Mesoionic compounds have a planar five membered heterocyclic ring with at least one side-chain whose a atom is also in the plane, giving rise to a high dipole moment. Besides being internally charged, a structure that favors strong interactions with macromolecules such as DNA and proteins, they are neutral overall and, therefore can cross biological membranes. Senff-Ribeiro et al. (2004) described an antimelanoma effect of a series of 4-phenyl-5-(2’-Y, 4’-X or 4’-X-cinnamoyl)-1,3,4-thiadiazolium-2-phenylamine chlorides, each one differing only as the cinnamoyl ring substituent (MI-D, X=NO₂, MI-J, X =OH; MI-2,4diF, X = Y= F; MI-4F, X =F). The most effective was MI-D, probably due to its stronger electron-withdrawing substituent group. The effect of MI-D on the energy-linked functions of mitochondria has long been recognized (Cadena et. al. 1998, 2002). We now extended these studies to other compounds of this series (MI-J, MI-4F, MI-4diF), in order to verify how chemical substitutions around the heterocyclic ring affects the bioenergetics of mitochondria. In isolated rat liver mitochondria, MI-J (130 nmol.mg^-1protein) inhibited state 3 by ~60%, this parameter being completely inhibited with MI-4F and MI-2,4diF at same concentration. All derivatives stimulated state 4. At low concentrations (6.5 nmol.mg^-1 protein), the stimulus was ~23%, ~140% and ~72% for MI-J, MI-4F e MI-2,4F, respectively and at 32.5 nmol.mg^-1 protein, the effect being the greatest for all compounds, so that the respiratory control coefficient (RCC) and ADP/O ratio were lowered. Consistently, NADH oxidase was inhibited being ~60%, ~80% and ~90% respectively for MI-J, MI-4-F and MI-2,4F, all at 130 nmol.mg^-1 protein. F₁F_o ATPase of intact mitochondria was stimulated by all compounds (6.5 - 32.5 nmol.mg^-1protein) but at higher concentrations (65 - 130 nmol.mg^-1protein), inhibition of this enzymatic complex was observed. Therefore, in contrast to that observed with the melanoma model, where the substituent NO₂ was the most effective, the effects on the mitochondrial function promoted by MI-4F and MI-2,4F seem to be more pronounced, when compared to those caused by MI-J, as well as MI-D. Thus, studies concerning the relationship of structures and its biological activities, besides the electronic nature of the substituents, must consider their lipophilicity and the biological model involved.