Design, Synthesis, and Biological Evaluation of Novel Phenoselenazine Derivatives as Amyloid Aggregation Inhibitors

Abstract

One of the leading challenges of modern medicine is Alzheimer’s disease (AD), a chronic and debilitating neurodegenerative disorder that poses a global health threat with profound implications for individuals and societies. The inception of AD in 1907 can be attributed to the pioneering research conducted by a German psychiatrist, Dr. Alois Alzheimer’s, who first identified two prevalent pathological features, plaques, and tangles, in the brain of his patient. These distinct plaques are made up of an amyloid protein called beta-amyloid (Aβ), as the chief component in AD`s plaques and a principal culprit throughout the progression of AD. The recent noteworthy accomplishments in monoclonal antibodies (mAbs) have marked a pivotal milestone, ushering in a new era where treatments targeting the amyloid cascade in Alzheimer's disease have emerged as a plausible avenue. Consequently, the amyloid cascade hypothesis is known as the dominant factor to develop diagnostics and therapies for AD. Despite the scientific breakthroughs made in the last few decades, there remains a notable lack of effective treatments for impeding disease progression. Therefore, researchers are now more desperate than ever to develop amyloid-cascade targeted small molecules, aiming to pave the way toward successful outcomes in AD treatment, as small molecules have a number of advantages over biological therapies. In this regard, this thesis research presented herein aimed to design and develop novel small molecules that have the potential to reduce/prevent the disease progression through targeting the aggregation cascade of the two common forms of Aβ, known as Aβ42 and Aβ40. Besides, our ring scaffold was able to target another key factor in AD pathology, the reactive oxygen species (ROS), and has the potential to mitigate their toxicity. A library of 47 compounds based on a novel fused tricyclic ring template was designed and developed by incorporating a selenium atom as a part of its heterocyclic ring, to obtain the phenoselenazine (PSZ) derivatives. The synthesized compound libraries were evaluated as potential inhibitors of Aβ42 aggregation by carrying out fluorescence aggregation kinetics experiments, transmission electron microscopy studies, neuroprotection experiments in mouse hippocampal HT22 neuronal cells exposed to Aβ42, evaluation of their antioxidant properties, blood-brain barrier permeability experiments and computational modeling studies.