Multitarget and network-driven medicinal chemistry strategies for the treatment of neuroinflammatory diseases

Neuroinflammatory based-diseases are a very challenging area for medicinal chemists. Several efforts have been made during the years; however, an effective treatment for these diseases, such as Alzheimer’s disease (AD) and multiple sclerosis (MS), does not exist yet. Neuroinflammatory -based diseases are multifactorial in nature with still unclear pathogenic mechanisms and scarce information on how neuroinflammation is interconnected with other concomitant events, such as neurodegeneration. Polypharmacology is one of the milestones for the development of therapies able to combat multifactorial diseases. Particularly, the development of multitarget compounds through different strategies (linking, fusing, merging) has permitted to expand the potential arsenal to treat multifactorial diseases. Based on these considerations, this thesis was focused on the development of multitarget molecules for combating neuroinflammatory diseases through different and innovative polyphamacological approaches in four projects. Projects 1 & 2 focused on the development of fatty acids (FAs)/drug conjugates for the treatment of MS and AD, respectively. Particularly, we applied a conjugation strategy among omega-3 FAs and valproic acid (project 1) or P2Y6-agonists (project 2), in order to obtain innovative multitarget molecules with potentially increased property in terms of efficacy and pharmacokinetics, and less cytotoxicity. Projects 3 & 4 focused on the design and synthesis of multitarget molecules derived from food byproduct (cashew nut-shell liquid) for the treatment of AD. Particularly, we developed different series of molecules as potentially globally accessible drugs, by applying a hybridization strategy. Notably, we developed a small library of dual sustainable HDAC/ferroptosis inhibitors (project 3), and a library of cholinergic inhibitors with potential anti-inflammatory profile (project 4) as multitarget hybrids for the treatment of AD.