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

2014
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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Show full item recordAbstract
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, 4134-4153Publisher:
- 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
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Institution/Community
IHTMTY - 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 . .