Uzuegbunam, B.C.; Li, J.; Paslawski, W.; Weber, W.; Svenningsson, P.; Ågren, H.; Hooshyar Yousefi, B. In Silico and In Vitro Study towards the Rational Design of 4,4′-Disarylbisthiazoles as a Selective α-Synucleinopathy Biomarker. Int. J. Mol. Sci.2023, 24, 16445.
Uzuegbunam, B.C.; Li, J.; Paslawski, W.; Weber, W.; Svenningsson, P.; Ågren, H.; Hooshyar Yousefi, B. In Silico and In Vitro Study towards the Rational Design of 4,4′-Disarylbisthiazoles as a Selective α-Synucleinopathy Biomarker. Int. J. Mol. Sci. 2023, 24, 16445.
Uzuegbunam, B.C.; Li, J.; Paslawski, W.; Weber, W.; Svenningsson, P.; Ågren, H.; Hooshyar Yousefi, B. In Silico and In Vitro Study towards the Rational Design of 4,4′-Disarylbisthiazoles as a Selective α-Synucleinopathy Biomarker. Int. J. Mol. Sci.2023, 24, 16445.
Uzuegbunam, B.C.; Li, J.; Paslawski, W.; Weber, W.; Svenningsson, P.; Ågren, H.; Hooshyar Yousefi, B. In Silico and In Vitro Study towards the Rational Design of 4,4′-Disarylbisthiazoles as a Selective α-Synucleinopathy Biomarker. Int. J. Mol. Sci. 2023, 24, 16445.
Abstract
The α-synucleinopathies are a group of neurodegenerative diseases characterized by the deposition of α-synuclein aggregates (α-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 α-syn and excellent selectivity over Aβ and tau fibrils. Based on prior in silico studies a focused library of 23 halide-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 [3H]PiB, and [3H]DCVJ. The DABTAs gave an overall chemical yield of 15 – 71%, with a calculated lipophilicity of 2.5 – 5.7. The ligands demonstrated an excellent affinity to α-syn with both [3H]PiB and [3H]DCVJ: Ki 0.1 – 4.9 nM and up to 20 – 3900-fold selectivity over Aβ 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.
Medicine and Pharmacology, Neuroscience and Neurology
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