Synthesis and Biological Evaluation of 3-Styrylchromone Derivatives as Free Radical Scavengers and α-Glucosidase Inhibitors

Abstract

A series of 3-styrylchromone derivatives (4-20) were synthesized and the structure-activity relationships for α-glucosidase inhibition and antioxidant activities were analyzed. Among the synthesized compounds, compounds 15 and 20, which contain a catechol moiety, showed both potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity (15: EC 50 17 µM; 20: EC 50 23 µM) and α-glucosidase inhibitory activity (15: IC 50 16 µM; 20: IC 50 10 µM). Our data suggest that 3-styrylchromone derivatives are novel α-glucosidase inhibitors that have the potential to counteract diet-induced hyperglycemia in diabetes.Key words 3-styrylchromone; α-glucosidase inhibitor; antioxidant; structure-activity relationship Diabetes mellitus is a metabolic disorder characterized by hyperglycemia resulting from insufficiency of secretion or action of endogenous insulin. α-Glucosidase has been recognized as a therapeutic target for modulation of postprandial hyperglycemia. α-Glycosidase inhibitors act to delay glucose absorption, making them potent drugs to control blood glucose levels.1) On the other hand, antioxidants function as free radical scavengers, chelating agents for pro-oxidant metals, quenchers of singlet oxygen formation, and reducing agents. 2,3)Because of their antioxidant characteristics, antioxidants are important in the prevention of human diseases. The accumulated evidence suggests that diabetic patients are under oxidative stress and that oxidative stress plays a major role in the pathogenesis of diabetes mellitus. 4) Recently, several researchers have evaluated α-glucosidase inhibitors possessing free-radical scavenging activity. 5-11)4H-1-Benzopyran-4-ones (chromones) are an important class of oxygenated heterocyclic compounds, and have attracted the attention of organic chemists and biochemists due to their biological activities and occurrence in natural products. This chromone core structure is found in flavones, isoflavones, and 2-styrylchromones. Flavones and isoflavones are distributed in several species of plants. In contrast, 2-styrylchromones constitute a small group of naturally occurring chromones. Synthetic 2-styrylchromones possess a number of biological activities, including antioxidant, 12,13) anti-allergic, 14) anti-inflammatory, 15) antitumor, [16][17][18] and antiviral [19][20][21] effects. The synthesis and evaluation of biological activities of 2-styrylchromones has been extensively investigated, while studies dealing with 3-styrylchromones are few. Moreover, although there are some examples of the synthesis of 3-styrylchromones, [22][23][24][25][26][27] only a few studies have evaluated the biological activity of 3-styrylchromones. 22,28) In order to further explore novel biological activities, a series of 3-styrylchromone derivatives were synthesized, containing newly prepared compounds, and structure-activity relationships in regards to antioxidant activity and α-glycosidase inhibition were investigated. Results and DiscussionChemistry 3-Styrylchromone derivatives presented in this...

Ionic Liquids and Ohmic Heating in Combination for Pd-Catalyzed Cross-Coupling Reactions: Sustainable Synthesis of Flavonoids

“…The combined extracts were dried over Na 2 SO 4 and evaporated under reduced pressure affording products 3. The physical data of known isoflavones 3a-f were comparable to those of the literature [34][35][36][37][38]. The physical data of the new isoflavones 3g-j are shown below.…”

Further Quantitative Structure–Cytotoxicity Relationship Analysis of 3-Styrylchromones

“…The TS of fourteen 3-styrylchromones [1][2][3][4][5][6][7][8][9][10][11][12][13][14] was correlated positively with MATS4e (topological shape and electric state) (r 2 =0.414, p=0.0131), H8s (3D shape) (r 2 =0.404, p=0.0145), MNDO_LUMO (energy of the LUMO) (r 2 =0.391, p=0.0168), and H8e (3D shape and electric state) (r 2 =0.343, p=0.0276), while negatively with AROM (aromaticity index) (r 2 =0.349, p=0.0259), FASA_H (3D shape, size and partial charges) (r 2 =0.346, p=0.0269) ( Figure 6).…”

“…Tumor-specificity of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] was reduced by the presence of methoxy group at R1 (6-position of chromone ring), but increased by the presence of methoxy group at R2 (7position of chromone ring) (Figure 7).…”

“…Top six chemical descriptors that showed higher correlation with cytotoxicity of fourteen 3-styrylchromones [1][2][3][4][5][6][7][8][9][10][11][12][13][14] Figure 6. Top six chemical descriptors that showed higher correlation with tumor-specificity of fourteen 3-styrylchromones [1][2][3][4][5][6][7][8][9][10][11][12][13][14] most potent compound [7] (TS=301.1) has methoxy group at 7-position and non-substituted styryl moiety, and replacing the methoxy group to 6-position yielded [5] with much reduced tumor-specificity (TS=0.8). This suggests that the introduction of methoxy group at 7-position is involved in the elevation of tumor-specificity.…”

“…were synthesized by Knoevenagel condensation of the appropriate 3-formylchromone with selected phenylacetic acid derivatives, according to previous methods (6). The compounds' structure is shown in Figure 1.…”