Karboanhidrazių slopiklių sintezė ir jų struktūros - aktyvumo tyrimas

The aim of this work was formulated - the synthesis of potent human carbonic anhydrase inhibitors, and their structure - activity study. The synthesized 136 new compounds were subjected to the studies of their inhibitory activity towards CA I, II, VII, XII and XIII (VU IBT). An efficient method for N-and S-alkylation of heterocyclic compounds (benzimidazole), S-alkylation of heterocyclic and aromatic compounds (imidazole, benzothiazole, benzimidazothiadiazole, pyrimidine, benzenethiol) with 3 - and 4 - (bromoacetyl)benzenesulfonamides and 4 - and 5 - (bromoacetyl)-2-chlorobenzenesulfonamides has ben deveoped. 2-[(6-oksopyrimidine-2-yl)thio]acetylbenzenesulfonamides in dimethylsulfoxide solution were found to exists in two forms - open chain and cyclic. 4-(Hetarylmethylcarbonyl)benzenesulfonamides exibited more inhibitory potency to CA than the 3-(hetarylmethylcarbonyl)benzenesulfonamides. Among all compound studied S-alkylated benzenethiol derivatives exibit the best CA inhibitory properties, while 1,3-thiazole derivatives – the lowest. Sulfonamide group position on the benzene ring is more important for CA binding than the acidic properties of sulfonamide group. The inhibitors having the selectivity of any one CA were selected from synthesized compounds. Most of the compounds possess selectivity to CA I and CA XIII, while selectivity to CA XII almost is not observed. The benzenesulfonamide ring position in CA II active site is unique to each class of compounds as showed in the superposition of X-ray cocrystal structures (VU IBT). The comparison of CA II active site with CA I, XII and XIII active sites in complexes of CA II, XII, XIII with the synthesized compounds was performed