Design and development of 5-(4H)-oxazolones as potential inhibitors of human carbonic anhydrase VA: towards therapeutic management of diabetes and obesity.

Abstract

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.

• Authors: Amarjyoti Das Mahapatra, Aarfa Queen, Mohd Yousuf, Parvez Khan, Afzal Hussain, Md Tabish Rehman, Mohamed F Alajmi, Bhaskar Datta, Md Imtaiyaz Hassan
• Journal: Journal of biomolecular structure & dynamics (J Biomol Struct Dyn) Vol. 40 Issue 7 Pg. 3144-3154 (04 2022) ISSN: 1538-0254 [Electronic] England
• PMID: 33183174 (Publication Type: Journal Article)

Chemical References

• Carbonic Anhydrase Inhibitors
• Oxazolone
• Carbonic Anhydrase IX
• Carbonic Anhydrases

Topics

• Carbonic Anhydrase IX
• Carbonic Anhydrase Inhibitors (chemistry, pharmacology)
• Carbonic Anhydrases
• Diabetes Mellitus
• HEK293 Cells
• Humans
• Obesity (drug therapy)
• Oxazolone (therapeutic use)
• Structure-Activity Relationship