6-Aminocoumarin oxime-ether/sulfonamides as selective hCA IX and XII inhibitors: Synthesis, evaluation, and molecular dynamics studies

Carbonic anhydrase isoforms IX and XII are overexpressed in hypoxic tumor cells regulating various physiological processes such as cell proliferation, invasion, and metastasis, resulting in the onset and spread of cancer. Selective inhibition of these enzymes is a promising strategy for anticancer therapy. Coumarin derivatives were identified as selective and potent inhibitors of these isoforms. This study reports 6-aminocoumarin sulfonamide and oxime ether derivatives linked through a chloroacetyl moiety tethered to piperazine and piperidone, respectively, showing selective inhibition against human carbonic anhydrase (hCA) IX and XII with K-i ranging from 0.51 to 1.18 & mu;M and 0.89-4.43 & mu;M. While the sulfonamide derivative 8a exhibited submicromolar inhibition against hCA IX and XII with K-i 0.89 and 0.51 & mu;M, the oxime ether derivatives showed lower activity than the sulfonamides, with the compound 5n inhibiting hCA IX and hCA XII with a K-i of 1.055 and 0.70 & mu;M, respectively. The above results demonstrate the potential of these derivatives as selective, potent inhibitors of carbonic anhydrase IX and XII and provide a foundation for further optimization and development as effective anticancer agents. Further, the binding mode of the synthesized derivatives in the active site were examined using molecular docking and dynamic simulation studies.

Automated summary

Carbonic anhydrase isoforms IX and XII are highly expressed in hypoxic tumor cells and play a role in cancer onset and spread. Coumarin derivatives were found to selectively inhibit these isoforms, offering a promising strategy for anticancer therapy. This study identified 6-aminocoumarin sulfonamide and oxime ether derivatives as potent inhibitors of human carbonic anhydrase IX and XII. The results demonstrate the potential of these derivatives as selective inhibitors and provide a foundation for further development as anticancer agents.