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

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• 作者：Yun Soo Bae^a ; ^&dagger ; ; Sun Choi^b ; ^&dagger ; ; Jung Jae Park^c ; Jung Hee Joo^a ; Minghua Cui^b ; Hyunsung Cho^c ; Won Jae Lee^d ; Sang Hyup Lee^c ; ^{sanghyup@duksung.ac.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Thiohydantoin ; Benzylidene ; Aluminum chloride ; NADPH oxidase (NOX)
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 September 2016
• 年：2016
• 卷：24
• 期：18
• 页码：4144-4151
• 全文大小：662 K

文摘

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.