Coumarin-thiazole and -oxadiazole derivatives: Synthesis,bioactivity and docking studies for aldose/aldehyde reductase inhibitors |
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| Institution: | 1. Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan;2. Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan;3. Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan;4. HEJ Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan;5. Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, D-53113 Bonn, Germany;6. Pharmaceutical Institute, University of Bonn, Ander Immenburg 4, D-53121 Bonn, Germany;1. Production Department, Egyptian Petroleum Research Institute (EPRI), Cairo, Egypt;2. Chemistry Department, Faculty of Science, Al-Azhar University, Cairo, Egypt;3. Chemistry Department, University college in Al-Jamoum, Umm Al- Qura Univesity, Makkah, Saudi Arabia;4. Chemistry Department, College of Science, Al- Baha University, Saudi Arabia;1. School of Chemistry and Life Science, Changchun University of Technology, Changchun 130012, PR China;2. Advanced Institute of Materials Science, Changchun University of Technology, Changchun 130012, PR China;3. College of Materials Science Engineering, Jilin University, Changchun 130012, PR China;1. Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan University, Bhubaneswar 751030, Odisha, India;2. Department of Pharmaceutical Sciences, Utkal University, Vanivihar, Bhubaneswar 751004, Odisha, India;1. Department of Chemistry, Faculty of Science, Gazi University, Teknikokullar, Ankara, 06500, Turkey;2. Department of Advanced Technology, Gazi University, 06100, Ankara, Turkey;1. School of Science, Anhui Agricultural University, 230036, Hefei, People''s Republic of China;2. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, 210093, Nanjing, People''s Republic of China;1. Department of Chemistry, National Institute of Technology, Warangal 506004, Telangana, India;2. Department of Biotechnology, National Institute of Technology, Warangal 506004, Telangana, India;3. Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana 500607, India;4. Department of Microbiology, Kakatiya University, Warangal, Telangana, India |
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| Abstract: | In continuation of our previous efforts directed towards the development of potent and selective inhibitors of aldose reductase (ALR2), and to control the diabetes mellitus (DM), a chronic metabolic disease, we synthesized novel coumarin-thiazole 6(a–o) and coumarin-oxadiazole 11(a–h) hybrids and screened for their inhibitory activity against aldose reductase (ALR2), for the selectivity against aldehyde reductase (ALR1). Compounds were also screened against ALR1. Among the newly designed compounds, 6c, 11d, and 11g were selective inhibitors of ALR2. Whereas, (E)-3-(2-(2-(2-bromobenzylidene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one 6c yielded the lowest IC50 value of 0.16 ± 0.06 μM for ALR2. Moreover, compounds (E)-3-(2-(2-benzylidenehydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6a; IC50 = 2.94 ± 1.23 μM for ARL1 and 0.12 ± 0.05 μM for ARL2) and (E)-3-(2-(2-(1-(4-bromophenyl)ethylidene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6e; IC50 = 1.71 ± 0.01 μM for ARL1 and 0.11 ± 0.001 μM for ARL2) were confirmed as dual inhibitors. Furthermore, compounds 6i, 6k, 6m, and 11b were found to be selective inhibitors for ALR1, among which (E)-3-(2-(2-((2-amino-4-chlorophenyl)(phenyl)methylene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6m) was most potent (IC50 = 0.459 ± 0.001 μM). Docking studies performed using X-ray structures of ALR1 and ALR2 with the given synthesized inhibitors showed that coumarinyl thiazole series lacks the carboxylate function that could interact with the anionic binding site being a common ALR1/ALR2 inhibitors trait. Molecular docking study with dual inhibitor 6e also suggested plausible binding modes for the ALR1 and ALR2 enzymes. Hence, the results of this study revealed that coumarinyl thiazole and oxadiazole derivatives could act as potential ALR1/ALR2 inhibitors. |
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| Keywords: | Coumarin Thiazole Oxadiazole Aldose reductase Molecular docking Enzyme inhibition |
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