Azobenzenesulfonamide Carbonic Anhydrase Inhibitors as New Weapons to Fight Helicobacter pylori: Synthesis, Bioactivity Evaluation, In Vivo Toxicity, and Computational Studies

Research into novel anti-<i>Helicobacter pylori</i> agents represents an important approach for the identification of new treatments for chronic gastritis and peptic ulcers, which are associated with a high risk of developing gastric carcinoma. In this respect, two series of azobenzenesulfonamides were designed, synthesized, and tested against a large panel of human and bacterial CAs to evaluate their inhibitory activity. In addition, computational studies of the novel primary benzenesulfonamides (<b>4a</b>-<b>j</b>) were performed to predict the putative binding mode to both HpCAs. Then, the antimicrobial activity versus <i>H. pylori</i> of the two series was also studied. The best-in-class compounds were found to be <b>4c</b> and <b>4e</b> among the primary azobenzenesulfonamides and <b>5c</b> and <b>5f</b> belonging to the secondary azobenzenesulfonamides series, showing themselves to exert a promising anti-<i>H. pylori</i> activity, with MIC values of 4-8 μg/mL and MBCs between 4 and 16 μg/mL. Moreover, the evaluation of their toxicity on a <i>G. mellonella</i> larva in vivo model indicated a safe profile for <b>4c</b>,<b>e</b> and <b>5c</b>,<b>f</b>. The collected results warrant considering these azobenzenesulfonamides as an interesting starting point for the development of a new class of anti-<i>H. pylori</i> agents.