Azo derivatives of monoterpenes as anti-Helicobacter pylori agents: from synthesis to structure-based target investigation

Helicobacter pylori (Hp) infection affects nearly half of the global population. Current therapeutic options include the administration of a combination of antibiotics and proton pump inhibitors, although antimicrobial resistance rise remains a big concern. Phenolic monoterpenes, e.g., eugenol, vanillin, carvacrol, and thymol, have always attracted researchers for their multifaced biological activities and the possibility to be easily derivatized. Thereby, herein we present the functionalization of such compounds through the conventional aryl diazotization reaction, generating a series of mono- and bis-azo derivatives (1–28). Also, to continue previous studies, we investigated the role of the free phenolic moiety of thymol with eight compounds (29–36). The compounds were tested against four Hp strains including three clinical isolates, finding some potent and selective inhibitors of bacterial growth. Thus, the representative compounds underwent in vitro cytotoxicity evaluation on two normal cell lines and putative target investigation by performing a structure-based approach based on docking calculations on some of the most studied pharmacological targets for Hp, e.g., urease, β-hydroxyacyl-acyl carrier protein dehydratase, glucose 6-phosphate dehydrogenase, and inosine 5′-monophosphate dehydrogenase.