2-(2-Hydroxyethyl)piperazine derivatives as potent human carbonic anhydrase inhibitors: Synthesis, enzyme inhibition, computational studies and antiglaucoma activity

Targeting Carbonic Anhydrases (CAs) represents a strategy to treat several diseases, from glaucoma to cancer. To widen the structure-activity relationships (SARs) of our series of piperazines endowed with potent human carbonic anhydrase (hCA) inhibition, a new series of chiral piperazines carrying a (2-hydroxyethyl) group was prepared. The Zn-binding function, the 4-sulfamoylbenzoyl moiety, was connected to one piperazine N-atom, while the other nitrogen was decorated with alkyl substituents. In analogy to the approach used for the synthesis of the previously reported series, the preparation of the new compounds started with ( R )- and ( S )-aspartic acid. A partial racemization occurred during the synthesis. In order to overcome this problem, other chemical strategies were investigated. The inhibitory activity of the new polar derivatives against four hCAs isoforms I, II, IV and IX using a stopped flow CO 2 hydrase assay was determined. Some compounds showed potency in the nanomolar range and a preference for inhibiting hCA IX. • 2- and 3-(2-hydroxyethyl)piperazine-1-carbonyl)-4-benzenesulfonamides have been synthesized from D and l -aspartic acid. • The new compounds have been tested on physiologically relevant hCA isoforms. • The compounds are potent inhibitors of hCA II and IX but not hCA IV. • Both ( R ) and ( S )- 13 are active in rabbit models of transient glaucoma.