Novel selenium-based molecules as drug candidates for Alzheimer`s disease

Although Alzheimer’s disease (AD) was first diagnosed over 100 years ago, the number of therapeutic options remains very limited, and the drug discovery process for AD is painstakingly slow. This is attributed to the complexity of the disease's pathophysiology. Consequently, AD research has shifted from a monotherapy approach into a multi-targeted approach where one molecule is able to hit multiple targets. Organoselenium compounds as multi-targeted drug ligands (MTDLs) have been developed as potential inhibitors of Aβ aggregation and to reduce oxidative stress in AD, and also to provide novel scaffolds for designing promising disease-modifying agents. By utilizing computational chemistry principles, organoselenium tricyclic scaffolds were designed that exhibited promising binding affinity, and efficiency toward Aβ protein, different organic chemistry procedures were applied to develop synthetic methods to obtain the target derivatives. Further studies include structure-activity relationship (SAR) optimization by carrying out in vitro fluorescence kinetic studies to determine the inhibition of Aβ40 aggregation, transmission electron microscopy (TEM) studies, evaluation of antioxidant properties, and cell culture studies to identify novel organoselenium derivatives as MTDLs. Preliminary studies demonstrate a significant reduction in the Aβ40 aggregation suggesting their application in the development of novel therapeutic agents for the treatment of AD.