Abstract
Misfolding and fibrillar aggregation of A beta is a characteristic hallmark of Alzheimer's disease and primarily participates in neurodegenerative pathologies. There has been no breakthrough made in the therapeutic regime of Alzheimer's disease while the pharmacological interventions against A beta are designed to sequester and clear A beta burden from the neurological tissues. Based on the physiological relevance of A beta, therapeutic approaches are required to inhibit and stabilize A beta fibrillization, instead of cleaning it from the neurological system. In this context, we have designed a selenadiazole-based library of compounds against the fibrillization paradigm of A beta. Compounds that completely inhibited the A beta fibrillization appeared to stabilize A beta at the monomeric stage as indicated by ThT assay, CD spectrophotometry, and TEM imaging. Partial inhibitors elongated the nucleation phase and allowed limited fibrillization of Afi into smaller fragments with slightly higher beta-sheets contents, while noninhibitors did not interfere in A beta aggregation and resulted in mature fibrils with fibrillization kinetics similar to A beta control. Molecular docking revealed the different binding positions of the compounds for three classes. Complete inhibitors alleviated A beta toxicity to SH-SY5Y neuroblastoma cells and permeated across the blood-brain barrier in zebrafish larvae. The amino acid residues from A beta peptide that interacted with the compounds from all three classes were overlapping and majorly lying in the amyloidogenic regions. However, compounds that stabilize A beta monomers displayed higher association constants (K-a) and lower dissociation constants (K-d) in comparison to partial and noninhibitors, as corroborated by ITC. These results support further structure activity-based preclinical development of these selenadiazole compounds for potential anti-Alzheimer's therapy.