Synthesis and biological evaluation of 3-substituted 5-benzylidene-1-methyl-2-thiohydantoins as potent NADPH oxidase (NOX) inhibitors

Yun Soo Bae, Sun Choi, Jung Jae Park, Jung Hee Joo, Minghua Cui, Hyunsung Cho, Won Jae Lee, Sang Hyup Lee

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13 Scopus citations

Abstract

We report the synthesis of novel 3-substituted 5-benzylidene-1-methyl-2-thiohydantoins 3, and their biological evaluation using NADPH oxidase (NOX) 1 and 4. Based on structural and pharmacophore analyses of known inhibitors such as hydroxypyrazole 2, we envisioned interesting 2-thiohydantoin compounds, 3-substituted 5-benzylidene-1-methyl-2-thiohydantoins 3 that would be expected to well match the structural features in 2. Efficient synthesis of eighteen target compounds 3 were achieved through the synthetic pathway of 4 → 11 → 3, established after consideration of several plausible synthetic pathways. The inhibitory activities of compounds 3 against NOX 1 and 4 were measured, with some of the target compounds showing similar or higher activities compared with reference 2; in particular, compounds 3bz, 3cz, and 3ez were found to be promising inhibitors of both NOX 1 and 4 with modest isozyme selectivities, which highlights the significance of the 2-thiohydantoin substructure for inhibition of NOX 1 and 4. This marks the first time these compounds have been applied to the inhibition of NOX enzymes.

Original languageEnglish
Pages (from-to)4144-4151
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume24
Issue number18
DOIs
StatePublished - 2016

Keywords

  • Aluminum chloride
  • Benzylidene
  • NADPH oxidase (NOX)
  • Thiohydantoin

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