Thioflavin-based molecular probes for application in Alzheimer's disease: from in silico to in vitro modelsElectronic supplementary information (ESI) available: Complete ref. 57; synthesis of HBXI and HBTI; Fig. S1-S5 corresponding to fluorescence spectra of the molecules in the presence and absence of synthetic Aβ1-40 fibrils; binding curves of ligand-Aβ1-40 fibrils complexes; ONIOM optimized geometries for HBTI and HBXI bound to Aβ1-40; cytotoxicity curves from MTT assays; TLC plates showing p

Alzheimer's disease (AD) is a neurological disease of confusing causation with no cure or prevention available. The definitive diagnosis is made postmortem , in part through the presence of amyloid-beta plaques in the brain tissue, which can be done with the small molecule thioflavin-T ( ThT ). Plaques are also found to contain elevated amounts of metal ions Cu( ii ) and Zn( ii ) that contribute to the neurotoxicity of amyloid-beta (Aβ). In this paper, we report in silico , in vitro , and ex vivo studies with ThT -derived metal binders 2-(2-hydroxyphenyl)benzoxazole ( HBX ), 2-(2-hydroxyphenyl)benzothiazole ( HBT ) and their respective iodinated counterparts, HBXI and HBTI . They exhibit low cytotoxicity in a neuronal cell line, potential blood-brain barrier penetration, and interaction with Aβ fibrils from senile plaques present in human and transgenic mice AD models. Molecular modelling studies have also been undertaken to understand the prospective ligand-Aβ complexes as well as to rationalize the experimental findings. Overall, our studies demonstrate that HBX , HBT , HBXI , and HBTI are excellent agents for future use in in vivo models of AD, as they show in vitro efficacy and biological compatibility. In addition to this, we present the glycosylated form of HBX ( GBX ), which has been prepared to take advantage of the benefits of the prodrug approach. Overall, the in vitro and ex vivo assays presented in this work validate the use of the proposed ThT -based drug candidate series as chemical tools for further in vivo development. The proposed ThT -based drug candidate series is validated as chemical tools for further in vivo development.