Rational design of multitarget-directed antioxidants: merging memoquin and lipocrine molecular frameworks

Recent experimental evidence has greatly expanded our understanding of the role of oxidative stress in the pathogenesis of Alzheimer’s disease (AD). This comes from the established interconnections among oxidative stress and other AD key events, such as apoptosis, amyloid-β (Aβ) secretion and tau phosphorylation, as well the disruption of Ca2+ homeostasis. Therefore, antioxidants might have therapeutic potential against AD. Coenzyme Q (CoQ) and α-lipoic acid (LA) are mitochondrial antioxidants with potentially neuroprotective effects in neurodegenerative diseases in which excessive oxidative stress is present. However, the disappointing results of clinical trials of these and other antioxidants suggest that single use of antioxidants may not be adequate, while optimal combinations of antioxidants may provide a more effective strategy. Recently, we proposed that a single molecule endowed with antioxidant properties and able to act at different sequential steps in the neurodegenerative process can produce additive neuroprotective effects. This concept, termed multi-target-directed ligands (MTDLs) design strategy, has been embodied in the development of two drug candidates, memoquin and lipocrine, which display a multitarget profile against AD. Memoquin, which presents the benzoquinone moiety of CoQ inserted into a polyamine chain, is able to modulate acetylcholinesterase and BACE-1 enzymes, Aβ and oxidative processes. A tacrine moiety coupled with LA led to lipocrine, which, in addition to the AChE inhibitory activity, has demonstrated the further ability to behave as an antioxidant. Following the same rationale, we reasoned that merging the antioxidant features of memoquin and lipocrine in a single chemical entity could, hopefully, lead to ligands with multiple antioxidant mechanisms, hence a better potential for AD prevention and therapy. The newly synthesized hybrids can be defined as multifunctional antioxidants, i.e., MTDLs with other pharmacological effects in addition to their antioxidant activity. Their capability to target oxidative and non-oxidative pathways of AD has been investigated in isolated-target and cell-based assays.