Synthesis and evaluation of β-amyloid aggregation inhibition of some benzothiazole derivatives using both experimental methods and molecular dynamic simulation method
Synthesis and evaluation of β-amyloid aggregation inhibition of some benzothiazole derivatives using both experimental methods and molecular dynamic simulation method
mohammad hossein asgarshamsi,1,*samira mahmoudi,2
2. Department of Microbial Biotechnology, School of Biological Sciences, Islamic Azad University Tehran North Branch, Tehran, Iran.
Introduction: some novel inhibitors based on the (benzo[d]thiazol-2-yl)-1-phenylmethanimine derivatives were designed to reduce the aggregation process in Alzheimer’s disease (AD). These structures seem to mimic stilbene-like scaffold while the benzothiazole moiety “locks” the thioflavin T (ThT) binding site. Other inhibitors were designed based on 2-((benzo[d]thiazol-2-ylimino)methyl)-5-(benzyloxy)-1-methylpyridin-4(H)-one derivatives.
Methods: Benzo[d]thiazol-2-amine derivatives were prepared by the reaction of aniline derivatives with ammonium thiocyanate in the presence of bromine/acetic acid. Then, the reaction of synthesized amines with benzaldehyde derivatives and 5-(benzyloxy)-1-methyl-4-oxo-1,4-dihydropyridine-2-carbaldehyde gave the desired compounds. The plate reader-based fibrillation assay was carried out to evaluate the inhibition of Aβ aggregation. To clarify the interaction manner of the designed compounds with Aβ formation, molecular dynamic simulation (MD) was carried out.
Results: The biological evaluation proved 4a, 5a, 5b and 5c and 7e as the best pro-aggregator and inhibitor of the Aβ aggregation. MD elucidated that the Aβ aggregation inhibitors in different concentrations represented different binding conformations throughout the entire or in one region of Aβ.MD simulation showed the ligands in lower concentrations accumulate in a region of Aβ aggregations and separate one fibril from the aggregated Aβ. On the contrary, in higher concentrations the ligands tend to be located through the entire Aβ.
Conclusion: The results were valuable for designing of novel pro-aggregator or inhibitors of Aβ aggregation. Future Studies on the compound 5a can be useful for design of novel multi-target directed ligands (MTDL) for treatment of Aβ based diseases.