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Several hundreds of studies published the last decade have reported that alpha-lipoic acid (LA) possess the potential to intervene in various therapeutically interesting pathways. However, it should be noted that LA reportedly exerts most of its effects at high micromolar concentrations; that amides of LA exhibit higher biological activity than the parent compound; and that molecular combinations (hybrids) obtained by coupling LA with an amino-substituted bioactive moiety, possess multifunctional activity. The design and synthesis of hybrid molecules encompassing two pharmacophores in one molecular scaffold is a well established approach to the synthesis of more potent drugs with dual activity. Using this approach, various research groups have recently designed and synthesized hybrid compounds with antioxidant activity hyphenated with a wide variety of other activities such as neuroprotective, cardioprotective, anti-inflammatory, antidiabetic and anticancer activity as well as enzyme inhibition. Moreover, LA represents an ideal chemical entity for the development of biologically interesting functionalized nanoparticles. Many recent publications describe the use of LA: i) as component of nanospheres and nanoprodrugs, ii) as a linker for the attachment of lipids, carbohydrates, proteins and oligonucleotides on gold nanoparticles to form Self Assembled Monolayers (SAMs) and iii) as surface ligand for cap exchange reactions to prepare water-soluble semiconducting nanocrystal Quantum Dots (QDs). This review is focused on the growing field of the design and synthesis of LA conjugates, for the development of novel molecules with a dual mode of action and the construction of nanosized antioxidants, Self Assembled Monolayers and Quantum Dots.

Novel 1,2-dithiolane/chroman hybrids bearing heterocyclic rings such as 1,2,4- and 1,3,4-oxadiazole, 1,2,3-triazole and tetrazole were designed and synthesized. The neuroprotective activity of the new analogues was tested against oxidative stress-induced cell death of glutamate-challenged HT22 hippocampal neurons. Our results show that bioisosteric replacement of amide group in 2-position of the chroman moiety, by 1,3,4-oxadiazole did not affect activity. However, analogue 5 bearing the 1,2,4-oxadiazole moiety showed improved neuroprotective activity. The presence of nitrogen heterocycles strongly influences the neuroprotective activity of 5-substituted chroman derivatives, depending on the nature of heterocycle. Replacement of the amide group of the first generation analogues by 1,2,4-oxadiazole or 1,2,3-triazole resulted in significant improvement of the activity against glutamate induced oxidative stress.

Novel hybrids of lipoic acid and trolox connected through triamine spacers as well as analogues in which the lipoic acid was attached at different positions of the chroman moiety of vitamin E through an amide bond, were synthesized and exhibited strong inhibition of the microsomal lipid peroxidation. Moreover, the new molecules, at 1 microM concentration, reduced reperfusion arrhythmias and MDA content on isolated rat heart preparations, with the 2- and 5-subtituted chromans possessing the better cardioprotective activity.

We designed and synthesized new analogues containing 1,2-dithiolane-3-alkyl and protected or free catechol moieties connected through heteroaromatic rings such as triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, tetrazole or thiazole in order to explore the influence of the bioisosteric replacement of the amide group on the neuroprotective activity of the lipoic acid/dopamine conjugate. Evaluation of the activity of the new compounds, using glutamate-challenged hippocampal HT22 cells, showed that incorporation of heteroaromatic rings in the alkyl-1,2-dithiolane moieties in conjunction with another antioxidant, in this case catechol, may result in strong neuroprotective activity.

We have synthesized a series of compounds combining the hydroxy-benzopyran ring of vitamin E with the methylsulfonylaminophenyl group of class III antiarrhythmic drugs, connected through tertiary amine moieties. Evaluation of the antiarrhythmic and antioxidant activity of the new compounds was carried out on isolated rat heart preparations using the non-recirculating Langendorff mode. The new analogues were present, at 10 microM concentration, during ischemia and reperfusion. Selected compounds were further studied by a conventional microelectrode method in order to get insight into their cellular mode of action. The most active compound, N-[4-[2-[[2-(3,4-dihydro-6-hydroxy-2,2,7,8-tetramethyl-2H-1-benzopyran-5-yl)ethyl] methylamine]ethyl]phenyl]methanesulfonamide (19a), reduces premature beats, prolongs QT and QRS intervals during ischemia and reperfusion, and reduces MDA content, leading to a fast recovery of the heart. In addition, it exhibits moderate class III antiarrhythmic action.