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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiparasitic Agents / chemical synthesis*
  • Antiparasitic Agents / pharmacokinetics
  • Antiparasitic Agents / pharmacology*
  • Cell Membrane Permeability
  • Chagas Disease / drug therapy
  • Chagas Disease / parasitology
  • Cricetinae
  • Cytochrome P-450 CYP3A / drug effects
  • Cytochrome P-450 CYP3A Inhibitors / chemical synthesis
  • Cytochrome P-450 CYP3A Inhibitors / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • ERG1 Potassium Channel / antagonists & inhibitors
  • Leishmania donovani / drug effects
  • Leishmania donovani / growth & development
  • Leishmania infantum / drug effects
  • Leishmania infantum / growth & development
  • Leishmaniasis, Visceral / drug therapy*
  • Leishmaniasis, Visceral / parasitology
  • Mesocricetus
  • Mice
  • Mice, Inbred BALB C
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / drug effects
  • Oxazines / chemical synthesis*
  • Oxazines / pharmacokinetics
  • Oxazines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Antiparasitic Agents
  • Cytochrome P-450 CYP3A Inhibitors
  • ERG1 Potassium Channel
  • Oxazines
  • Cytochrome P-450 CYP3A
  • cytochrome P450 3A4, mouse