Tacrine-sugar mimetic conjugates as enhanced cholinesterase inhibitors
Quelli Larissa Oliveira de Santana1, Tereza C Santos Evangelista1, Petra Imhof2
1Department of Chemistry, Bioscience and Environmental Engineering, Faculty of Science and Technology, University of Stavanger, NO-4036 Stavanger, Norway. emil.lindback@uis.no and Department of Organic Chemistry, Chemistry Institute, Federal University of Rio de Janeiro, UFRJ, 21949-900 Rio de Janeiro, RJ, Brazil.
Abstract:
We have used the Cu(i)-catalyzed azide-alkyne Huisgen cycloaddition reaction to obtain two families of bivalent heterodimers where tacrine is connected to an azasugar or iminosugar, respectively, via linkers of variable length. The heterodimers were investigated as cholinesterase inhibitors and it was found that their activity increased with the length of the linker. Two of the heterodimers were significantly stronger acetylcholinesterase inhibitors than the monomeric tacrine. Molecular modelling indicated that the longer heterodimers fitted better into the active gorge of acetylcholinesterase than the shorter counterparts and the former provided more efficient simultaneous interaction with the tryptophan residues in the catalytic anionic binding site (CAS) and the peripheral anionic binding site (PAS).
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