Neurodegenerative diseases are complex disorders with several pathoetiological pathways leading to cell death.
Rationally designed multi-targeted agents, or “multi-targeted designed drugs” (MTDD) show significant promise in preclinical
studies as neuroprotective and disease-modifying agents. In this review, we highlight the use of chemical scaffolds
that lend themselves exquisitely to the development of MTDDs in neurodegeneration. Notably, synthetic polycyclic cage
compounds have served as scaffolds for novel voltage-gated calcium channel blockers, NMDA receptor antagonists, and
sigma-receptor ligands – attractive targets in neurodegeneration. In an entirely different approach, compounds containing
the thiazolidinedione moiety (referred to as glitazones) alter mitochondrial function through the mitochondrial protein mitoNEET,
an attractive new drug target for the treatment of neurodegenerative diseases. The design strategy for yet another
agent, ladostigil, employed the amalgamation of active chemical moieties of the AChE inhibitor rivastigmine, and the
monoamine oxidase-B (MAO-B) inhibitor rasagiline, leading to a single compound that targets both enzymes simultaneously.
Natural products have also served as design templates for several MTDD design studies. In particular, the stilbene
scaffold has become popular in particular due to the neuroprotective effects of the non-flavonoid natural product resveratrol.
Recently, stilbene scaffold-based compounds were developed to reduce – through chelation with metal ions that interact
with beta-amyloid – both metal-induced beta-amyloid protein aggregation, and ROS generated from this aggregate.
Other subtle modifications of the stilbene motif led to the creation of reversible, non-competitive MAO inhibitors. Finally,
compounds derived from the xanthine scaffold afford neuroprotection in Parkinson’s disease through mechanisms that include
dual adenosine A2A receptor antagonism and MAO-B inhibition.