Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents

Bioorganic & Medicinal Chemistry
Marvin J MeyersXiaoping Chen

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 ...Continue Reading

Citations

Jul 12, 2018·Organic & Biomolecular Chemistry·Samuel D GriggsPaul A Clarke
Apr 5, 2018·Malaria Journal·Cedric D J MbounaFabrice F Boyom
Jan 17, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Rokhyatou SeckChristian Cavé
Sep 17, 2019·European Journal of Medicinal Chemistry·Anudeep K NarulaLalit M Nainwal
Jan 10, 2019·European Journal of Medicinal Chemistry·SeoHyun ChoDongyun Shin
Nov 10, 2018·The Journal of Organic Chemistry·Pierre ThilmanyGwilherm Evano
Jun 24, 2017·Chemical Reviews·Laure KonnertEvelina Colacino

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Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

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Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.