title: Neuritogenic activity of bi-functional bis-tryptoline triazole.
abstract: Alzheimer's disease (AD) is a common neurodegenerative disorder, one of the hallmarks of which is the deposition of aggregated β-amyloid peptides (Aβ40,42) as plaques in the brain. Oligomers of these peptides have been reported to be toxic and to inhibit neurite outgrowth, as evidenced by neurite dystrophy and significant loss of synaptic connectivity of neurons in the AD brain resulting in cognitive decline. These peptides also react with biological metal in the brain to generate free radicals, thereby aggravating neuronal cell injury and death. Herein, multifunctional triazole-based compounds acting on multiple targets, namely β-secretase (BACE1), β-amyloid peptides (Aβ) as well as those possessing metal chelation and antioxidant properties, were developed and evaluated for neuritogenic activity in P19-derived neurons. At the non-cytotoxic concentration (1nM), all multifunctional compounds significantly enhanced neurite outgrowth. New bis-tryptoline triazole (BTT) increased the neurite length and neurite number, by 93.25% and 136.09% over the control, respectively. This finding demonstrates the ability of multifunctional compounds targeting Aβ to enhance neurite outgrowth in addition to their neuroprotective action.
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellent for Innovation in Drug Design and Discovery and Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudhya Road, Bangkok 10400, Thailand. Electronic address: jutamas.jia@cmu.ac.th.
authors.forename: Jutamas
authors.initials: J
authors.lastname: Jiaranaikulwanitch
authors.affiliation: Department of Pharmacognosy, Faculty of Pharmacy, Srinakharinwirot University, 63 Moo 7 Rangsit-Nakhonnayok Road, Ongkharak, Nakhonnayok 26120, Thailand.
authors.forename: Sarin
authors.initials: S
authors.lastname: Tadtong
authors.affiliation: Center for Neuroscience, Faculty of Science, Mahidol University, 272 Rama VI Road, Rajathevi, Bangkok 10400, Thailand.
authors.forename: Piyarat
authors.initials: P
authors.lastname: Govitrapong
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10500 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Valery V
authors.initials: VV
authors.lastname: Fokin
authors.affiliation: Center of Excellent for Innovation in Drug Design and Discovery and Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudhya Road, Bangkok 10400, Thailand.
authors.forename: Opa
authors.initials: O
authors.lastname: Vajragupta
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002243:Carbolines / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002243:Carbolines; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D014230:Triazoles; C009804:tryptoline; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Bis-tryptoline triazole; Multifunctional activity; Neuritogenic activity; β-amyloid aggregation; β-secretase inhibitor