DNDI-6148: A novel benzoxaborole preclinical candidate for the treatment of visceral leishmaniasis

Charles E. Mowbray (Lead / Corresponding author), Stéphanie Braillard, Paul A. Glossop, Gavin A. Whitlock, Robert T. Jacobs, Jason Speake, Bharathi Pandi, Bakela Nare, Louis Maes, Vanessa Yardley, Yvonne Freund, Richard J. Wall, Sandra Carvalho, Davide Bello, Magali Van den Kerkhof, Guy Caljon, Ian H. Gilbert, Victoriano Corpas-Lopez, Iva Lukac, Stephen PattersonFabio Zuccotto, Susan Wyllie

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Abstract

Visceral leishmaniasis (VL) is a parasitic disease endemic across multiple regions of the world and is fatal if untreated. Current therapies are unsuitable, and there is an urgent need for safe, short-course, and low-cost oral treatments to combat this neglected disease. The benzoxaborole chemotype has previously delivered clinical candidates for the treatment of other parasitic diseases. Here, we describe the development and optimization of this series, leading to the identification of compounds with potent in vitro and in vivo antileishmanial activity. The lead compound (DNDI-6148) combines impressive in vivo efficacy (>98% reduction in parasite burden) with pharmaceutical properties suitable for onward development and an acceptable safety profile. Detailed mode of action studies confirm that DNDI-6148 acts principally through the inhibition of Leishmania cleavage and polyadenylation specificity factor (CPSF3) endonuclease. As a result of these studies and its promising profile, DNDI-6148 has been declared a preclinical candidate for the treatment of VL.

Original languageEnglish
Pages (from-to)16159-16176
Number of pages18
JournalJournal of Medicinal Chemistry
Volume64
Issue number21
Early online date29 Oct 2021
DOIs
Publication statusPublished - 11 Nov 2021

Keywords

  • Anatomy
  • Redox reactions
  • Toxicity
  • Parasites
  • Stability

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