Synthesis, Crystal Structure, Inhibitory Activity and Molecular Docking of Coumarins/Sulfonamides Containing Triazolyl Pyridine Moiety as Potent Selective Carbonic Anhydrase IX and XII Inhibitors

Abstract

In this work, two classes of Carbonic Anhydrase (CA) inhibitors, sulfonamide and coumarin derivatives linked to pyta moiety (2a-b) and their corresponding rhenium complexes (3a-b), were designed. These compounds were synthesized and fully characterized by classical analytical methods and X-ray diffraction. All the synthesized compounds were evaluated for their inhibitory activity against the hCA isoforms I, II, IX and XII. They exhibited high inhibitory activities in the range of nanomolar for both hCA IX and hCA XII isoforms. The sulfonamide compound 2a showed the strongest inhibition against the tumour-associated hCA IX isoform with a Ki of 11.7 nM. The tumour-associated isoforms hCA IX and hCA XII were selectively inhibited by all the coumarin derivatives, with inhibition constants ranging from 12.7 nM (2b) to 44.5 nM (3b), while the hCA I and II isoforms were slightly inhibited (in the micromolar range), as expected. In terms of selectivity, compared to previously published rhenium complex-based CA inhibitors, complex 3b showed one of the highest selectivities against hCA IX and hCA XII compared to the off-target isoforms hCA I and hCA II, making it a potential anti-cancer drug candidate. Molecular docking calculations were performed to investigate the inhibition profiles of the investigated compounds at the tumour-associated hCA IX active site and to rationalize our results.

Medicinal inorganic chemistry – challenges, opportunities and guidelines to develop the next generation of radioactive, photoactivated and active site inhibiting metal-based medicines

“…The mechanism of action of complex 36 involves the blocking of the enzyme cavity, producing the closed (non-hydrolyzed) and hydrolyzed form interaction of the fac -Re(CO) 3 moiety to efficiently encumber the active site. 34…”

“…The mechanism of action of complex 36 involves the blocking of the enzyme cavity, producing the closed (nonhydrolyzed) and hydrolyzed form interaction of the fac-Re(CO) 3 moiety to efficiently encumber the active site. 34 Most recently, Re + -tricarbonyl compounds incorporating the 2,2 0 -bipyridine ligand have been described for the inhibition of cysteine protease to disrupt the viral life cycle of SARS-CoV-2. 35 The mechanism of action involves formation of a reversible covalent bond between the rhenium complex and the catalytically active cysteine amino acid in the active site.…”

Derivatives of 4-methyl-1,2,3-benzoxathiazine 2,2-dioxide as selective inhibitors of human carbonic anhydrases IX and XII over the cytosolic isoforms I and II

“…Classical CA inhibitors (CAIs) usually have a sulphonamide moiety as a zinc-binding group (ZBG), such as clinically used CAIs acetazolamide and methazolamide. On the other hand, the non-classical CAIs do not rely on ZBG 13 , 14 . Non-classical CAIs such as coumarins, carboxylic acids, phenols, polyamines inhibit the catalytic activity of CA by different mechanisms rather than coordinating to the zinc 12 .…”

Novel 3-(6-methylpyridin-2-yl)coumarin-based chalcones as selective inhibitors of cancer-related carbonic anhydrases IX and XII endowed with anti-proliferative activity

“…Classical CA inhibitors (CAIs) are mostly based on a sulphonamide moiety as a zinc-binding group (ZBG) among which the clinically used CAIs; such as acetazolamide and methazolamide. On the other hand, the non-classical CAIs do not rely on ZBG 11 , 12 . Among the non-classical CAIs; coumarins, carboxylic acids, phenols, and polyamines can inhibit the catalytic activity of CA by different mechanisms rather than coordinating to the zinc 13 , 14 .…”

“…Coumarin was shown to undergo hydrolysis to form cis-2-hydroxy-cinnamic acid ( II , Figure 1 ), instead of binding the CA active site with its intact coumarin moiety. The substantial selective inhibitory effect towards h CA IX and XII is attributable to the binding of the hydrolysis product II to the amino acid residues constituting the rim of the active site cavity, which differed significantly between different h CA isoforms 12 , 17 , 18 . These findings grasped the attention for developing a variety of coumarin-based CAIs, such as compounds III–V ( Figure 1 ), which exerted efficient and selective inhibition activity towards the cancer-related isozymes IX and XII over the constitutional isozymes CA I and II 18–20 .…”