Design and development of 5-(4H)-oxazolones as potential inhibitors of human carbonic anhydrase VA: towards therapeutic management of diabetes and obesity
| Autor: | Afzal Hussain, Tabish Rehman, Aarfa Queen, Mohamed F. Alajmi, Amarjyoti Das Mahapatra, Parvez Khan, Imtaiyaz Hassan, Bhaskar Datta, Mohd Yousuf |
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| Rok vydání: | 2020 |
| Předmět: |
Gene isoform
genetic structures 030303 biophysics Pharmacology Mitochondrion 03 medical and health sciences Structure-Activity Relationship Structural Biology Diabetes mellitus Carbonic anhydrase Diabetes Mellitus Medicine Humans Obesity Carbonic Anhydrase IX Carbonic Anhydrase Inhibitors Molecular Biology Carbonic Anhydrases 0303 health sciences biology Drug discovery business.industry Oxazolone Cancer General Medicine medicine.disease CARBONIC ANHYDRASE VA HEK293 Cells cardiovascular system biology.protein sense organs business |
| DOI: | 10.6084/m9.figshare.13234029.v1 |
| Popis: | Inhibitors of carbonic anhydrase (CAIs) hold promise for addressing various diseases, including cancer, diabetes, and other metabolic syndromes. CAV is the only isoform present in the mitochondria and is considered a potential drug target for obesity. In this work, we have developed C2, and C4 substituted oxazole-5(4H)-one derivatives as a new scaffold for the selective inhibition of human carbonic anhydrase VA (hCAVA). Synthesized compounds were characterized by 1H NMR, 13C NMR, and LC-MS mass spectrometry and subsequently evaluated for in vitro hCAVA inhibition. Two compounds, 4 and 5 showed a considerably higher binding affinity for hCAVA in comparison to the hCAII. Further, cell-based studies showed that these compounds decrease the expression of CAVA and GLUT4 in adipocytes and non-toxic to HEK293 cells. The present work opens a platform for the use of oxazole-5(4H)-ones and holds promise for further refinement of potent and selective hCAVA inhibitors. Communicated by Ramaswamy H. Sarma |
| Databáze: | OpenAIRE |
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