Photoactivatable Heptamethine-Based Carbonic Anhydrase Inhibitors Leading to New Anti-Antibacterial Agents

Abstract

With the aim to propose innovative antimicrobial agents able to not only selectively inhibit bacterial carbonic anhydrases (CAs) but also to be photoactivated by specific wavelengths, new heptamethine-based compounds decorated with a sulfonamide moiety were synthesized by means of different spacers. The compounds displayed potent CA inhibition and a slight preference for bacterial isoforms. Furthermore, minimal inhibitory and bactericidal concentrations and the cytotoxicity of the compounds were assessed, thus highlighting a promising effect under irradiation against S. epidermidis. The hemolysis activity test showed that these derivatives were not cytotoxic to human red blood cells, further corroborating their favorable selectivity index. This approach led to the discovery of a valuable scaffold for further investigations.

Benzenesulfonamide decorated dihydropyrimidin(thi)ones: carbonic anhydrase profiling and antiproliferative activity

“…Inhibitor and enzyme solutions were preincubated together for 15 min at r.t. prior to the assay, to allow for the formation of the E–I complex. 44,45 The inhibition constants were obtained by non-linear least-squares methods using PRISM 3 and the Cheng–Prusoff equation as reported earlier 46 and represent the mean from at least three different determinations. hCAs I and II were purchased from Merck, while hCAs VII, IX, and XII are recombinant and obtained in-house.…”

Discovery of a New Class of 1-(4-Sulfamoylbenzoyl)piperidine-4-carboxamides as Human Carbonic Anhydrase Inhibitors

“…Currently 15 CAs have been discovered and described in humans and are involved in several physiological and biochemical processes, such as pH homeostasis, gluco­neogenesis, liquid secretion, and tumor­genicity. The active site of human CAs (hCAs) contains zinc ions in a tetrahedral geometric shape, coordinated by three amino acid residues, H94, H96, and H119, in addition to a H 2 O molecule or OH – ion. − The hCA IX and hCA XII isoenzymes have been deeply studied due to their important role in cancer cell survival. − Although small metabolic changes are tolerated in cancer cells, strong pH control is necessary for their survival and proliferation . Hydrogen carbonate ions, which are important pH buffers, are imported by transporters such as Cl – /HCO 3 – anion exchanger and Na + /HCO 3 – co-transporter, consuming cytosolic protons to give a new molecule of CO 2 which leaves the cytoplasm to be hydrated by hCA IX and XII .…”