Synthesis of Altenusin Analogues as Tau Aggregation Inhibitors

Abstract

A large amount of research currently focuses on direct inhibition of tau aggregation with small molecules as one approach to slow the disease progression of Alzheimer’s disease, the most common form of dementia. Accordingly, the Kassiou group has performed a methodical structure activity relationship (SAR) study to determine which structural features of Altenusin, a polyphenolic natural product, contribute to its in vitro anti-tau aggregation activity. The lead compound from the library of ‘hybrid’ molecules displayed similar activity to Altenusin. However, the presence of certain functional groups might contribute to low brain penetration and could present potential metabolic liabilities.

In this thesis, many different bioisoteric replacements of catechol groups, ester groups and the indole core were explored. Novel compounds have been assessed using fluorescence-based assays, which are commonly used as an indicator of anti-tau aggregation activity. Several analogues demonstrated similar or improved activity in comparison with Altenusin. These derivatives not only contribute to a new fragment library for this study, but also generate dozens of ‘hybrid’ molecules, which may lead to the discovery of next generation aggregation inhibitors. In parallel to the SAR study, pharmaceutical properties of those synthesized compounds were also predicted by two different systems, and both indicated superior blood-brain barrier permeability versus lead compound Altenusin.

In summary, a comprehensive SAR study of the lead compound has been conducted and has resulted in the identification of a wide range of Altenusin analogues as potential tau aggregation inhibitors, which show similar pharmacological activity with better predicted drug-like properties. These results offer valuable insights into future work in the field of small molecule tau aggregation inhibitors.