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From BACE1 Inhibitor to Multifunctionality of Tryptoline and Tryptamine Triazole Derivatives for Alzheimer’s Disease

1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudhya Road, Bangkok 10400, Thailand
2
Center for Neuroscience, Faculty of Science, Mahidol University, 272 Rama VI Road, Rajathevi, Bangkok 10400, Thailand
3
Department of Chemistry, The Scripps Research Institute, 10500 North Torrey Pines Road, La Jolla, CA 92037, USA
*
Author to whom correspondence should be addressed.
Molecules 2012, 17(7), 8312-8333; https://doi.org/10.3390/molecules17078312
Received: 7 May 2012 / Revised: 25 June 2012 / Accepted: 5 July 2012 / Published: 10 July 2012
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. View Full-Text
Keywords: multifunction drugs; BACE1 inhibitor; anti-amyloid aggregation; chelator; antioxidant; neuroprotection multifunction drugs; BACE1 inhibitor; anti-amyloid aggregation; chelator; antioxidant; neuroprotection
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Jiaranaikulwanitch, J.; Govitrapong, P.; Fokin, V.V.; Vajragupta, O. From BACE1 Inhibitor to Multifunctionality of Tryptoline and Tryptamine Triazole Derivatives for Alzheimer’s Disease. Molecules 2012, 17, 8312-8333.

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