Pharmacological features of mesoionic compounds: antitumoral effects and bioenergetic disruption of sydnones and 1,3,4-thiadiazolium derivatives.

Mesoionic compounds are five-membered heterocyclic betaines that cannot be satisfactorily represented by a single covalent or polar structure. Because their positive and negative charges are delocalized over separate regions of the ring, they yield a net-neutral molecule with a high dipole moment. This unique electronic configuration confers amphiphilic character and pronounced affinity for biological membranes, including mitochondria, underlying a broad pharmacological profile that includes antitumoral, anti-inflammatory and analgesic activities. Among the several mesoionic scaffolds, sydnones (1,2,3-oxadiazolium-5-olate) and 1,3,4-thiadiazolium derivatives have been the most extensively studied, drawing particular attention to their pronounced antineoplastic activity against melanoma, hepatocellular carcinoma, breast cancer and glioblastoma models. Their anticancer effects are closely linked to mitochondrial bioenergetic disruption, including uncoupling of oxidative phosphorylation, inhibition of respiratory complexes, dissipation of the mitochondrial membrane potential, and stimulation of F1Fo-ATPase activity, which together cause ATP depletion, redox imbalance, and apoptosis induction. This review provides a comprehensive analysis of the structural features that govern these biological properties, the antitumor efficacy of sydnones and thiadiazolium derivatives across various cancer models, and the underlying mitochondrial mechanisms. By integrating chemical, pharmacological, and bioenergetic perspectives, this article highlights the potential of mesoionic compounds as versatile scaffolds for the anticancer drug development, emphasizing their preclinical antitumoral activities, the mechanisms related to cell bioenergetics, and the challenges to improve the bioviability through nanotechnologies.