From BACE1 inhibitor to multifunctionality of tryptoline and tryptamine triazole derivatives for Alzheimer's disease.
Efforts to discover new drugs for Alzheimer's disease emphasizing multiple targets was conducted seeking to inhibit amyloid oligomer formation and to prevent radical formation. The tryptoline and tryptamine cores of BACE1 inhibitors previously identified by virtual screening were modified in silico for additional modes of action. These core structures were readily linked to different side chains using 1,2,3-triazole rings as bridges by copper catalyzed azide-alkyne cycloaddition reactions. Three compounds among the sixteen designed compounds exerted multifunctional activities including β-secretase inhibitory action, anti-amyloid aggregation, metal chelating and antioxidant effects at micromolar levels. The neuroprotective effects of the multifunctional compounds 6h, 12c and 12h on Aβ₁₋₄₂ induced neuronal cell death at 1 μM were significantly greater than those of the potent single target compound, BACE1 inhibitor IV and were comparable to curcumin. The observed synergistic effect resulting from the reduction of the Aβ₁₋₄₂ neurotoxicity cascade substantiates the validity of our multifunctional strategy in drug discovery for Alzheimer's disease.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudhya Road, Bangkok 10400, Thailand.
Jutamas
J
Jiaranaikulwanitch
Piyarat
P
Govitrapong
Valery V
VV
Fokin
Opa
O
Vajragupta
D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D001681:Biological Assay; D002243:Carbolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000494:pharmacology*; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D014363:Tryptamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
D016229:Amyloid beta-Peptides; D002243:Carbolines; D002614:Chelating Agents; D011480:Protease Inhibitors; D020011:Protective Agents; D014230:Triazoles; D014363:Tryptamines; C030820:tryptamine; C009804:tryptoline; D016282:Aspartic Acid Endopeptidases