Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents

[Display omitted] Given the rise of parasite resistance to all currently used antimalarial drugs, the identification of novel chemotypes with unique mechanisms of action is of paramount importance. Since Plasmodium expresses a number of aspartic proteases necessary for its survival, we have mined an...

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Published in:Bioorganic & medicinal chemistry 2015-08, Vol.23 (16), p.5144-5150
Main Authors: Meyers, Marvin J., Anderson, Elizabeth J., McNitt, Sarah A., Krenning, Thomas M., Singh, Megh, Xu, Jing, Zeng, Wentian, Qin, Limei, Xu, Wanwan, Zhao, Siting, Qin, Li, Eickhoff, Christopher S., Oliva, Jonathan, Campbell, Mary A., Arnett, Stacy D., Prinsen, Michael J., Griggs, David W., Ruminski, Peter G., Goldberg, Daniel E., Ding, Ke, Liu, Xiaorong, Tu, Zhengchao, Tortorella, Micky D., Sverdrup, Francis M., Chen, Xiaoping
Format: Article
Language:English
Subjects:
Animals
Antimalarial
Antimalarials - chemistry
Antimalarials - metabolism
Antimalarials - pharmacokinetics
Antimalarials - pharmacology
Antiplasmodial
Aspartic Acid Endopeptidases - antagonists & inhibitors
Aspartic Acid Endopeptidases - metabolism
Aspartic protease inhibitors
Drug Discovery
Humans
Hydantoins - chemistry
Hydantoins - metabolism
Hydantoins - pharmacokinetics
Hydantoins - pharmacology
Malaria, Falciparum - drug therapy
Malaria, Falciparum - parasitology
Mice
Microsomes, Liver - metabolism
Piperidines - chemistry
Piperidines - metabolism
Piperidines - pharmacokinetics
Piperidines - pharmacology
Plasmodium falciparum - drug effects
Plasmodium falciparum - enzymology
Plasmodium falciparum - metabolism
Rats
Spiro Compounds - chemistry
Spiro Compounds - metabolism
Spiro Compounds - pharmacokinetics
Spiro Compounds - pharmacology
Spiropiperidine hydantoins
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Summary:[Display omitted] Given the rise of parasite resistance to all currently used antimalarial drugs, the identification of novel chemotypes with unique mechanisms of action is of paramount importance. Since Plasmodium expresses a number of aspartic proteases necessary for its survival, we have mined antimalarial datasets for drug-like aspartic protease inhibitors. This effort led to the identification of spiropiperidine hydantoins, bearing similarity to known inhibitors of the human aspartic protease β-secretase (BACE), as new leads for antimalarial drug discovery. Spiropiperidine hydantoins have a dynamic structure–activity relationship profile with positions identified as being tolerant of a variety of substitution patterns as well as a key piperidine N-benzyl phenol pharmacophore. Lead compounds 4e (CWHM-123) and 12k (CWHM-505) are potent antimalarials with IC50 values against Plasmodium falciparum 3D7 of 0.310μM and 0.099μM, respectively, and the former features equivalent potency on the chloroquine-resistant Dd2 strain. Remarkably, these compounds do not inhibit human aspartic proteases BACE, cathepsins D and E, or Plasmodium plasmepsins II and IV despite their similarity to known BACE inhibitors. Although the current leads suffer from poor metabolic stability, they do fit into a drug-like chemical property space and provide a new class of potent antimalarial agents for further study.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2015.02.050