7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis
Andrew M. Thompson*† 
, Patrick D. O’Connor†, Andrew J. Marshall†, Vanessa Yardley‡, Louis Maes§, Suman Gupta∥, Delphine Launay⊥, Stephanie Braillard⊥, Eric Chatelain⊥, Scott G. Franzblau#, Baojie Wan#, Yuehong Wang#, Zhenkun Ma∇, Christopher B. Cooper∇, and William A. Denny†
, Patrick D. O’Connor†, Andrew J. Marshall†, Vanessa Yardley‡, Louis Maes§, Suman Gupta∥, Delphine Launay⊥, Stephanie Braillard⊥, Eric Chatelain⊥, Scott G. Franzblau#, Baojie Wan#, Yuehong Wang#, Zhenkun Ma∇, Christopher B. Cooper∇, and William A. Denny†
† Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
‡ Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom
§ Laboratory for Microbiology, Parasitology and Hygiene, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium
∥ Division of Parasitology, CSIR—Central Drug Research Institute, Lucknow 226031, India
⊥ Drugs for Neglected Diseases initiative, 15 Chemin Louis Dunant, 1202 Geneva, Switzerland
# Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
∇ Global Alliance for TB Drug Development, 40 Wall Street, New York 10005, United States
J. Med. Chem., 2017, 60 (10), pp 4212–4233
DOI: 10.1021/acs.jmedchem.7b00034
Publication Date (Web): May 1, 2017
Copyright © 2017 American Chemical Society
Abstract
Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one phenyl by pyridine or pyrimidine showed improved solubility and potency, whereas more hydrophilic side chains reduced VL activity. In a Leishmania donovani mouse model, two racemic phenylpyridines (71 and 93) were superior, with the former providing >99% inhibition at 12.5 mg/kg (b.i.d., orally) in the Leishmania infantum hamster model. Overall, the 7R enantiomer of 71 (79) displayed more optimal efficacy, pharmacokinetics, and safety, leading to its selection as the preferred development candidate.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.7b00034.
- Additional biological assay data, synthetic schemes, graphs of PK and assay data, experimental procedures and characterizations for compounds, combustion analytical data, and representative NMR spectra (PDF)
- Molecular formula strings spreadsheet (CSV)
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