlatović, Mario and Sciotti, Richard J. and Bavari, Sina and Šolaja, Bogdan",
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 = "American Chemical Society (ACS)",
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., Burnett, J. C., Gomba, L., Nuss, J. E., Selaković, Ž., Konstantinović, J. M., Krstic, M., Šegan, S., Zlatović, M., Sciotti, R. J., Bavari, S.,& Šolaja, B.. (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
American Chemical Society (ACS)., 57(10), 4134-4153.
https://doi.org/10.1021/jm500033r
Videnović M, Opsenica D, Burnett JC, Gomba L, Nuss JE, Selaković Ž, Konstantinović JM, Krstic M, Šegan S, Zlatović M, Sciotti RJ, Bavari S, Šolaja B. 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, Burnett, James C., Gomba, Laura, Nuss, Jonathan E., Selaković, Života, Konstantinović, Jelena M., Krstic, Maja, Šegan, Sandra, Zlatović, Mario, Sciotti, Richard J., Bavari, Sina, Šolaja, Bogdan, "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 . .

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