Synthesis of gallinamide A analogues as potent falcipain inhibitors and antimalarials

Trent Conroy; Jin T Guo; Nabiha Elias; Katie M Cergol; Jiri Gut; Jennifer Legac; Lubna Khatoon; Yang Liu; Sheena McGowan; Philip J Rosenthal; Nicholas H Hunt; Richard J Payne

doi:10.1021/jm501439w

Synthesis of gallinamide A analogues as potent falcipain inhibitors and antimalarials

J Med Chem. 2014 Dec 26;57(24):10557-63. doi: 10.1021/jm501439w. Epub 2014 Dec 8.

Authors

Trent Conroy¹, Jin T Guo, Nabiha Elias, Katie M Cergol, Jiri Gut, Jennifer Legac, Lubna Khatoon, Yang Liu, Sheena McGowan, Philip J Rosenthal, Nicholas H Hunt, Richard J Payne

Affiliation

¹ School of Chemistry, The University of Sydney , Building F11, Sydney, New South Wales 2006, Australia.

PMID: 25412465
DOI: 10.1021/jm501439w

Abstract

Analogues of the natural product gallinamide A were prepared to elucidate novel inhibitors of the falcipain cysteine proteases. Analogues exhibited potent inhibition of falcipain-2 (FP-2) and falcipain-3 (FP-3) and of the development of Plasmodium falciparum in vitro. Several compounds were equipotent to chloroquine as inhibitors of the 3D7 strain of P. falciparum and maintained potent activity against the chloroquine-resistant Dd2 parasite. These compounds serve as promising leads for the development of novel antimalarial agents.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antimalarials / chemical synthesis*
Antimalarials / pharmacology*
Antimicrobial Cationic Peptides
Cysteine Endopeptidases / chemistry*
Cysteine Endopeptidases / metabolism
HEK293 Cells
Humans
Malaria, Falciparum / drug therapy
Malaria, Falciparum / parasitology
Models, Molecular
Molecular Structure
Peptides / chemistry*
Peptides / pharmacology*
Plasmodium falciparum / drug effects*
Structure-Activity Relationship

Substances

Antimalarials
Antimicrobial Cationic Peptides
Peptides
gallinamide A
Cysteine Endopeptidases
falcipain 2
falcipain 3