Synthesis and carbonic anhydrase inhibition of tetrabromo chalcone derivatives

Abstract

In the present study, human carbonic anhydrase (hCA) enzyme was purified and characterized from fresh blood human red cells by Sepharose-4B-l-tyrosine-sulfanilamide affinity gel chromatography. Secondly, a series of new tetrabromo chalcone derivatives containing 4,7-methanoisoindol-1,3-dione (2a-i) were synthesized from the addition of Br-2 to related chalcone derivatives (1a-i). The structures of the new molecules (2a-i) were confirmed by means of H-1 NMR, C-13 NMR and elemental analysis. Finally, the inhibitory effects of 2a-i on CA activities were investigated using the esterase method under in vitro conditions. The compounds 2a-i exhibited excellent inhibitory effects, in the low nanomolar range, with K-i values in the range of 11.30-21.22nM against hCA I and in the range of 8.21-12.86nM against hCA II. Our findings suggest that the new compounds 2a-i have superior inhibitory effect over acetazolamide (AZA), which is used as clinical CA inhibitor, with obtained K-i values of 34.50 and 28.93nM against the hCA I and II isozymes, respectively. In addition to the inhibition assays, molecular modeling approaches were implemented for prediction of the binding affinities of compounds 2a and 2c, which had the highest inhibition effects, against the hCA I and II isozymes.