Synthesis and biological evaluation of new 3-substituted coumarin derivatives as selective inhibitors of human carbonic anhydrase IX and XII

The Carbonic anhydrase isoforms IX and XII play a significant role in regulating the intracellular and extracellular pH in hypoxic tumours abetting the metastasis of solid tumours. Selective and potent inhibitors targeting carbonic anhydrase IX and XII reduce the activity of these isoforms in hypoxic tumours, representing an antitumor and antimetastatic mechanism. Coumarin-based derivatives are selective inhibitors of CA isoforms IX and XII. In this study, we report the design and synthesis of new 3-substituted coumarin derivatives with different functional moieties and their inhibitory activity against various carbonic anhydrase isoforms. We found that the tertiary sulphonamide derivative 6c showed selective inhibition against CA IX with IC50 of 4.1 mu M. Similarly, the carbothioamides 7c, 7b and oxime ether derivative 20a exhibited good inhibition against CA IX and CA XII. Additionally, the binding mode was predicted and validated using molecular docking and dynamic simulations.

Automated summary

Carbonic anhydrase isoforms IX and XII play a crucial role in regulating pH in hypoxic tumors and promoting the metastasis of solid tumors. Selective inhibitors targeting these isoforms can reduce their activity, providing an anti-tumor and anti-metastatic mechanism. Coumarin-based derivatives are selective inhibitors of CA isoforms IX and XII. In this study, new 3-substituted coumarin derivatives were designed and synthesized, and their inhibitory activity against various carbonic anhydrase isoforms was evaluated. Tertiary sulphonamide derivative 6c showed selective inhibition against CA IX, while carbothioamides 7c, 7b, and oxime ether derivative 20a exhibited good inhibition against both CA IX and CA XII. The binding mode was predicted and validated using molecular docking and dynamic simulations.