2. Academic Validation
  3. DNDI-6148: A Novel Benzoxaborole Preclinical Candidate for the Treatment of Visceral Leishmaniasis

DNDI-6148: A Novel Benzoxaborole Preclinical Candidate for the Treatment of Visceral Leishmaniasis

  • J Med Chem. 2021 Nov 11;64(21):16159-16176. doi: 10.1021/acs.jmedchem.1c01437.
Charles E Mowbray 1,  Stéphanie Braillard 1,  Paul A Glossop 2,  Gavin A Whitlock 2,  Robert T Jacobs 3,  Jason Speake 3,  Bharathi Pandi 3,  Bakela Nare 3,  Louis Maes 4,  Vanessa Yardley 5,  Yvonne Freund 6,  Richard J Wall 7,  Sandra Carvalho 7,  Davide Bello 7,  Magali Van den Kerkhof 4,  Guy Caljon 4,  Ian H Gilbert 7,  Victoriano Corpas-Lopez 7,  Iva Lukac 7,  Stephen Patterson 7,  Fabio Zuccotto 7,  Susan Wyllie 7
Affiliations

Affiliations

  • 1 Drugs for Neglected Diseases initiative (DNDi), 15 Chemin Louis-Dunant, 1202 Geneva, Switzerland.
  • 2 Sandexis Medicinal Chemistry Ltd, Innovation House, Discovery Park, Ramsgate Road, Sandwich, Kent CT13 9ND, U.K.
  • 3 Scynexis, 3501 C Tricenter Boulevard, Durham, North Carolina 27713, United States.
  • 4 Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium.
  • 5 Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, U.K.
  • 6 Anacor Pharmaceuticals, 1020 East Meadow Circle, Palo Alto, California 94303, United States.
  • 7 Division of Biological Chemistry and Drug Discovery, Wellcome Centre for Anti-infectives Research, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
PMID: 34711050 DOI: 10.1021/acs.jmedchem.1c01437
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.

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