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

Keywords:

• Carbonic anhydrase inhibitors
• carbonic anhydrase VA
• oxazolone derivatives
• obesity
• drug discovery

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This work is funded by the Council of Scientific and Industrial Research (Grant no. 37(1665)/15/EMR-II). AQ acknowledges the Indian Council of Medical Research (Government of India) for the award of Senior Research Fellowship (G. No: 45/63/2018-PHA/BMS/OL). MY is thankful to the Indian Council of Medical Research (Government of India) for the award of Senior Research Fellowship. MFA and AH acknowledge the generous support from Research Supporting Project (No. RSP-2020-122) by King Saud University, Riyadh, Kingdom of Saudi Arabia. The authors thank the Department of Science and Technology, Government of India for the FIST support (FIST program No. SR/FST/LSI-541/2012). BD is grateful to CSIR for financial support through grant no. 02(0342)/18/EMR-II.