Novel Multifunctional Ascorbic Triazole Derivatives for Amyloidogenic Pathway Inhibition, Anti-Inflammation, and Neuroprotection

Abstract

Alzheimer’s disease (AD) is a common neurodegenerative disorder. The number of patients with AD is projected to reach 152 million by 2050. Donepezil, rivastigmine, galantamine, and memantine are the only four drugs currently approved by the United States Food and Drug Administration for AD treatment. However, these drugs can only alleviate AD symptoms. Thus, this research focuses on the discovery of novel lead compounds that possess multitarget regulation of AD etiopathology relating to amyloid cascade. The ascorbic acid structure has been designated as a core functional domain due to several characteristics, including antioxidant activities, amyloid aggregation inhibition, and the ability to be transported to the brain and neurons. Multifunctional ascorbic derivatives were synthesized by copper (I)-catalyzed azide–alkyne cycloaddition reaction (click chemistry). The in vitro and cell-based assays showed that compounds 2c and 5c exhibited prominent multifunctional activities as beta-secretase 1 inhibitors, amyloid aggregation inhibitors, and antioxidant, neuroprotectant, and anti-inflammatory agents. Significant changes in activities promoting neuroprotection and anti-inflammation were observed at a considerably low concentration at a nanomolar level. Moreover, an in silico study showed that compounds 2c and 5c were capable of being permeated across the blood–brain barrier by sodium-dependent vitamin C transporter-2.

Pathogenesis of Alzheimer’s Disease and Diversity of 1,2,3-Triazole Scaffold in Drug Development: Design Strategies, Structural Insights, and Therapeutic Potential

“…Among them, compound 37 was the most potent inhibitor with IC 50 value of 92.33 μM (Figure ). Structure–activity relationship indicated that substitution of tryptoline next to triazole ring was more preferable than phenol or 2-methoxy phenol . In order to optimize the above studies, Jiaranaikulwanitch et al replaced the tryptoline with tryptamine, and on the other side ascorbic acid was replaced with the metal chelator aromatic ring based on the structural features reported by the Reinke and Gestwicki .…”

“…Structure− activity relationship indicated that substitution of tryptoline next to triazole ring was more preferable than phenol or 2methoxy phenol. 155 In order to optimize the above studies, Jiaranaikulwanitch et al replaced the tryptoline with trypt- amine, and on the other side ascorbic acid was replaced with the metal chelator aromatic ring based on the structural features reported by the Reinke and Gestwicki. 156 The series of tryptamine triazole derivatives was synthesized and evaluated as amyloid-β aggregation inhibitors.…”

New insights into the neuroprotective and beta-secretase1 inhibitor profiles of tirandamycin B isolated from a newly found Streptomyces composti sp. nov.

“…Alzheimer’s disease (AD) is a common neurodegenerative disorder found in elderly people 1 . This disease is a common form of dementia, including loss of memory and cognitive function impairments 2 , 3 . The etiology of AD is unknown.…”

Modulation of the Gut Microbiota and Glycometabolism by a Probiotic to Alleviate Amyloid Accumulation and Cognitive Impairments in AD Rats

“…According to the data from International Dementia Association, there are more than 50 million people with dementia worldwide, and the total number of people with dementia is predicted to reach 152 million in 2050, with one patient almost every 3 s. [1,2] Alzheimer's disease (AD) is currently the DOI: 10.1002/mnfr.202200265 most widespread and afflicted dementia in the world. [3] The pathogenesis of AD is very complex and has not yet been fully resolved, there are multiple pathogenic hypotheses, such as the amyloid cascade, [4] abnormal phosphorylation of tau protein, [5] cholinergic, [6] neuroinflammation, [7] mitochondrial dysfunction, [8] etc.…”