3-Methoxy-2-phenylimidazo[1,2-b]pyridazines highly active against Mycobacterium tuberculosis and Mycobacterium marinum

Kyle D. Farrell, Yamin Gao, Deborah A. Hughes, Robin Henches, Zhengchao Tu, Michael V. Perkins, Tianyu Zhang, Craig L. Francis

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Abstract

A series of 3-methoxy-2-phenylimidazo[1,2-b]pyridazine derivatives which were highly active against autoluminescent Mycobacterium tuberculosis (Mtb) and Mycobacterium marinum (Mm) in an in vitro assay were identified. SAR analysis showed that the most active compounds, which included a phenyl group bearing fluoro substituent(s) at C2, a methoxy function at C3, and a benzyl-heteroatom moiety at C6, exhibited in vitro MIC90 values generally around 0.63–1.26 μM against Mtb and Mm. However, these compounds were inactive against Mtb in vivo (mice), and investigations revealed very short metabolic half-lives (<10 min) when incubated with mouse liver microsomes. Multiple observations of side products produced from oxidative cleavage of the imidazole moiety during the chemical synthesis work suggested that this is a likely metabolic pathway leading to the lack of observed activity in vivo.

Original languageEnglish
Article number115637
Number of pages27
JournalEuropean Journal of Medicinal Chemistry
Volume259
Early online date19 Jul 2023
DOIs
Publication statusPublished - 5 Nov 2023

Keywords

  • Antimycobacterial activity
  • Imidazo[1,2-b]pyridazine
  • Metabolism
  • Mycobacterium tuberculosis
  • Pharmacokinetic
  • SAR
  • Synthesis

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