Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions

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...

Full description

Saved in:
Bibliographic Details
Published in:European journal of medicinal chemistry 2016-03, Vol.110, p.43-64
Main Authors: Drinkwater, Nyssa, Vinh, Natalie B., Mistry, Shailesh N., Bamert, Rebecca S., Ruggeri, Chiara, Holleran, John P., Loganathan, Sasdekumar, Paiardini, Alessandro, Charman, Susan A., Powell, Andrew K., Avery, Vicky M., McGowan, Sheena, Scammells, Peter J.
Format: Article
Language:English
Subjects:
Aminopeptidase inhibitors
Aminopeptidases - antagonists & inhibitors
Aminopeptidases - chemistry
Aminopeptidases - metabolism
Antimalarials - chemistry
Antimalarials - pharmacology
HEK293 Cells
Humans
Hydroxamic acid
Hydroxamic Acids - chemistry
Hydroxamic Acids - pharmacology
Malaria
Malaria, Falciparum - drug therapy
Models, Molecular
Plasmodium falciparum
Plasmodium falciparum - drug effects
Protease Inhibitors - chemistry
Protease Inhibitors - pharmacology
Protozoan Proteins - antagonists & inhibitors
Protozoan Proteins - chemistry
Protozoan Proteins - metabolism
Structure-Activity Relationship
Zinc - metabolism
Zinc-binding group
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 PfA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics. [Display omitted] •Dual inhibition of PfA-M1 and PfA-M17 is proposed as a novel antimalarial strategy.•Compound series containing hydroxamic acid zinc binding group optimized by SBDD.•Compounds elaborated into S1 pockets of PfA-M1 and PfA-M17.•Optimized compounds possess superior PfA-M1 and PfA-M17 inhibitory activity.•The potent, dual inhibitors inhibit multi-drug resistant Pf growth in culture.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2016.01.015