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Found 1 result for PubMed Citation for id: 1952429
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. 2023 Jan 21;14(3):470-481.
doi: 10.1039/d2md00341d. eCollection 2023 Mar 22.

Design, synthesis, and evaluation of benzofuran-based chromenochalcones for antihyperglycemic and antidyslipidemic activities

Venkateswarlu Korthikunta  1 , Rohit Singh  1   2   3 , Rohit Srivastava  4 , Jyotsana Pandey  4   2 , Atul Srivastava  4 , Upma Chaturvedi  4 , Akansha Mishra  4 , Arvind K Srivastava  4 , Akhilesh K Tamrakar  4   2 , Narender Tadigoppula  1   2
Affiliations

Design, synthesis, and evaluation of benzofuran-based chromenochalcones for antihyperglycemic and antidyslipidemic activities

Venkateswarlu Korthikunta et al. RSC Med Chem. .

Abstract

A series of benzofuran-based chromenochalcones (16-35) were synthesized and evaluated for in vitro and in vivo antidiabetic activities in L-6 skeletal muscle cells and streptozotocin (STZ)-induced diabetic rat models, respectively, and further in vivo dyslipidemia activity of the compounds was evaluated in a Triton-induced hyperlipidemic hamster model. Among them, compounds 16, 18, 21, 22, 24, 31, and 35 showed significant glucose uptake stimulatory effects in skeletal muscle cells and were further evaluated for in vivo efficacy. Compounds 21, 22, and 24 showed a significant reduction in blood glucose levels in STZ-induced diabetic rats. Compounds 16, 20, 21, 24, 28, 29, 34, 35, and 36 were found active in antidyslipidemic studies. Furthermore, compound 24 effectively improved the postprandial and fasting blood glucose levels, oral glucose tolerance, serum lipid profile, serum insulin level, and the HOMA-index of db/db mice, following 15 days of successive treatment.

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Conflict of interest statement

The authors have declared that there is no conflict of interest.

Figures

Fig. 1
Fig. 1. Structure of marketed antidiabetic drugs (I–V) and naturally occurring antidiabetic chalcones (VI and VII), chromene-containing moieties as diabetic agents (VII and IX), and benzofuran-containing compounds as antidiabetic agents (X and XII). XII: hybrid structure from VI, IX, and X (it was designed by molecular hybridization based on antidiabetic moieties).
Scheme 1
Scheme 1. Synthesis of C-4′-hydroxyl engaged benzofuran-based chromenochalcones. Reagents and conditions: (a) HMTA in TFA, 98 °C, 24 h. (b) K2CO3 in MeCN, reflux, 4 h. (c) 3-Methyl-but-2-enal/citral dimethyl acetal, pyridine, 150 °C, 10 h. (d) 2.5 equivalents of NaH, dry THF, 4–6 h, rt., N2. (e) Excess NaH, dry THF, 4–6 h, rt., N2.
Scheme 2
Scheme 2. Synthesis of C-2′-hydroxyl engaged benzofuran-based chromenochalcones. Reagents and conditions: (a) HMTA in TFA, 98 °C, 24 h. (b) K2CO3 in MeCN, reflux, 4 h. (c) 3-Methyl-but-2-enal/citral dimethyl acetal, pyridine, 150 °C, 10 h. (d) 2.5 equivalents of NaH, dry THF, 4–6 h, rt., N2. (e) Excess NaH, dry THF, 4–6 h, rt., N2.
Scheme 3
Scheme 3. Synthesis of C-2′,4′-hydroxyl engaged benzofuran-based chromenochalcones. Reagents and conditions: (a) HMTA in TFA, 98 °C, 24 h. (b) K2CO3 in MeCN, reflux, 4 h. (c) 3-Methyl-but-2-enal/citral dimethyl acetal, pyridine, 150 °C, 10 h. (d) 2.5 equivalents of NaH, dry THF, 4–6 h, rt., N2. (e) Excess NaH, dry THF, 4–6 h, rt., N2.
Fig. 2
Fig. 2. Concentration-dependent effect of benzofuran-based chromenochalcones on glucose uptake in L6 GLUT4myc myotubes. Cells were incubated overnight with indicated concentrations of test compounds, followed by measurement of glucose uptake. Results are expressed as fold stimulation over control basal. **p < 0.01, ***p < 0.001 relative to control.
Fig. 3
Fig. 3. Effect of benzofuran-based chromenochalcones (22 and 24) on insulin-stimulated glucose uptake in L6-GLUT4myc myotubes. Results are mean ± SEM, expressed as fold stimulation over control basal. *p < 0.05, ***p < 0.001 relative to control.
Fig. 4
Fig. 4. Effect of benzofuran-based chromenochalcones (22 and 24) on GLUT4myc translocation to the cell surface in L-6 GLUT4myc myotubes. Results are mean ± SEM, expressed as fold stimulation over control basal. *p < 0.05, **p < 0.01 relative to respective control condition.
Fig. 5
Fig. 5. Antidiabetic effect of compound 24 in db/db mice. Animals were treated with compound 24 (30 mg kg−1) for 15 consecutive days. Effect on blood glucose level (A) and glucose tolerance tests at day 10 (B) and day 15 (C) are shown. Data are expressed as mean ± SEM (n = 5); *p < 0.05, **p < 0.01 compared to control.
Fig. 6
Fig. 6. Antidiabetic effect of compound 24 in db/db mice. Animals were treated with compound 24 (30 mg kg−1) for 15 consecutive days. Effects on fasting blood glucose (A), serum insulin (B), and HOMA-index (C) are shown. Data are expressed as mean ± SEM (n = 5); **p < 0.01 compared to control.
Fig. 7
Fig. 7. Effect of compound 24 on the pAKT and GLUT4 levels in skeletal muscle of db/db mice. Skeletal muscle was dissected out and lysed and equal amounts of protein samples were immunoblotted with specific antibodies against pAKT (Ser-473) and GLUT4. β-Actin was used as the loading control. Shown are representative blots (A) and densitometric quantification of three independent experiments, expressed as the ratio of pAKT or GLUT4 to β-actin (B and C), presented as mean ± SEM. **p < 0.01, ***p < 0.001 relative to control.
Fig. 8
Fig. 8. Antidyslipidemic effect of compound 24 in db/db mice. Shown are the effects on serum triglycerides (A), total cholesterol (B), HDL-c (C), and body weight (D). Values are mean ± SEM, n = 5, *p < 0.05, **p < 0.01 compared to control.
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