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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:
  • Amer Chemical Soc, Washington
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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URI
http://cer.ihtm.bg.ac.rs/handle/123456789/1580
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