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

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.