Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 14, Pages -Publisher
MDPI
DOI: 10.3390/ijms23147685
Keywords
carbonic anhydrases; sulfonamides; coumarins; squaramides; docking simulations
Funding
- Spanish Ministry for Science and Innovation, MCIN/AEI [PID2020-116460RB-I00]
- Junta de Andalucia [FQM-134]
- Canary Islands Government (ACIISI/FEDER, UE) [ProID2020010101]
- Italian Ministry for University and Research (MIUR) [2017XYBP2R]
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In this study, a series of compounds inhibiting carbonic anhydrases were successfully synthesized by appending a hydrophobic aromatic tail and using squaramides as linkers. Interesting structure-activity relationships were obtained by modifying the structural parameters of the compounds. Among them, m-substituted derivative 11 and 16c exhibited good activity and selectivity.
(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.
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