Targeting mitochondrial oxidative stress is an effective therapeutic strategy. In this context, a rational design of mitochondriotropic antioxidants (compounds 22-27) based on a dietary antioxidant (caffeic acid) was performed. Jointly named as AntiOxCINs, these molecules take advantage of the known ability of the triphenylphosphonium cation to target active molecules to mitochondria. The study was guided by structure-activity-toxicity-property relationships, and we demonstrate in this work that the novel AntiOxCINs act as mitochondriotropic antioxidants. In general, AntiOxCINs derivatives prevented lipid peroxidation and acted as inhibitors of the mitochondrial permeability transition pore. AntiOxCINs toxicity profile was found to be dependent on the structural modifications performed on the dietary antioxidant. On the basis of mitochondrial and cytotoxicity/antioxidant cellular data, compound 25 emerged as a potential candidate for the development of a drug candidate with therapeutic application in mitochondrial oxidative stress-related diseases. Compound 25 increased GSH intracellular levels and showed no toxicity on mitochondrial morphology and function.

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The biological effects attributed to nitric oxide ( NO) and nitroxyl (HNO) have been extensively studied, propelling their array of putative clinical applications beyond cardiovascular disorders toward other age-related diseases, like cancer and neurodegenerative diseases. In this context, the unique properties and reactivity of the N-O bond enabled the development of several classes of compounds with potential clinical interest, among which NO and HNO donors, nitrones, and nitroxides are of particular importance. Although primarily studied for their application as cardioprotective agents and/or molecular probes for radical detection, continuous efforts have unveiled a wide range of pharmacological activities and, ultimately, therapeutic applications. These efforts are of particular significance for diseases in which oxidative stress plays a key pathogenic role, as shown by a growing volume of in vitro and in vivo preclinical data. Although in its early stages, these efforts may provide valuable guidelines for the development of new and effective N-O-based drugs for age-related disorders. In this report, we review recent advances in the chemistry of NO and HNO donors, nitrones, and nitroxides and discuss its pharmacological significance and potential therapeutic application.

A novel mitochondria-targeted antioxidant (TPP-OH) was synthesized by attaching the natural hydrophilic antioxidant caffeic acid to an aliphatic lipophilic carbon chain containing a triphenylphosphonium (TPP) cation. This compound has similar antioxidant activity to caffeic acid as demonstrated by measurement of DPPH/ABTS radical quenching and redox potentials, but is significantly more hydrophobic than its precursor as indicated by the relative partition coefficients. The antioxidant activity of both compounds was intrinsic related to the ortho-catechol system, as the methoxylation of the phenolic functions, namely in TPP-OCH(3) and dimethoxycinnamic acid, gave compounds with negligible antioxidant action. The incorporation of the lipophilic TPP cation to form TTP-OH and TPP-OCH(3) allowed the cinnamic derivatives to accumulate within mitochondria in a process driven by the membrane potential. However, only TPP-OH was an effective antioxidant: TPP-OH protected cells against H(2)O(2) and linoleic acid hydroperoxide-induced oxidative stress. As mitochondrial oxidative damage is associated with a number of clinical disorders, TPP-OH may be a useful lead that could be added to the family of mitochondria-targeted antioxidants that can decrease mitochondrial oxidative damage.

The increased bacterial multidrug resistance caused by inappropriate use and overuse of antimicrobials is a global concern. To circumvent this issue, a quest for the development of new active agents has been widely recognized. Some phytochemical products, produced by plants as part of their chemical defense strategies, are regarded as new stimulus to develop novel antimicrobials that are not as vulnerable as current drugs to bacterial resistance mechanisms. In this study, the antimicrobial activity and mode of action of caffeic acid (CAF) and a series of CAF alkyl esters was assessed against Escherichia coli and Staphylococcus aureus, with the aim of analyzing the influence of the alkyl ester side chain length on the activity. Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), changes in physicochemical surface properties and intracellular potassium leakage were used as physiological indices for the antimicrobial mode of action. CAF alkyl esters were found to be effective antimicrobial agents against both bacteria. Their activity was directly dependent on their lipophilicity, which affected bacterial susceptibility, the physicochemical properties of the bacteria and the integrity of the membranes. E. coli was less susceptible than S. aureus to the action of the compounds. Longer alkyl side chains were more effective against the Gram-positive bacterium, while medium length alkyl side chain compounds were more effective against the Gram-negative bacterium. Caffeic acid derivatives are proposed to act as cell permeabilizers, inducing membrane alterations, causing rupture with potassium leakage, particularly on the Gram positive bacterium, and consequent cell death.

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