Synthesis and biological evaluation of 3-substituted 5-benzylidene-1-methyl-2-thiohydantoins as potent NADPH oxidase (NOX) inhibitors |
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| Institution: | 1. Department of Life Science, College of Natural Sciences, Ewha Womans University, Seoul 03760, Republic of Korea;2. College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea;3. College of Pharmacy and Innovative Drug Center, Duksung Women’s University, Seoul 01369, Republic of Korea;4. Department of Life Science, Seoul National University, Seoul 08826, Republic of Korea;1. Laboratorio Síntesis Orgánica, Instituto de Química de Recursos Naturales, Universidad de Talca, Casilla 747, Talca, Chile;2. Faculty of Sciences, Department of Chemistry, University of Chile, Las Palmeras 3425, Ñuñoa, Santiago, Chile;3. Facultad de Ciencias Naturales y Matemáticas, Universidad de Ibagué, Carrera 22 Calle 67, Ibagué, Colombia;4. Facultad de Ciencias Exactas, Departamento de Ciencias Químicas, Universidad Andrés Bello, Avenida República 275, Piso 3, Santiago, Chile;5. Faculty of Sciences, Department of Biology, University of Chile, Santiago, Chile;6. Grupo de Investigación en Compuestos Heterocíclicos, Programa de Química, Facultad de Ciencias Básicas, Universidad del Atlántico, Km 7 Antigua vía Puerto Colombia, Barranquilla-Atlántico, Colombia;7. Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Santiago 6094411, Chile;1. Department of Chemistry, Institute of Biology, Pedagogical University of Cracow, ul. Podchorążych 2, 30-084 Kraków, Poland;2. Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary;3. Faculty of Chemistry, Jagiellonian University, ul. Ingardena 3, 30-060 Kraków, Poland;4. Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland;1. Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, China;2. Department of Clinical Laboratory, The 309th Hospital of Chinese People’s Liberation Army, Beijing 100091, China |
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| 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. |
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| Keywords: | Thiohydantoin Benzylidene Aluminum chloride NADPH oxidase (NOX) |
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