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J Med Chem. 2018 Mar 22;61(6):2329-2352. doi: 10.1021/acs.jmedchem.7b01581. Epub 2018 Mar 6.

Development of (6 R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5 H-imidazo[2,1- b][1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis.

Author information

1
Auckland Cancer Society Research Centre, School of Medical Sciences , The University of Auckland , Private Bag 92019, Auckland 1142 , New Zealand.
2
Faculty of Infectious & Tropical Diseases , London School of Hygiene & Tropical Medicine , Keppel Street , London WC1E 7HT , United Kingdom.
3
Laboratory for Microbiology, Parasitology and Hygiene, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences , University of Antwerp , Universiteitsplein 1 , B-2610 Antwerp , Belgium.
4
Division of Parasitology , CSIR-Central Drug Research Institute , Lucknow 226031 , India.
5
Drugs for Neglected Diseases initiative, 15 Chemin Louis Dunant , 1202 Geneva , Switzerland.
6
Institute for Tuberculosis Research, College of Pharmacy , University of Illinois at Chicago , 833 South Wood Street , Chicago , Illinois 60612 , United States.
7
Global Alliance for TB Drug Development , 40 Wall Street , New York , New York 10005 , United States.

Abstract

Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo[2,1- b][1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1- b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1- b][1,3]oxazepines), but the results for these seemed less attractive. Following the screening of a 900-compound pretomanid analogue library, several hits with more suitable potency, solubility, and microsomal stability were identified, and the superior efficacy of newly synthesized 6 R enantiomers with phenylpyridine-based side chains was established through head-to-head assessments in a Leishmania donovani mouse model. Two such leads ( R-84 and R-89) displayed promising activity in the more stringent Leishmania infantum hamster model but were unexpectedly found to be potent inhibitors of hERG. An extensive structure-activity relationship investigation pinpointed two compounds ( R-6 and pyridine R-136) with better solubility and pharmacokinetic properties that also provided excellent oral efficacy in the same hamster model (>97% parasite clearance at 25 mg/kg, twice daily) and exhibited minimal hERG inhibition. Additional profiling earmarked R-6 as the favored backup development candidate.

PMID:
29461823
PMCID:
PMC5867678
DOI:
10.1021/acs.jmedchem.7b01581
[Indexed for MEDLINE]
Free PMC Article

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