Nitroimidazo-oxazole Compound (DNDI-VL-2098) - An Orally Effective Preclinical Drug Candidate for the Treatment of Visceral Leishmaniasis

Abstract

Objective: Identification of 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 (DD8-LUCI) amastigotes. 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 on hamster model at various dose regimens. Cytokines and inducible nitric oxide synthase (iNOS) estimation 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 0.03µM against DD8 strain) showed excellent in vivo activity in both mouse and hamster models, with an ED90 value of 3.7 mg/kg and <25 mg/kg respectively and was also found very effective in higher grade of infection in hamster model. Our studies revealed that along with leishmanicidal activity, DNDI-VL-2098 was also capable to induce host protective immune cells to suppress Leishmania parasites in hamsters. Conclusion: These studies led to the identification of compound DNDI-VL-2098 as a preclinical candidate for further drug development as oral treatment of VL.