Nitroimidazo-oxazole compound DNDI-VL-2098: an orally effective preclinical drug candidate for the treatment of visceral leishmaniasis
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
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.
Suman Gupta; Yardley, V.; Preeti Vishwakarma; Shivahare, R.; Sharma, B.; Launay, D.; Martin, D.; Puri, S.K. Nitroimidazo-oxazole compound DNDI-VL-2098: an orally effective preclinical drug candidate for the treatment of visceral leishmaniasis. Journal of Antimicrobial Chemotherapy (2014) : [DOI: 10.1093/jac/dku422]