期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 110, 期 -, 页码 43-64出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.01.015
关键词
Plasmodium falciparum; Malaria; Aminopeptidase inhibitors; Hydroxamic acid; Zinc-binding group
资金
- National Health and Medical Research Council [1063786]
- ARC [LP120200557]
- Endeavour Fellowship [4100-2014]
- National Health and Medical Research Council of Australia [1063786] Funding Source: NHMRC
Malaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. Plasmodium falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PIA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics. (C) 2016 Elsevier Masson SAS. All rights reserved.
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