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

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

  • Eur J Med Chem. 2023 Nov 5;259:115637. doi: 10.1016/j.ejmech.2023.115637.
Kyle D Farrell 1,  Yamin Gao 2,  Deborah A Hughes 3,  Robin Henches 3,  Zhengchao Tu 4,  Michael V Perkins 1,  Tianyu Zhang 5,  Craig L Francis 6
Affiliations

Affiliations

  • 1 College of Science and Engineering, Flinders University, Bedford Park, SA 5042, Australia.
  • 2 State Key Laboratory of Respiratory Disease, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 Drug Discovery Chemistry Team, CSIRO, Clayton, VIC, 3168, Australia.
  • 4 Drug Discovery Pipeline & Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Guangzhou, 510530, China.
  • 5 State Key Laboratory of Respiratory Disease, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: [email protected].
  • 6 Drug Discovery Chemistry Team, CSIRO, Clayton, VIC, 3168, Australia. Electronic address: [email protected].
PMID: 37524009 DOI: 10.1016/j.ejmech.2023.115637
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.

Keywords

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

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