Synthesis of Some Benzothiazole Derivatives Based on 3-Hydroxypyridine-4-one and Benzaldehyde and Evaluation of Their ß-Amyloid Aggregation Inhibition Using both Experimental Methods and Molecular Dynamic Simulation

Abstract

Some novel inhibitors based on the (benzodthiazol-2-yl)-1phenylmethanimine derivatives were designed to reduce the aggregation process in Alzheimer's disease. These structures seem to mimic stilbene-like scaffold, while the benzothiazole moiety "locks" the thioflavin T binding site. Other inhibitors were designed based on 2-((benzodthiazol-2-ylimino)methyl)5-(benzyloxy)-1-methylpyridin-4(H)-one derivatives. Benzodthiazol-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 amines with benzaldehyde derivatives and 5-(benzyloxy)-1methyl-4-oxo-1,4-dihydropyridine-2-carbaldehyde gave the desired compounds. The plate reader-based fibrillation assay was done to evaluate the inhibition of A ss aggregation. Also, molecular dynamic simulation was carried out to clarify the interaction manner of the designed compounds with A ss formation. The biological evaluation proved 5a and 7e as the best inhibitor of the A ss aggregation. compound 5a in the concentration of 50 mu M inhibited A ss fibril formation better than 7e. MD simulation elucidated that the A ss aggregation inhibitors in different concentrations represented different binding conformations throughout the entire or in one area of A ss. MD showed the ligands in lower concentrations accumulate in an area of A ss aggregations and separate one fibril from the aggregated A ss. On the contrary, in higher concentrations, the ligands tend to be located through the entire A ss.