In Silico and In Vitro Study towards the Rational Design of 4,4-Disarylbisthiazoles as a Selective -Synucleinopathy Biomarker

The alpha-synucleinopathies are a group of neurodegenerative diseases characterized by the deposition of alpha-synuclein aggregates (alpha-syn) in the brain. Currently, there is no suitable tracer to enable a definitive early diagnosis of these diseases. We reported candidates based on 4,4 '-disarylbisthiazole (DABTA) scaffold with a high affinity towards alpha-syn and excellent selectivity over A beta and tau fibrils. Based on prior in silico studies, a focused library of 23 halogen-containing and O-methylated DABTAs was prepared. The DABTAs were synthesized via a modified two-step Hantzsch thiazole synthesis, characterized, and used in competitive binding assays against [H-3]PiB and [H-3]DCVJ. The DABTAs were obtained with an overall chemical yield of 15-71%, and showed a calculated lipophilicity of 2.5-5.7. The ligands demonstrated an excellent affinity to alpha-syn with both [H-3]PiB and [H-3]DCVJ: K-i 0.1-4.9 nM and up to 20-3900-fold selectivity over A beta and tau fibrils. It could be concluded that in silico simulation is useful for the rational design of a new generation of DABTAs. Further investigation of the leads in the next step is encouraged: radiolabeling of the ligands with radioisotopes such as fluorine-18 or carbon-11 for in vivo, ex vivo, and translational research and for further in vitro experiments on human-derived protein aggregates.