Nitroimidazo-oxazole compound DNDI-VL-2098: an orally effective preclinical drug candidate for the treatment of visceral leishmaniasis

J Antimicrob Chemother. 2015 Feb;70(2):518-27. doi: 10.1093/jac/dku422. Epub 2014 Nov 10.

Abstract

Objectives: The objective of this study was to identify a nitroimidazo-oxazole lead molecule for the treatment of visceral leishmaniasis (VL).

Methods: A library of 72 nitroimidazo-oxazoles was evaluated in vitro for their antileishmanial activity against luciferase-transfected DD8 amastigotes of Leishmania donovani. On the basis of their in vitro potency and pharmacokinetic properties, the promising compounds were tested in acute BALB/c mouse and chronic hamster models of VL via oral administration and efficacy was evaluated by microscopic counting of amastigotes after Giemsa staining. The best antileishmanial candidates (racemate DNDI-VL-2001) and its R enantiomer (DNDI-VL-2098) were evaluated in vitro against a range of Leishmania strains. These candidates were further studied in a hamster model using various dose regimens. Cytokine and inducible nitric oxide synthase estimations by real-time PCR and nitric oxide generation by Griess assay were also carried out for DNDI-VL-2098.

Results: In vitro screening of nitroimidazo-oxazole compounds identified the racemate DNDI-VL-2001 (6-nitroimidazo-oxazole derivative) and its enantiomers as candidates for further evaluation in in vivo models of VL. DNDI-VL-2098 (IC50 of 0.03 μM for the DD8 strain) showed excellent in vivo activity in both mouse and hamster models, with an ED90 value of 3.7 and <25 mg/kg, respectively, and was also found to be very effective against high-grade infection in the hamster model. Our studies revealed that, along with leishmanicidal activity, DNDI-VL-2098 was also capable of inducing host-protective immune cells to suppress Leishmania parasites in hamsters.

Conclusions: These studies led to the identification of compound DNDI-VL-2098 as a preclinical candidate for further drug development as an oral treatment for VL.

Keywords: chemotherapy; hamster; mouse; nitroimidazoles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antiprotozoal Agents / administration & dosage
  • Antiprotozoal Agents / pharmacology*
  • Chemistry, Pharmaceutical
  • Cricetinae
  • Cytokines / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Compounding
  • Drug Evaluation, Preclinical
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Leishmania donovani / drug effects*
  • Leishmaniasis, Visceral / drug therapy*
  • Leishmaniasis, Visceral / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • Nitroimidazoles / administration & dosage
  • Nitroimidazoles / pharmacology
  • Parasitic Sensitivity Tests
  • Time Factors

Substances

  • Antiprotozoal Agents
  • Cytokines
  • Nitroimidazoles
  • Nitric Oxide
  • Nitric Oxide Synthase Type II