Squaramide-Tethered Sulfonamides and Coumarins: Synthesis, Inhibition of Tumor-Associated CAs IX and XII and Docking Simulations

[EN] (1) Background: carbonic anhydrases (CAs) are attractive targets for the development of new anticancer therapies; in particular, CAs IX and XII isoforms are overexpressed in numerous tumors. (2) Methods: following the tail approach, we have appended a hydrophobic aromatic tail to a pharmacophore responsible for the CA inhibition (aryl sulfonamide, coumarin). As a linker, we have used squaramides, featured with strong hydrogen bond acceptor and donor capacities. (3) Results: Starting from easily accessible dimethyl squarate, the title compounds were successfully obtained as crystalline solids, avoiding the use of chromatographic purifications. Interesting and valuable SARs could be obtained upon modification of the length of the hydrocarbon chain, position of the sulfonamido moiety, distance of the aryl sulfonamide scaffold to the squaramide, stereoelectronic effects on the aromatic ring, as well as the number and type of substituents on C-3 and C-4 positions of the coumarin. (4) Conclusions: For sulfonamides, the best profile was achieved for the m-substituted derivative 11 (K-i = 29.4, 9.15 nM, CA IX and XII, respectively), with improved selectivity compared to acetazolamide, a standard drug. Coumarin derivatives afforded an outstanding selectivity (K-i > 10,000 nM for CA I, II); the lead compound (16c) was a strong CA IX and XII inhibitor (K-i = 19.2, 7.23 nM, respectively). Docking simulations revealed the key ligand-enzyme interactions. This research was funded by the Spanish Ministry for Science and Innovation, MCIN/AEI/10.13039/501100011033 (grant number PID2020-116460RB-I00), the Junta de Andalucia (FQM-134), the Canary Islands Government (ACIISI/FEDER, UE, grant number ProID2020010101) and by the Italian Ministry for University and Research (MIUR), grant PRIN: prot. 2017XYBP2R (CTS). Arrighi, G.; Puerta, A.; Petrini, A.; Hicke-García, FJ.; Nocentini, A.; Fernandes, MX.; Padrón, JM... (2022). Squaramide-Tethered Sulfonamides and Coumarins: Synthesis, Inhibition of Tumor-Associated CAs IX and XII and Docking Simulations. International Journal of Molecular Sciences. 23(14):1-24. https://doi.org/10.3390/ijms23147685