title: Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents.
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.
authors: 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.
authors: Marvin J
authors: MJ
authors: Meyers
authors: Center for World Health and Medicine, Saint Louis University School of Medicine, 1402 South Grand Blvd, M132 Schwitalla Hall, Saint Louis, MO 63104, USA.
authors: Elizabeth J
authors: EJ
authors: Anderson
authors: Center for World Health and Medicine, Saint Louis University School of Medicine, 1402 South Grand Blvd, M132 Schwitalla Hall, Saint Louis, MO 63104, USA.
authors: Sarah A
authors: SA
authors: McNitt
authors: Center for World Health and Medicine, Saint Louis University School of Medicine, 1402 South Grand Blvd, M132 Schwitalla Hall, Saint Louis, MO 63104, USA.
authors: Thomas M
authors: TM
authors: Krenning
authors: Center for World Health and Medicine, Saint Louis University School of Medicine, 1402 South Grand Blvd, M132 Schwitalla Hall, Saint Louis, MO 63104, USA.
authors: Megh
authors: M
authors: Singh
authors: Drug Discovery Pipeline at the Guangzhou Institutes for Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors: Jing
authors: J
authors: Xu
authors: Drug Discovery Pipeline at the Guangzhou Institutes for Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors: Wentian
authors: W
authors: Zeng
authors: 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.
authors: Limei
authors: L
authors: Qin
authors: 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.
authors: Wanwan
authors: W
authors: Xu
authors: 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.
authors: Siting
authors: S
authors: Zhao
authors: 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.
authors: Li
authors: L
authors: Qin
authors: Center for World Health and Medicine, Saint Louis University School of Medicine, 1402 South Grand Blvd, M132 Schwitalla Hall, Saint Louis, MO 63104, USA.
authors: Christopher S
authors: CS
authors: Eickhoff
authors: Center for World Health and Medicine, Saint Louis University School of Medicine, 1402 South Grand Blvd, M132 Schwitalla Hall, Saint Louis, MO 63104, USA.
authors: Jonathan
authors: J
authors: Oliva
authors: Center for World Health and Medicine, Saint Louis University School of Medicine, 1402 South Grand Blvd, M132 Schwitalla Hall, Saint Louis, MO 63104, USA.
authors: Mary A
authors: MA
authors: Campbell
authors: Center for World Health and Medicine, Saint Louis University School of Medicine, 1402 South Grand Blvd, M132 Schwitalla Hall, Saint Louis, MO 63104, USA.
authors: Stacy D
authors: SD
authors: Arnett
authors: Center for World Health and Medicine, Saint Louis University School of Medicine, 1402 South Grand Blvd, M132 Schwitalla Hall, Saint Louis, MO 63104, USA.
authors: Michael J
authors: MJ
authors: Prinsen
authors: Center for World Health and Medicine, Saint Louis University School of Medicine, 1402 South Grand Blvd, M132 Schwitalla Hall, Saint Louis, MO 63104, USA.
authors: David W
authors: DW
authors: Griggs
authors: Center for World Health and Medicine, Saint Louis University School of Medicine, 1402 South Grand Blvd, M132 Schwitalla Hall, Saint Louis, MO 63104, USA.
authors: Peter G
authors: PG
authors: Ruminski
authors: Departments of Medicine and Molecular Microbiology, Washington University in St. Louis, Saint Louis, MO, USA.
authors: Daniel E
authors: DE
authors: Goldberg
authors: Key Laboratory of Regenerative Biology, Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors: Ke
authors: K
authors: Ding
authors: Drug Discovery Pipeline at the Guangzhou Institutes for Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors: Xiaorong
authors: X
authors: Liu
authors: Drug Discovery Pipeline at the Guangzhou Institutes for Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors: Zhengchao
authors: Z
authors: Tu
authors: Drug Discovery Pipeline at the Guangzhou Institutes for Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors: Micky D
authors: MD
authors: Tortorella
authors: Center for World Health and Medicine, Saint Louis University School of Medicine, 1402 South Grand Blvd, M132 Schwitalla Hall, Saint Louis, MO 63104, USA.
authors: Francis M
authors: FM
authors: Sverdrup
authors: 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.
authors: Xiaoping
authors: X
authors: Chen
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D006827:Hydantoins / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D013141:Spiro Compounds / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D006827:Hydantoins; D010880:Piperidines; D013141:Spiro Compounds; D016282:Aspartic Acid Endopeptidases
keywords: Antimalarial; Antiplasmodial; Aspartic protease inhibitors; Spiropiperidine hydantoins