Nitroimidazo-oxazole compound DNDI-VL-2098: an orally effective preclinical drug candidate for the treatment of visceral leishmaniasis.
OBJECTIVE
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.
Division of Parasitology, CSIR-Central Drug Research Institute, Jankipuram extension, Lucknow 226 031, India gupta_suman@yahoo.com.
Suman
S
Gupta
Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK.
Vanessa
V
Yardley
Division of Parasitology, CSIR-Central Drug Research Institute, Jankipuram extension, Lucknow 226 031, India.
Preeti
P
Vishwakarma
Division of Parasitology, CSIR-Central Drug Research Institute, Jankipuram extension, Lucknow 226 031, India.
Rahul
R
Shivahare
DNDi India (ICMR 2nd Campus) TB Association Building, 3 Red Cross Road, New Delhi 110 001, India.
Bhawna
B
Sharma
Drugs for Neglected Diseases initiative (DNDi), 15 Chemin Louis Dunant, 1202 Geneva, Switzerland.
Delphine
D
Launay
Drugs for Neglected Diseases initiative (DNDi), 15 Chemin Louis Dunant, 1202 Geneva, Switzerland.
Denis
D
Martin
Division of Parasitology, CSIR-Central Drug Research Institute, Jankipuram extension, Lucknow 226 031, India.
Sunil K
SK
Puri
D000284:Administration, Oral; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical; D006224:Cricetinae; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D013997:Time Factors
D000981:Antiprotozoal Agents; D016207:Cytokines; D009593:Nitroimidazoles; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II
chemotherapy; hamster; mouse; nitroimidazoles