Imidazo[2,1‑<i>b</i>][1,3]thiazine\nDerivatives as Potential Modulators of Alpha-Synuclein Amyloid Aggregation

Insoluble amyloid fibrils accumulate in the intercellular\nspaces\nof organs and tissues, leading to various amyloidosis-related disorders\nin the human body. Specifically, Parkinson’s disease is associated\nwith the aggregation of alpha-synuclein. However, current treatments\nfor Parkinson’s primarily focus on managing motor symptoms\nand slowing disease progression. Efforts to prevent and halt the progression\nof these diseases involve the search for small molecular compounds.\nIn this work, we synthesized imidazo[2,1-<i>b</i>][1,3]thiazines\nin an atom-economic way by cyclization of 2-alkynylthioimidazoles\nusing 10% AuCl as the catalyst. We identified several compounds with\nspecific functional groups capable of both inhibiting the aggregation\nof alpha-synuclein and redirecting the fibril formation pathway. The\ninvestigation into how these substances function revealed that imidazo[2,1-<i>b</i>][1,3]thiazine derivatives can influence alpha-synuclein\naggregation in several ways. They not only inhibit the primary nucleation\nprocess and maintain a balance toward nonaggregated protein states\nbut also stabilize smaller oligomeric species of alpha-synuclein and\ncause the formation of fibrils with unique structures and forms. These\nimidazo[2,1-<i>b</i>][1,3]thiazines could potentially be\nused in developing highly efficient, small molecular weight protein\naggregation inhibitors.