title: Synthesis and biological evaluation of 3-substituted 5-benzylidene-1-methyl-2-thiohydantoins as potent NADPH oxidase (NOX) inhibitors.
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.
authors.affiliation: Department of Life Science, College of Natural Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
authors.forename: Yun Soo
authors.initials: YS
authors.lastname: Bae
authors.affiliation: College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
authors.forename: Sun
authors.initials: S
authors.lastname: Choi
authors.affiliation: College of Pharmacy and Innovative Drug Center, Duksung Women's University, Seoul 01369, Republic of Korea.
authors.forename: Jung Jae
authors.initials: JJ
authors.lastname: Park
authors.affiliation: Department of Life Science, College of Natural Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
authors.forename: Jung Hee
authors.initials: JH
authors.lastname: Joo
authors.affiliation: College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
authors.forename: Minghua
authors.initials: M
authors.lastname: Cui
authors.affiliation: College of Pharmacy and Innovative Drug Center, Duksung Women's University, Seoul 01369, Republic of Korea.
authors.forename: Hyunsung
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Life Science, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Won Jae
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Innovative Drug Center, Duksung Women's University, Seoul 01369, Republic of Korea. Electronic address: sanghyup@duksung.ac.kr.
authors.forename: Sang Hyup
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000818:Animals; D001597:Benzylidene Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008745:Methylation; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013867:Thiohydantoins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D001597:Benzylidene Compounds; D004791:Enzyme Inhibitors; D013867:Thiohydantoins; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C402799:NOX1 protein, human; C498910:NOX4 protein, human
keywords: Aluminum chloride; Benzylidene; NADPH oxidase (NOX); Thiohydantoin