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

• Published in: Journal of antimicrobial chemotherapy 2015-02, Vol.70 (2), p.518-527
• Main Authors: Gupta, Suman, Yardley, Vanessa, Vishwakarma, Preeti, Shivahare, Rahul, Sharma, Bhawna, Launay, Delphine, Martin, Denis, Puri, Sunil K
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antimicrobial agents; 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; Fever; Humans; Inhibitory Concentration 50; Leishmania donovani - drug effects; Leishmaniasis, Visceral - drug therapy; Leishmaniasis, Visceral - metabolism; Medical treatment; Mice; Mice, Inbred BALB C; Molecules; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - metabolism; Nitroimidazoles - administration & dosage; Nitroimidazoles - pharmacology; Parasitic protozoa; Parasitic Sensitivity Tests; R&D; Research & development; Time Factors
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dku422

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