2. Academic Validation
  3. Falcipain Inhibitors Based on the Natural Product Gallinamide A Are Potent in Vitro and in Vivo Antimalarials

Falcipain Inhibitors Based on the Natural Product Gallinamide A Are Potent in Vitro and in Vivo Antimalarials

  • J Med Chem. 2019 Jun 13;62(11):5562-5578. doi: 10.1021/acs.jmedchem.9b00504.
Alexander Stoye 1,  Annette Juillard 2,  Arthur H Tang 1,  Jennifer Legac 3,  Jiri Gut 3,  Karen L White 4,  Susan A Charman 4,  Philip J Rosenthal 3,  Georges E R Grau 2,  Nicholas H Hunt 2,  Richard J Payne 1
Affiliations

Affiliations

  • 1 School of Chemistry , Building F11, The University of Sydney , Sydney , New South Wales 2006 , Australia.
  • 2 School of Medical Sciences, Sydney Medical School , Building K25, The University of Sydney , Medical Foundation, Sydney , New South Wales 2006 , Australia.
  • 3 Department of Medicine, San Francisco General Hospital , University of California , San Francisco , California 94143 , United States.
  • 4 Centre for Drug Candidate Optimisation , Monash University , Victoria 3052 , Australia.
PMID: 31062592 DOI: 10.1021/acs.jmedchem.9b00504
Abstract

A library of analogues of the cyanobacterium-derived depsipeptide natural product gallinamide A were designed and prepared using a highly efficient and convergent synthetic route. Analogues were shown to exhibit potent inhibitory activity against the Plasmodium falciparum cysteine proteases falcipain 2 and falcipain 3 and against cultured chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of P. falciparum. Three lead compounds were selected for evaluation of in vivo efficacy against Plasmodium berghei Infection in mice on the basis of their improved blood, plasma, and microsomal stability profiles compared with the parent natural product. One of the lead analogues cured P. berghei-infected mice in the Peters 4 day-suppressive test when administered 25 mg kg-1 intraperitoneally daily for 4 days. The compound was also capable of clearing parasites in established infections at 50 mg kg-1 intraperitoneally daily for 4 days and exhibited moderate activity when administered as four oral doses of 100 mg kg-1.

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