Endoperoxides in combating bacterial infections: synthetic pathways, mechanism, biological activity and mode of action

Endoperoxides are heterocyclic compounds with a peroxide functional group embedded in one or more rings. These compounds have gathered significant interest in the last two decades owing to their biological activities and pharmaceutical relevance. The most prominent endo-peroxide with pharmacological activity is artemisinin, which is currently used as part of combination therapies, as the standard treatment for malaria. However, endoperoxides have also shown antibiotic properties, and the development of new antibiotics has been limited in recent decades. Therefore, this review provides a comprehensive overview of the potential of endoperoxides in combating bacterial pathogens. Here, we are highlighting the recent advances in natural and synthetically derived endoperoxide which have shown potential antibacterial activity. Their structures are analysed to elucidate the critical features influencing antibacterial efficacy, providing insights into rational design strategies for potent derivatives. It also delves into the mechanism of action of endoperoxides, emphasizing their reactive oxygen species (ROS)-mediated antibacterial activity and potential to circumvent existing resistance mechanisms. Furthermore, we evaluate the biological activity of various synthetic and natural endoperoxides, underscoring their effectiveness against a broad spectrum of bacterial strains, including multidrug-resistant pathogens. By integrating these aspects, we aim to inspire further research into endoperoxides as a promising frontier in the development of next-generation antibacterial agents.