Imidazo2,1-b1,3thiazine Derivatives as Potential Modulators of Alpha-Synuclein Amyloid Aggregation

• Published in: ACS chemical neuroscience 2024-12, Vol.15 (24), p.4418
• Main Authors: Misiu Naitė, Indrė, Mikalauskaitė, Kamilė, Paulauskaitė, Martyna, Sniečkutė, Ru Ta, Smirnovas, Vytautas, Brukštus, Algirdas, Žiaunys, Mantas, Žutautė, Ieva
• Format: Article
• Language: English
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.4c00451

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