Synthesis, Characterization, and Activity of a Triazine Bridged Antioxidant Small Molecule

Abstract

Metal-ion misregulation and oxidative stress continue to be components of the continually evolving hypothesis describing the molecular origins of Alzheimer's disease. Therefore, these features are viable targets for synthetic chemists to explore through hybridizations of metal-binding ligands and antioxidant units. To date, the metal-binding unit in potential therapeutic small molecules has largely been inspired by clioquinol with the exception of a handful of heterocyclic small molecules and open-chain systems. Heterocyclic small molecules such as cyclen (1,4,7,10-tetraazacyclododecane) have the advantage of straightforward N-based modifications, allowing the addition of functional groups. In this work, we report the synthesis of a triazine bridged system containing two cyclen metal-binding units and an antioxidant coumarin appendage inspired by nature. This new potential therapeutic molecule shows the ability to bind copper in a unique manner compared to other chelates proposed to treat Alzheimer's disease. DPPH and TEAC assays exploring the activity of N-(2-((4,6-di(1,4,7,10-tetraazacyclododecan-1-yl)-1,3,5-triazin-2-yl)amino)ethyl)-2-oxo-2H-chromene-3-carboxamide (molecule 1) show that the molecule is antioxidant. Cellular studies of molecule 1 indicate a low toxicity (EC = 80 μM) and the ability to protect HT-22 neuronal cells from cell death induced by Aβ + copper(II), thus demonstrating the potential for molecule 1 to serve as a multimodal therapeutic for Alzheimer's disease.

Antioxidative Activity of 1,3,5-Triazine Analogues Incorporating Aminobenzene Sulfonamide, Aminoalcohol/Phenol, Piperazine, Chalcone, or Stilbene Motifs

“…Oxidative stress or damage is the imbalance between the capacity of antioxidative protection systems of the organism and the occurrence of reactive oxygen species and/or reactive nitrogen species [1,2]. Oxygen reactive species, relevant as free radicals, can be produced by metabolic pathways, UV irradiation, environmental pollutants, and others [1][2][3][4][5][6].…”

New 1,3,5-Triazine Derivatives Incorporating Aminobenzenesulfonamide, Aminoalcohol, Piperazine, Chalcone or Stilbene Structural Motifs and Evaluation of Their Antioxidative Activity

“…Oxidative stress or damage is the imbalance between the capacity of antioxidative protection systems of the organism and the occurrence of reactive oxygen species and/or reactive nitrogen species [1,2]. Oxygen reactive species, such as free radicals, can be produced by metabolic pathways, UV irradiation, environmental pollutants, and others [1][2][3][4][5][6].…”

“…Damage of cells caused by oxidative stress is correlated to pathophysiology and pathogenesis of a wide range of diseases, i.e., Alzheimer's, Huntington's, and Parkinson's diseases, inflammatory diseases, cardiovascular diseases, diabetes, and cancer [1,3,4,[7][8][9].…”

“…Recently, triazine derivatives with desirable antioxidant activity were described. Gonzalez et al proved the antioxidant activity of their 1,3,5-triazine bridged small molecules ( Figure 1a) [3]. 5,6-Diphenyl-3-oxo-1,2,4-triazine linked piperazine derivatives ( Figure 1b) [10] or arylidene hydrazine derivatives of substituted 1,2,4-triazine scaffolds also exhibit attractive radical scavenging effects ( Figure 1c) [11].…”

“…Examples of diversity of antioxidants with high activity: (a) 1,3,5-triazine bridged small molecules [3]; (b) biphenyl-3-oxo-1,2,4-triazine linked piperazine derivatives [10]; (c) arylidene hydrazine derivatives of substituted 1,2,4-triazine [11]; (d) substituted aminobenzenesulfonamides [12]; (e) chalcone derivatives [13]; (f) stilbene derivatives (resveratrol) [4].…”