4-Amino-7-chloroquinolines: Probing Ligand Efficiency Provides Botulinum Neurotoxin Serotype A Light Chain Inhibitors with Significant Antiprotozoal Activity
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Nuss, Jonathan E.
Sciotti, Richard J.
Burnett, James C.
Šolaja, Bogdan A.
Article (Published version)
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Structurally simplified analogues of dual antimalarial and botulinum neurotoxin serotype A light chain (BoNT/A LC) inhibitor bis-aminoquinoline (1) were prepared. New compounds were designed to improve ligand efficiency while maintaining or exceeding the inhibitory potency of 1. Three of the new compounds are more active than 1 against both indications. Metabolically, the new inhibitors are relatively stable and nontoxic. 12, 14, and 15 are more potent BoNT/A LC inhibitors than 1. Additionally, 15 has excellent in vitro antimalarial efficacy, with IC90 values ranging from 4.45 to 12.11 nM against five Plasmodium falciparum (Pf) strains: W2, D6, C235, C2A, and C2B. The results indicate that the same level of inhibitory efficacy provided by 1 can be retained/exceeded with less structural complexity. 12, 14, and 15 provide new platforms for the development of more potent dual BoNT/A LC and P.f. inhibitors adhering to generally accepted chemical properties associated with the druggability ...of synthetic molecules.
Source:Journal of Medicinal Chemistry, 2013, 56, 14, 5860-5871
- Amer Chemical Soc, Washington
- The synthesis of aminoquinoline-based antimalarials and botulinum neurotoxin A inhibitors (RS-172008)
- National Cancer Institute, National Institutes of Health [HHSN261200800001E]
- Defense Threat Reduction Agency [3.10084_09_RD_B, Y3CM 100505]
- NATO [SfP983638]
- Serbian Academy of Sciences and Arts
- Supplementary material: http://cherry.chem.bg.ac.rs/handle/123456789/3465