title: Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors.
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.
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Shailesh N
authors.initials: SN
authors.lastname: Mistry
authors.forename: Nyssa
authors.initials: N
authors.lastname: Drinkwater
authors.forename: Chiara
authors.initials: C
authors.lastname: Ruggeri
authors.forename: Komagal Kannan
authors.initials: KK
authors.lastname: Sivaraman
authors.forename: Sasdekumar
authors.initials: S
authors.lastname: Loganathan
authors.forename: Sabine
authors.initials: S
authors.lastname: Fletcher
authors.forename: Marcin
authors.initials: M
authors.lastname: Drag
authors.forename: Alessandro
authors.initials: A
authors.lastname: Paiardini
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scammells
authors.forename: Sheena
authors.initials: S
authors.lastname: McGowan
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000201:enzymology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D015800:Protozoan Proteins; D000626:Aminopeptidases