Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors

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Mistry, Shailesh N., Drinkwater, Nyssa, Ruggeri, Chiara, Sivaraman, Komagal Kannan, Loganathan, Sasdekumar, Fletcher, Sabine, Drag, Marcin, Paiardini, Alessandro, Avery, Vicky M., Scammells, Peter J. and McGowan, Sheena (2014) Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors. Journal of Medicinal Chemistry, 57 (21). pp. 9168-9183. ISSN 0022-2623

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Official URL: http://pubs.acs.org/doi/abs/10.1021/jm501323a

Abstract

Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection and have been validated as potential antimalarial targets. Using compound-bound crystal structures of both enzymes, we have used a structure-guided approach to develop a novel series of inhibitors capable of potent inhibition of both PfA-M1 and PfA-M17 activity and parasite growth in culture. Herein we describe the design, synthesis, and evaluation of a series of hydroxamic acid-based inhibitors and demonstrate the compounds to be exciting new leads for the development of novel antimalarial therapeutics.

Item Type:	Article
Additional Information:	This document is the unedited author's version of a Submitted Work that was subsequently accepted for publication in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review. To access the final edited and published work, see http://pubs.acs.org/doi/abs/10.1021/jm501323a
Schools/Departments:	University of Nottingham, UK > Faculty of Science > School of Pharmacy
Identification Number:	https://doi.org/10.1021/jm501323a
Depositing User:	Mistry, Dr Shailesh
Date Deposited:	09 Oct 2015 08:49
Last Modified:	08 May 2020 12:45
URI:	https://eprints.nottingham.ac.uk/id/eprint/30311

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Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors. (deposited 09 Oct 2015 08:49) [Currently Displayed]
- Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors. (deposited 09 Oct 2015 13:53)

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