The design of multitarget-directed ligands (MTDLs) is an effective approach to obtain effective drugs against complex pathologies. MTDLs that combine neurorestorative properties and block the first step of the neurotoxic cascade may be long-needed drugs for the treatment of neurodegenerative diseases (ND). New CNS-permeable flavonoids were obtained by linking two specialized scaffolds with ND targets, flavonoids and N,N-dibenzyl (N-methyl)amine (DBMA) fragments, with well-known activities- DBMA hybrids (1–13). They were biologically evaluated in a range of targets implicated in Alzheimer's disease (AD) and other NDs, namely human cholinesterase (hAChE/hBuChE), β-secretase (hBACE-1), monoamine oxidase (hMAO-A/B), lipoxygenase 5 (hLOX-5) and σ receptors (σ1R/σ2R). After funnel screening, 6,7-dimethoxychromone – DBMA (6) was highlighted due to its neurogenic properties and interesting MTD distributions in methyl amine hAChE, hLOX-5, hBACE-1 and σ1R. Molecular dynamics simulations revealed the most relevant drug-protein interactions for hybrid 6, which can synergistically promote neuronal regeneration and block neurodegeneration.

Key words: multi-target targeting ligands, neurogenesis, sigma receptors, human β-secretase, human lipoxygenase-5, human cholinesterase, Alzheimer's disease, neurodegenerative diseases
Despite tremendous progress in understanding the pathophysiology of Alzheimer's disease (AD), our current understanding of the disease remains an incomplete puzzle. Several hypotheses have attempted to explain its origin based on different pathogenic factors, such as amyloid-β peptide (Aβ) accumulation, abnormal tau phosphorylation, defects in cholinergic transmission, exacerbated neuroinflammatory responses, and oxidative damage. However, so far, all of these are only loose pieces of the puzzle, and none of them have been able to explain the complexity of AD1.

This brings us to the main fact that is clear today, namely the multifactorial nature of the disease, in which different factors contribute to its onset and progression. However, currently approved drugs that primarily act on a single target, acetylcholinesterase (AChE) or the N-methyl-D-aspartate receptor (NMDA), do little to modify disease progression 2 . This failure lies in the complex network of pathophysiological processes underlying the origin of AD-associated neurodegeneration, and our lack of understanding of the primordial event (if only one) that triggers the others. So far, we have learned that genetic, epigenetic and environmental factors are involved in neurodegeneration. Furthermore, accumulating evidence suggests that some systemic alterations in AD should be understood as echoes of underlying processes related to the origin of the disease, rather than merely secondary effects of neuronal death. Some of these systemic changes include immune abnormalities and antioxidant responses, metabolic disturbances, liver dysfunction, cardiovascular disease, and gut microbiota disturbances, among others. This suggests that treatments based on a single and simple mechanism of action cannot halt or prevent multifactorial processes such as AD.