Synthesis and biological evaluation of 3-substituted 5-benzylidene-1-methyl-2-thiohydantoins as potent NADPH oxidase (NOX) inhibitors. Issue 18 (15th September 2016)

• Record Type: Journal Article
• Authors: Bae, Yun Soo; Choi, Sun; Park, Jung Jae; Joo, Jung Hee; Cui, Minghua; Cho, Hyunsung; Lee, Won Jae; Lee, Sang Hyup
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 18(2016)
• Page Start: 4144
• Page End: 4151
• Publication Date: 2016-09-15
• Subjects: Thiohydantoin -- Benzylidene -- Aluminum chloride -- NADPH oxidase (NOX); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.06.056
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: We report the synthesis of novel 3-substituted 5-benzylidene-1-methyl-2-thiohydantoins3, and their biological evaluation using NADPH oxidase (NOX) 1 and 4. Based on structural and pharmacophore analyses of known inhibitors such as hydroxypyrazole2, we envisioned interesting 2-thiohydantoin compounds, 3-substituted 5-benzylidene-1-methyl-2-thiohydantoins3 that would be expected to well match the structural features in2 . Efficient synthesis of eighteen target compounds3 were achieved through the synthetic pathway of4 → 11 → 3, established after consideration of several plausible synthetic pathways. The inhibitory activities of compounds3 against NOX 1 and 4 were measured, with some of the target compounds showing similar or higher activities compared with reference2 ; in particular, compounds3bz, 3cz, and3ez 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.