Hexahydropyrrolo[2,3-b]indole Compounds as Potential Therapeutics for Alzheimer's Disease

Alzheimer's disease (AD) is the most common form of dementia among the elderly and has become a leading public health concern worldwide. It represents a huge economic and psychological burden to caregivers and families. The presence of extracellular amyloid beta (Aβ) plaques is one of the hallmarks of this neurodegenerative disorder. Amyloid plaques are comprised of aggregates of Aβ peptides, mainly Aβ₄₂, originated by the cleavage of the amyloid precursor protein (APP). Aβ is a crucial target for the treatment of AD, but to date, no effective treatment for the clearance of Aβ has been found. We have identified four new hexahydropyrroloindoles (HPI) synthetic compounds that are able to inhibit the aggregation of Aβ₄₂ and/or disaggregate the fibril. Docking experiments suggest that the nonpolar component of the interaction of compounds with Aβ₄₂ contributes favorably to the binding free energy of each complex. Molecular dynamics simulations suggested fibril disaggregating activity of compounds 1 via interaction with hydrophobic moieties of the fibril. Consistently, compounds 1 and 2 were able to mitigate Aβ₄₂ fibrils induced death in rat pheochromocytoma cells (PC 12). One of the compounds reduces the formation of Aβ aggregates in vivo and the paralysis associated with Aβ toxicity in Caenorhabditis elegans. Our study thus augments efforts for the identification and characterization of new agents that may help stop or delay the progression of AD.