Carbonic Anhydrase Inhibitorswith Dual-Tail MoietiesTo Match the Hydrophobic and Hydrophilic Halves of the Carbonic AnhydraseActive Site.

We present a new approach to carbonicanhydrase II (CA II) inhibitordesign that enables close interrogation of the regions of the CA activesite where there is the greatest variability in amino acid residuesamong the different CA isozymes. By appending dual tail groups ontothe par excellenceCA inhibitor acetazolamide, compoundsthat may interact with the distinct hydrophobic and hydrophilic halvesof the CA II active site were prepared. The dual-tail combinationsselected included (i) two hydrophobic moieties, (ii) two hydrophilicmoieties, and (iii) one hydrophobic and one hydrophilic moiety. TheCA enzyme inhibition profile as well as the protein X-ray crystalstructure of compound 3, comprising one hydrophobic andone hydrophilic tail moiety, in complex with CA II is described. Thisnovel dual-tail approach has provided an enhanced opportunity to morefully exploit interactions with the CA active site by enabling thesemolecules to interact with the distinct halves of the active site.In addition to the dual-tail compounds, a corresponding set of single-tailderivatives was synthesized, enabling a comparative analysis of thesingle-tail versus dual-tail compound CA inhibition profile. [ABSTRACT FROM AUTHOR]