Synthesis and structure-activity relationship of 2,6-disubstituted pyridine derivatives as inhibitors of beta-amyloid-42 aggregation

It is assumed that amyloid-beta aggregation is a crucial event in the pathogenesis of Alzheimer's disease. Novel 2,6-disubstituted pyridine derivatives were designed to interact with the beta-sheet conformation of A beta via donor-acceptor-donor hydrogen bond formation. A series of pyridine derivatives were synthesized and tested regarding their potential to inhibit the aggregation of A beta. The 2,6-diaminopyridine moiety was identified as a key component to inhibit A beta aggregation. Overall, compounds having three 2,6-disubstituted pyridine units separated by at least one C2 -or C3-linker displayed the most potent inhibition of A beta aggregation. (C) 2016 Elsevier Ltd. All rights reserved.