Novel carbonic anhydrase inhibitors for the treatment of Helicobacter pylori infection

Introduction: Helicobacter pylori, the causative agent of peptic ulcer, gastritis, and gastric cancer encodes two carbonic anhydrases (CA, EC 4.2.1.1) belonging to the alpha- and beta-class (HpCA alpha/beta), which have been validated as antibacterial drug targets. Acetazolamide and ethoxzolamide were also clinically used for the management of peptic ulcer. Areas covered: Sulfonamides were the most investigated HpCA alpha/beta compounds, with several low nanomolar inhibitors identified, some of which also crystallized as adducts with HpCA alpha, allowing for the rationalization of the structure-activity relationship. Few data are available for other classes of inhibitors, such as phenols, sulfamides, sulfamates, dithiocarbamates, arylboronic acids, some of which showed effective in vitro inhibition and for phenols, also inhibition of planktonic growth, biofilm formation, and outer membrane vesicles spawning. Expert opinion: Several recent drug design studies reported selenazoles incorporating seleno/telluro-ethers attached to benzenesulfonamides, hybrids incorporating the EGFR inhibitor erlotinib and benzenesulfonamides, showing K(I)s < 100 nM against HpCA alpha and MICs in the range of 8-16 mu g/mL for the most active derivatives. Few drug design studies for non-sulfonamide inhibitors were performed to date, although inhibition of these enzymes may help the fight of multidrug resistance to classical antibiotics which emerged in the last decades also for this bacterium.