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Open Access Publications from the University of California

Inhibition of myeloperoxidase: Evaluation of 2H-indazoles and 1H-indazolones

  • Author(s): Roth, A
  • Ott, S
  • Farber, KM
  • Palazzo, TA
  • Conrad, WE
  • Haddadin, MJ
  • Tantillo, DJ
  • Cross, CE
  • Eiserich, JP
  • Kurth, MJ
  • et al.

© 2014 Elsevier Ltd. All rights reserved. Myeloperoxidase (MPO) produces hypohalous acids as a key component of the innate immune response; however, release of these acids extracellularly results in inflammatory cell and tissue damage. The two-step, one-pot Davis-Beirut reaction was used to synthesize a library of 2H-indazoles and 1H-indazolones as putative inhibitors of MPO. A structure-activity relationship study was undertaken wherein compounds were evaluated utilizing taurine-chloramine and MPO-mediated H2O2consumption assays. Docking studies as well as toxicophore and Lipinski analyses were performed. Fourteen compounds were found to be potent inhibitors with IC50values <1 μM, suggesting these compounds could be considered as potential modulators of pro-oxidative tissue injury pertubated by the inflammatory MPO/H2O2/HOCl/HOBr system.

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