Discovery of Hydroxybenzothiazole Urea Compounds as Multitargeted Agents Suppressing Major Cytotoxic Mechanisms in Neurodegenerative Diseases

Abstract

Multiple factors are causally responsible and/or contribute to the progression of Alzheimer's and Parkinson's diseases. The protein kinase Dyrk1A was identified as a promising target as it phosphorylates tau protein, α-synuclein, and parkin. The first goal of our study was to optimize our previously identified Dyrk1A inhibitors of the 6-hydroxy benzothiazole urea chemotype in terms of potency and selectivity. Our efforts led to the development of the 3-fluorobenzyl amide derivative 16b, which displayed the highest potency against Dyrk1A (IC 50 = 9.4 nM). In general, the diversification of the benzylamide moiety led to an enhanced selectivity over the most homologous isoform, Dyrk1B, which was a meaningful indicator, as the high selectivity could be confirmed in an extended selectivity profiling of 3b and 16b. Eventually, we identified the novel phenethyl amide derivative 24b as a triple inhibitor of Dyrk1A kinase activity (IC 50 = 119 nM) and the aggregation of tau and α-syn oligomers. We provide evidence that the novel combination of selective Dyrk1A inhibition and suppression of tau and α-syn aggregations of our new lead compound confers efficacy in several established cellular models of neurotoxic mechanisms relevant to neurodegenerative diseases, including α-synand 6-hydroxydopamine-induced cytotoxicities.

Oligomeropathies, inflammation and prion protein binding

“…Thus a single molecule might combine multiple pharmacological targets and doxycycline repositioning has the advantage of being immediately available for clinical investigations ( D’Souza et al, 2020 ). This multi-target activity is shared by several other molecules and treatments ( Dias Viegas et al, 2018 ; Aboushady et al, 2021 ; Santamaria et al, 2021 ; Fantacuzzi et al, 2022 ), that need to be tested at the clinical level with appropriate trial design.…”