Synthesis and biological evaluation of novel benzo[c][1,2,5]thiadiazol-5-yl and thieno[3,2-c]- pyridin-2-yl imidazole derivatives as ALK5 inhibitors |
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| Institution: | 1. College of Pharmacy, Yanbian University, Yanji 133002, PR China;2. Key Laboratory of Natural Resources of Changbai Mountain and Functional Molecules, Ministry of Education, Molecular Medicine Research Center, Yanbian University, Yanji 133002, PR China;3. Department of Pharmaceutics, College of Pharmacy, Yanbian University, Yanji 133002, PR China;4. Department of Radiology, Yanbian University Hospital, Yanji 133002, PR China;1. Department of Food Science and Biotechnology, Daegu University, Gyeongsan 38453, Republic of Korea;2. Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea;1. School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Wenhua Road 103, Shenyang 110016, China;2. Tianjin Vocational College of Bioengineering, Tianjin 300462, China;1. Center for Biomaterials, Korea Institute of Science & Technology (KIST School), Seongbuk-gu, Seoul 02792, Republic of Korea;2. University of Science & Technology (UST), Yuseong-gu, Daejeon 34113, Republic of Korea;3. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Modern University of Technology and Information (MTI), Cairo 12055, Egypt;4. Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre NRC (ID: 60014618), Dokki, Giza 12622, Egypt;5. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza 12566, Egypt;6. Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea;7. Department of Beauty Science, Hanseo University, Seosan 31962, Republic of Korea;1. College of Veterinary Medicine, Midwestern University, 19555 N. 59th Ave., Glendale, AZ 85308, United States;2. Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia;3. Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan;4. Department of Chemistry, School of Science and Human Development, Methodist University, Fayetteville, NC, United States;5. Department of Pathology and Population Medicine, College of Veterinary Medicine, Midwestern University, 19555 N. 59th Ave., Glendale, AZ 85308, United States;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Menoufia University, Egypt;3. Department of Chemistry, Faculty of Science, Sohag University, Egypt;4. Chemistry Department, Faculty of Science, Albaha University, P.O. Box 1988, Albaha, Saudi Arabia;5. Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, Menoufia, Egypt;6. Medicinal and Pharmaceutical Chemistry Department, National Research Centre, Dokki, Cairo, Egypt;7. Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Egypt |
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| Abstract: | Transforming growth factor (TGF-β), a key mediator of tumor growth and metastasis, has been recognized as an important cancer drug target. A series of benzoc]1,2,5]thiadiazol-5-yl imidazoles (14a–g) and thieno3,2-c]-pyridin-2-yl imidazoles (20a–g) were designed, synthesized, and evaluated for their activin receptor-like kinase 5 (ALK5) activities. Among these compounds, 14c showed the highest activity (IC50 = 0.008 μM) against ALK5 kinase, which was 16.1-fold and 1.8-fold higher than those of positive control compounds LY-2157299 (IC50 = 0.129 μM) and EW-7197 (IC50 = 0.014 μM), respectively. Compound 14g (350) showed the highest selectivity index of ALK5 against p38α MAP kinase, which was significantly higher than that of positive control compounds LY-2157299 (4) and EW-7197 (211). The inhibitory effects of compound 14c on TGF-β-induced Smad signaling and cell motility were studied in SPC-A1, HepG2 and HUVEC cells using western blot analysis and wound healing assay. ADMET prediction analysis showed that compounds 14c and 14g had good pharmacokinetics and drug-likeness behaviors. |
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| Keywords: | ALK5 TGF-β Imidazole Inhibitors ADMET |
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