Synthesis and Biological Evaluation of Carbonic Anhydrase III and IX Inhibitors using Gas Chromatography with Modified pH Sensitive Pellets

Abstract

Fifteen compounds were synthesized and tested as potential carbonic anhydrase III (CAIII) and carbonic anhydrase IX (CAIX) inhibitors, six of which are novel. Amides (a1-4), hydroxamic acids (b1-2), and imines (c1-9) derivatives were evaluated for their inhibitory activity against CAII and CAIX using gas chromatography with modified pH-sensitive pellets. The derivatives showed inhibition percentages between 12-56% for CAIII and 44-59% for CAIX, compared to 49% and 63% for captopril (the positive control), respectively. Imines showed the best inhibition of CAIII, while all derivatives showed comparable activity against CAIX. It is hypothesized that the nitrogen atom in imine, amide, or hydroxamic acid moieties in the vicinity of an ionizable group is in coordination with the zinc ion in the active site. Furthermore, the candidates were tested for their antimicrobial and antifungal activity. Generally, they showed low to zero activity against some gram-positive and negative bacteria. This supports the theory of their ability to bind to human carbonic anhydrase but not to bacterial one. These compounds could serve as useful scaffolds to develop more potent and selective carbonic anhydrase inhibitors as anti-obesity and anticancer candidates.