2. Academic Validation
  3. Discovery of a Series of Macrocycles as Potent Inhibitors of Leishmania Infantum

Discovery of a Series of Macrocycles as Potent Inhibitors of Leishmania Infantum

  • J Med Chem. 2024 Oct 24;67(20):18170-18193. doi: 10.1021/acs.jmedchem.4c01370.
Federico Riu 1,  Larissa Alena Ruppitsch 1,  Duc Duy Vo 1 2,  Richard S Hong 3,  Mohit Tyagi 1,  An Matheeussen 4,  Sarah Hendrickx 4,  Vasanthanathan Poongavanam 1,  Guy Caljon 4,  Ahmad Y Sheikh 5,  Peter Sjö 6,  Jan Kihlberg 1
Affiliations

Affiliations

  • 1 Department of Chemistry - BMC, Uppsala University, 751 23 Uppsala, Sweden.
  • 2 Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, 751 24 Uppsala, Sweden.
  • 3 Molecular Profiling and Drug Delivery, Research & Development, AbbVie Inc., Worcester, Massachusetts 01605, United States.
  • 4 Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
  • 5 Molecular Profiling and Drug Delivery, Research & Development, AbbVie Inc, North Chicago, Illinois 60064, United States.
  • 6 Drugs for Neglected Diseases initiative (DNDi), 15 Chemin Camille-Vidart, 1202 Geneva, Switzerland.
PMID: 39378318 DOI: 10.1021/acs.jmedchem.4c01370
Abstract

Macrocycles are prominent among drugs for treatment of infectious disease, with many originating from Natural Products. Herein we report on the discovery of a series of macrocycles structurally related to the natural product hymenocardine. Members of this series were found to inhibit the growth of Plasmodium falciparum, the Parasite responsible for most malaria cases, and of four kinetoplastid parasites. Notably, macrocycles more potent than miltefosine, the only oral drug used for the treatment of the neglected tropical disease visceral leishmaniasis, were identified in a phenotypic screen of Leishmania infantum. In vitro profiling highlighted that potent inhibitors had satisfactory cell permeability with a low efflux ratio, indicating their potential for oral administration, but low solubility and metabolic stability. Analysis of predicted crystal structures suggests that optimization should focus on the reduction of π-π crystal packing interactions to reduce the strong crystalline interactions and improve the solubility of the most potent lead.

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