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Bioorg Med Chem. 2015 Aug 15;23(16):5144-50. doi: 10.1016/j.bmc.2015.02.050. Epub 2015 Mar 4.

Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents.

Author information

1
Center for World Health and Medicine, Saint Louis University School of Medicine, 1402 South Grand Blvd, M132 Schwitalla Hall, Saint Louis, MO 63104, USA. Electronic address: mmeyers8@slu.edu.
2
Center for World Health and Medicine, Saint Louis University School of Medicine, 1402 South Grand Blvd, M132 Schwitalla Hall, Saint Louis, MO 63104, USA.
3
Drug Discovery Pipeline at the Guangzhou Institutes for Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
4
Laboratory of Pathogen Biology, State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190, Kaiyuan Avenue, Guangzhou Science Park, Guangzhou 510530, China.
5
Departments of Medicine and Molecular Microbiology, Washington University in St. Louis, Saint Louis, MO, USA.
6
Key Laboratory of Regenerative Biology, Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
7
Laboratory of Pathogen Biology, State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190, Kaiyuan Avenue, Guangzhou Science Park, Guangzhou 510530, China. Electronic address: chen_xiaoping@gibh.ac.cn.

Abstract

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 0.310 μM and 0.099 μM, 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.

KEYWORDS:

Antimalarial; Antiplasmodial; Aspartic protease inhibitors; Spiropiperidine hydantoins

PMID:
25797165
PMCID:
PMC4550221
DOI:
10.1016/j.bmc.2015.02.050
[Indexed for MEDLINE]
Free PMC Article

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