Carbonic anhydrase inhibitors: inhibition of human and bovine isoenzymes by benzenesulphonamides, cyclitols and phenolic compounds

Abstract

Carbonic anhydrase inhibitors (CAIs) are a class of pharmaceuticals used as anti-glaucoma agents, diuretics and anti-epileptics. We report here the inhibitory capacities of benzenesulphonamides, cyclitols and phenolic compounds 1-11 against three human CA isozymes (hCA I, hCA II and hCA VI) and bovine skeletal muscle carbonic anhydrase III (bCA III). The four isozymes showed quite diverse inhibition profiles with K(i) values ranging from low micromolar to millimolar concentrations against all isoenzymes. Compound 5 and 6 had more powerful inhibitory action against hCA I and very similar action against hCA II and hCA VI as compared with acetazolamide (AZA) and sulphapyridine (SPD), specific CAIs. Probably the inhibition mechanism of the tested compounds is distinct of the sulphonamides with RSO(2)NH(2) groups and similar to that of the coumarins/lacosamide, i.e. binding to a distinct part of the active site than that where sulphonamides bind. These data may lead to drug design campaigns of effective CAIs possessing a diverse inhibition mechanism compared to other sulphonamide/sulphamate inhibitors.

Kinetic andin silicostudies of hydroxy-based inhibitors of carbonic anhydrase isoforms I and II

“…It is interesting to note that the compounds 7-12 and 15 were much better hCA I inhibitors as compared to the corresponding compounds 13 and 14. Kinetic investigations (Lineweaver-Burk plots, data not shown) indicate that similarly to sulfonamides and inorganic anions [5][6][7][8][9][10][11][12][25][26][27][28][29][30] , all the investigated natural compounds act as competitive inhibitors with 4-NPA as substrate (i.e. they bind in different regions of the active site cavity as compared to the substrate).…”

“…Our group recently investigated the interaction of CA isozymes I, II with salicylic acid derivatives, antioxidant phenolic compounds, organic nitrates, organic sulphate, hydroxy group containing compounds, etc. (Figure 1) [6][7][8][9][10][11][12] . We wanted to extend these earlier investigations to some hydroxy compounds in order to discover powerful CA inhibitors (CAIs) which might have implications in medicine [6][7][8][9][10] .…”

“…These isozymes play important roles in different tissues [2][3][4][5] . CAs constitute interesting targets for the design of pharmacological agents that are useful in the treatment or prevention of a variety of disorders such as glaucoma, acidbase disequilibria, epilepsy and other neuromuscular diseases, altitude sickness, edema and obesity [3][4][5][6][7][8][9] . Many hydroxy compound derivatives have been widely used as pro-drugs or drugs.…”

Kinetic andin silicoanalysis of thiazolidin-based inhibitors of α-carbonic anhydrase isoenzymes

“…Although various carbonic anhydrase inhibitors have been identified up to now, it is critically important to explore further classes of potent CAIs in order to detect compounds with a different inhibition profile to find novel applications for the inhibitors of these widespread enzymes [35][36][37][38][39][40] .…”

Synthesis and characterization of quinazoline derivatives: search for hybrid molecule as diuretic and antihypertensive agents

“…Interestingly, all the above-mentionerd compounds possess similar or closely related to quinazoline moiety. Quinazoline derivatives, which belong to the N-containing heterocyclic compounds, have universal concerns due to their wide and distinct biological activities such as diuretic [5][6][7] , antihypertensive 8 , antihistaminic 9,10 analgesic and anti-inflammatory 11,12 anticancer 13 and anti-HIV 14 activities. On the other hand, sulphonamide exhibits acidity in the molecule; these acidic protons enable the formation of the corresponding water-soluble sodium salt and also prevent the carbonic acid from acquiring deprotonated state due to the Zn(II) ion within the enzyme active site which causes diuresis 15,16 .…”