Flavonoids as Antidiabetic and Anti-Inflammatory Agents: A Review on Structural Activity Relationship-Based Studies and Meta-Analysis
<p>Flavonoids’ main classes.</p> "> Figure 2
<p>Structure of quercetin (<b>1</b>) and the labelled functional groups that are important in COX-2 inhibition [<a href="#B25-ijms-23-12605" class="html-bibr">25</a>].</p> "> Figure 3
<p>The chemical structures of studied flavonoids in inhibiting the formation of LTB4 [<a href="#B27-ijms-23-12605" class="html-bibr">27</a>].</p> "> Figure 4
<p>Quercetin and its metabolites inhibited inflammatory eicosanoid production from human leukocytes [<a href="#B29-ijms-23-12605" class="html-bibr">29</a>].</p> "> Figure 5
<p>Flavonoids studied for their anti-inflammatory effect [<a href="#B30-ijms-23-12605" class="html-bibr">30</a>].</p> "> Figure 6
<p>Chemical structures of flavonoids isolated from <span class="html-italic">M. paniculata</span> [<a href="#B32-ijms-23-12605" class="html-bibr">32</a>].</p> "> Figure 7
<p>Chemical structures of flavonoids isolated from <span class="html-italic">V. grandifolia</span> [<a href="#B33-ijms-23-12605" class="html-bibr">33</a>].</p> "> Figure 8
<p>Synthesis pathway of new flavone derivatives and their chemical structures [<a href="#B38-ijms-23-12605" class="html-bibr">38</a>].</p> "> Figure 9
<p>Chemical structure of isolated flavonoids from <span class="html-italic">A. heterophyllus</span> [<a href="#B39-ijms-23-12605" class="html-bibr">39</a>].</p> "> Figure 10
<p>Chemical structures of new flavanonol derivatives [<a href="#B42-ijms-23-12605" class="html-bibr">42</a>].</p> "> Figure 11
<p>Chemical structures of flavonoids isolated from the root bark of <span class="html-italic">Morus alba</span> L. [<a href="#B43-ijms-23-12605" class="html-bibr">43</a>].</p> "> Figure 12
<p>The structure of <b>44</b> and the functional groups responsible for the inhibition of glycogen phosphorylase [<a href="#B46-ijms-23-12605" class="html-bibr">46</a>].</p> "> Figure 13
<p>Chemical structure of <b>46</b> [<a href="#B50-ijms-23-12605" class="html-bibr">50</a>].</p> "> Figure 14
<p>The flavonoids isolated as α-glucosidase inhibitors from <span class="html-italic">P. anserine</span> [<a href="#B51-ijms-23-12605" class="html-bibr">51</a>].</p> "> Figure 15
<p>The structures of flavonoids isolated from <span class="html-italic">T. gallica</span> [<a href="#B52-ijms-23-12605" class="html-bibr">52</a>].</p> "> Figure 16
<p>The structures of flavonoids isolated from <span class="html-italic">S. dendroideum</span> [<a href="#B53-ijms-23-12605" class="html-bibr">53</a>].</p> "> Figure 17
<p>The SAR of flavonoids for α-glucosidase inhibition activity [<a href="#B54-ijms-23-12605" class="html-bibr">54</a>].</p> "> Figure 18
<p>The SAR of flavonoids for α-amylase inhibition activity [<a href="#B55-ijms-23-12605" class="html-bibr">55</a>].</p> "> Figure 19
<p>The SAR of flavonoids for α-glucosidase inhibition activity [<a href="#B56-ijms-23-12605" class="html-bibr">56</a>].</p> "> Figure 20
<p>The structures of flavonoids isolated from <span class="html-italic">B. rotunda</span> [<a href="#B57-ijms-23-12605" class="html-bibr">57</a>].</p> "> Figure 21
<p>The SAR of flavonoids for α-glucosidase inhibition activity [<a href="#B58-ijms-23-12605" class="html-bibr">58</a>].</p> "> Figure 22
<p>SARs of chalcones for PTP1B inhibition activity [<a href="#B59-ijms-23-12605" class="html-bibr">59</a>].</p> "> Figure 23
<p>SARs of chalcones for α-glucosidase inhibition activity [<a href="#B59-ijms-23-12605" class="html-bibr">59</a>].</p> "> Figure 24
<p>SARs of chalcones for ALR inhibition activity [<a href="#B59-ijms-23-12605" class="html-bibr">59</a>].</p> "> Figure 25
<p>SARs of chalcones for PPAR-gamma activation activity [<a href="#B59-ijms-23-12605" class="html-bibr">59</a>].</p> "> Figure 26
<p>The chemical structures of studied flavonoids for PPAR-γ activation [<a href="#B62-ijms-23-12605" class="html-bibr">62</a>].</p> "> Figure 27
<p>The chemical structures of synthesized flavone derivatives that were investigated for α-glucosidase inhibition [<a href="#B63-ijms-23-12605" class="html-bibr">63</a>].</p> "> Figure 28
<p>(<b>a</b>) Forest plot from meta-analysis of antidiabetic (inhibition of α-glucosidase) activity. (<b>b</b>) Forest plot from meta-analysis of anti-inflammatory (inhibition of NO production) activity.</p> "> Figure 28 Cont.
<p>(<b>a</b>) Forest plot from meta-analysis of antidiabetic (inhibition of α-glucosidase) activity. (<b>b</b>) Forest plot from meta-analysis of anti-inflammatory (inhibition of NO production) activity.</p> "> Figure 29
<p>The SAR of flavonoids as anti-inflammatory agent.</p> "> Figure 30
<p>The SAR of flavonoids as an antidiabetic agent.</p> "> Figure 31
<p>The SAR of flavonoids as dual action via anti-inflammatory and antidiabetic effects. Flavonoids have been reported to reduce diabetes complications, improve insulin secretion and pancreatic β cell mass, reduce β cell apoptosis, hepatic glucose output, insulin resistance, and circulating fatty acids, and downregulate ROS and inflammation markers such as IL-β and IL-6, Tnf-α, COX-2, and i-NOS.</p> ">
Abstract
:1. Introduction
2. Anti-Inflammatory Activity of Flavonoids
3. Antidiabetic Activity of Flavonoids
4. Analysis of the SAR of Flavonoids as Anti-Inflammatory and Antidiabetic Agents
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Anti-Inflammatory Activities | ||||||||
---|---|---|---|---|---|---|---|---|
References | Flavonoids | Assay | Negative Control | Activity of Flavonoids | Std Dev | Positive Control | Std Dev | |
[25] | Quercetin (1) | Suppressive action on the transcriptional activity of the COX-2 gene in human colon cancer DLD-1 cells Reporter gene assay | N/A | IC50 10.5 μM | 0.7 | N/A | N/A | |
Rhamnetin (2) | IC50 18.6 μM | 2.1 | ||||||
Genistein (3) | IC50 20.7 μM | 1.4 | ||||||
Eriodyctiol (4) | IC50 22.0 μM | 0.2 | ||||||
Luteolin (5) | IC50 22.0 μM | 0.4 | ||||||
Kaempferol (6) | IC50 39.3 μM | 2.1 | ||||||
Fisetin (7) | IC50 47.9 μM | 2.9 | ||||||
Phloretin (8) | IC50 52.5 μM | 3.4 | ||||||
Catechin (9) | IC50 415.3 μM | 25.4 | ||||||
Epicatechin (10) | IC50 415.3 μM | 17.0 | ||||||
Epigallocatechin (11) | IC50 >500 μM | - | ||||||
Myricetin (12) | IC50 >500 μM | - | ||||||
[27] | 5 | Inhibition of the generation of leukotriene B4 (LTB4) by human neutrophils | N/A | IC50 1.6 μM | 0.3 | Nordihydroguaiaretic acid (NDGA), IC50 56.6 μM | 2.5 | |
3′,4′-dihydroxy flavone (14d) | IC50 1.7 μM | 0.1 | ||||||
3′,4′,7-trihydroxy flavone (16d) | IC50 2.0 μM | 0.7 | ||||||
3′,4′,5-trihydroxy flavone (15d) | IC50 2.9 μM | 0.8 | ||||||
1 | IC50 4.0 μM | 1.2 | ||||||
[28] | 1 | Inhibition on rabbit reticulocyte 15-LOX-1 | N/A | IC50 4.0 μM | N/A | N/A | N/A | |
5 | IC50 0.6 μM | N/A | ||||||
Naringenin (18) | IC50 250 μM | N/A | ||||||
Hesperidin (19) | IC50 90 μM | N/A | ||||||
10 | IC50 60 μM | N/A | ||||||
Taxifolin (13) | IC50 25 μM | N/A | ||||||
1 | Inhibition on soybean LOX L-1 | N/A | IC50 4.5 μM | N/A | N/A | N/A | ||
5 | IC50 3.0 μM | N/A | ||||||
13 | IC50 1000 μM | N/A | ||||||
[29] | 1 | Inhibitory effect on LTB4 production | N/A | IC50 2.0 μM | N/A | N/A | N/A | |
3′-O-methylquercetin (20) | IC50 2.0 μM | N/A | ||||||
Quercetin-3′-O-sulfate (21) | IC50 2.0 μM | N/A | ||||||
[32] | 28 | Anti-inflammatory effect on murine macrophage cell line and gastric epithelial cell (GES-1) | N/A | IC50 53.40 μM | N/A | N/A | N/A | |
29 | IC50 120.98 μM | |||||||
30 | IC50 10.73 μM | |||||||
[33] | Isoorientin (26) | Nuclear factor kappa B (NF-κB) inhibition | N/A | IC50 8.9 μg/mL | N/A | Parthenolide, IC50 0.9 μg/mL | N/A | |
Orientin (31) | IC50 12.0 μg/mL | N/A | ||||||
Isovitexin (32) | IC50 18.0 μg/mL | N/A | ||||||
26 | Inducible nitric oxide synthase (iNOS) inhibition | IC50 48.0 μg/mL | N/A | Parthenolide, IC50 0.18 μg/mL | N/A | |||
31 | IC50 54.0 μg/mL | N/A | ||||||
32 | IC50 21.0 μg/mL | N/A | ||||||
[37] | Apigenin (17c) | Inhibition of NO production | 7-Nitroindazole, IC50 > 100 μM | IC50 23 μM | N/A | 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine Hydrochloride (AMT), IC50 0.09 μM | N/A | |
5 | IC50 27 μM | N/A | ||||||
18 | IC50 >100 μM | N/A | ||||||
Apiin (34) | IC50 >100 μM | N/A | ||||||
Galangin (35) | IC50 >100 μM | N/A | ||||||
1 | IC50 107 μM | N/A | ||||||
[39] | 37 | Inhibition of NO production | N/A | IC50 19.87 μM | 0.21 | Hydrocortisone, IC50 3.83 μM | 0.12 | |
38 | IC50 15.69 μM | 0.16 | ||||||
39 | IC50 9.19 μM | 0.07 | ||||||
40 | IC50 10.32 μM | 0.08 | ||||||
41 | IC50 18.43 μM | 0.19 | ||||||
Antidiabetic activities | ||||||||
References | Flavonoids | Assay | Negativecontrol | Activity of flavonoids | Std Dev | Positive control | Std Dev | |
[46] | Quercetagetin (3,3′,4′,5,6,7-Hexahydroxyflavone [44]) | Glycogen phosphorylase inhibition | N/A | IC50 9.7 μM | N/A | N/A | N/A | |
[47] | Chrysin (17a) | Rat lens aldose reductase (RLAR) inhibition | N/A | IC50 8.5 μM | N/A | N/A | N/A | |
Diosmetin 7-O-β-D-glucopyranoside (45) | IC50 23.0 μM | N/A | ||||||
Diosmetin (17f) | IC50 8.5 μM | N/A | ||||||
17c | IC50 2.2 μM | N/A | ||||||
6 | IC50 10.0 μM | N/A | ||||||
[50] | Sophoflavescenol (46) | Rat lens aldose reductase (RLAR) inhibition | N/A | IC50 0.30 μM | 0.06 | Epalrestat, IC50 0.07 μM | 0.00 | |
Human recombinant aldose reductase (HRAR) inhibition | N/A | IC50 0.17 μM | 0.03 | Epalrestat, IC50 0.15 μM | 0.01 | |||
Advanced glycation end products (AGE) inhibitory activity | N/A | IC50 17.89 μM | 1.44 | Aminoguanidine, IC50 81.05 μM | 0.35 | |||
[51] | 47 | α-glucosidase inhibition | N/A | IC50 8.96 μM | 0.90 | Acarbose, IC50 28.06 μM | 0.82 | |
48 | IC50 82.47 μM | 0.22 | ||||||
1 | IC50 75.80 μM | 0.81 | ||||||
49 | IC50 1.05 μM | 0.03 | ||||||
50 | IC50 3.76 μM | 0.17 | ||||||
51 | IC50 2.57 μM | 0.25 | ||||||
52 | IC50 3.02 μM | 0.54 | ||||||
53 | IC50 2.99 μM | 0.86 | ||||||
54 | IC50 3.22 μM | 0.01 | ||||||
55 | IC50 155.57 μM | 1.27 | ||||||
[55] | 62 | Pancreatic α-amylase inhibition | N/A | IC50 44 μM | 3.0 | Acarbose, IC50 1.3 μM | 0.2 | |
[57] | 12 | α-Glucosidase inhibition | N/A | IC50 11.63 μM | 0.36 | Acarbose, IC50 0.59 μM | 0.14 | |
Apigenin-7-O-glucoside (63) | IC50 22.80 μM | 0.24 | ||||||
7 | IC50 46.39 μM | 0.34 | ||||||
Pinocembrin (68) | α-Glucosidase inhibition (Sucrase activity) | N/A | IC50 0.39 μM | 0.02 | Acarbose | N/A | ||
Pinocembrin (68) | α-Glucosidase inhibition (Maltase activity) | N/A | IC50 0.35 μM | 0.021 | ||||
[62] | 75a | PPAR-γ agonism | N/A | EC50 47.07 μM | N/A | Bavachinin, EC50 18.74 μM | N/A | |
75b | EC50 11.25 μM | N/A | ||||||
75c | EC50 3.30 μM | N/A | ||||||
75d | EC50 13.61 μM | N/A | ||||||
75e | EC50 114.33 μM | N/A | ||||||
75f | Inactive | N/A | ||||||
76a | EC50 42.53 μM | N/A | ||||||
76b | EC50 3.55 μM | N/A | ||||||
[63] | 77a | α-Glucosidase inhibition | N/A | IC50 45 μM | N/A | N/A | N/A | |
77r | IC50 86 μM | N/A | ||||||
77t | IC50 960 μM | N/A | ||||||
77u | IC50 1000 μM | N/A | ||||||
[64] | 1 | α-Glucosidase inhibition | IC50 4.92 μg/mL | 7.06 | Quercetin (commercial), IC50 4.30 μg/mL | 1.06 | ||
Isoscutellarein (78) | IC50 7.15 μg/mL | 0.96 | ||||||
6 | IC50 12.19 μg/mL | 4.63 | ||||||
Hypoletin (79) | IC50 48.42 μg/mL | 9.71 | ||||||
1 | DPP-4 inhibition | IC50 21.75 μg/mL | 5.81 | Sitagliptin, IC50 24.51 μg/mL | 1.01 | |||
78 | IC50 22.32 μg/mL | 1.52 | ||||||
6 | IC50 45.93 μg/mL | 8.61 | ||||||
79 | IC50 34.89 μg/mL | 7.44 |
Anti-Inflammatory Activity of Flavonoids | |||||||||||
References | A-Ring | B-Ring | C-Ring | ||||||||
C5 | C6 | C7 | C8 | C2′ | C3′ | C4′ | C5′ | C2 | C3 | C4 | |
[25] | OH ↑ | OH ↑ | OH ↑ | OH ↑ | C2=C3 ↑ | C=O ↑ | |||||
[26] | OH ↑ | OH ↑ | C2=C3 ↑ | OH ↓ | |||||||
[27] | OH ↑ | OH ↑ | C2=C3 ↑ | OH ↓ | |||||||
[28] | Catechol moiety ↑ | Catechol moiety ↑ | C2=C3 ↑ | C=O ↑ | |||||||
[29] | Conjugation of OH ↓ | C2=C3 ↑ | Glucuronidation of OH ↓ | ||||||||
[30] | OH ↑ | Glycosylation of OH or C ↑ | OH ↑ | OH ↑ | OH ↑ | ||||||
[31] | Glucopyranosyl ↑ | OMe ↑ | C2=C3 ↓ | OH and sugar moiety ↓ | |||||||
[32] | Methylation ↑ OH ↓ | ||||||||||
[33] | Glycosylation ↑ | OH ↑ | OH ↑ | C2=C3 ↑ | |||||||
[34] | OH ↑ | OH ↑ | OH ↑ | OH ↑ | OH ↑ | C2=C3 ↑ | Sugar moiety ↓ | ||||
[35] | OH ↑ | OH ↑ | C2=C3 ↑ | ||||||||
[36] | OH ↑ | OH ↑ | C2=C3 ↑ | C=O ↑ | |||||||
[37] | OH ↑ | OH ↑ | OMe ↑ | OH ↑ | OH ↑ | C2=C3 ↑ | OH ↓ | ||||
[38] | OH ↑ | OH ↑ | |||||||||
[39] | OH ↑ | OH ↑ | OH ↑ | ||||||||
[40] | OH ↑ | OH ↑ | C2=C3 ↑ | OH ↑ | C=O ↑ | ||||||
[41] | OH ↑ | OH ↑ | OH ↑ | OH ↑ | |||||||
[42] | OH ↑ Conjugation of OH ↓ | OH ↑ Conjugation of OH ↓ | Substitution ↓ | ||||||||
Antidiabetic activity of flavonoids | |||||||||||
References | A-Ring | B-Ring | C-Ring | ||||||||
C5 | C6 | C7 | C8 | C2′ | C3′ | C4′ | C5′ | C2 | C3 | C4 | |
[46] | OH ↑ | OH ↑ | C2=C3 ↑ | ||||||||
[47] | Sugar moiety ↓ | OH ↑ | OH ↑ | OH ↓ | |||||||
[48] | OH ↑ | OH ↑ Glycosylation of OH ↓ | OH ↑ Conjugation of OH ↓ | OH ↑ Conjugation of OH ↓ | Methylation of OH ↑ | ||||||
[49] | OMe ↑ | ||||||||||
[50] | OMe ↑ | Prenyl group ↑ | OH ↑ | OH ↑ | |||||||
[51] | Gallolyl moiety ↑ OH ↑ | OH ↑ | OH ↑ | OH ↑ | |||||||
[52] | OH ↑ | ||||||||||
[53] | Rhamnosyl moiety ↑ | Rhamnosyl moiety ↑ | |||||||||
[54] | OH ↑ | OH ↑ | OH ↑ | OH ↑ | OH ↑ | C2=C3 ↑ | OH ↑ | ||||
[55] | OH ↑ | OH ↑ | OH ↑ | OH ↑ | C2=C3 ↑ | Cl ↑ | |||||
[56] | Bulky group and H bond acceptor ↑ | Minor group and EDG ↑ | |||||||||
[57] | OH ↑ | ||||||||||
[58] | OH ↑ | Glycosylation of OH ↓ | OH ↑ | OH ↑ | C2=C3 ↑ | Galloylation of OH ↑ Glycosylation of OH ↓ | |||||
[59] | OH ↑ | OH ↑ | OH ↑ | OMe ↑ | |||||||
[62] | Isopentyl moiety ↑ | Geranyl moiety ↓ | EDG or EWG ↑ | ||||||||
[63] | OH ↑ | OH ↑ | OH ↑ | OH ↓ F ↑ | |||||||
[64] | OH ↑ | OH ↑ | C2=C3 ↑ | C=O ↑ |
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Shamsudin, N.F.; Ahmed, Q.U.; Mahmood, S.; Shah, S.A.A.; Sarian, M.N.; Khattak, M.M.A.K.; Khatib, A.; Sabere, A.S.M.; Yusoff, Y.M.; Latip, J. Flavonoids as Antidiabetic and Anti-Inflammatory Agents: A Review on Structural Activity Relationship-Based Studies and Meta-Analysis. Int. J. Mol. Sci. 2022, 23, 12605. https://doi.org/10.3390/ijms232012605
Shamsudin NF, Ahmed QU, Mahmood S, Shah SAA, Sarian MN, Khattak MMAK, Khatib A, Sabere ASM, Yusoff YM, Latip J. Flavonoids as Antidiabetic and Anti-Inflammatory Agents: A Review on Structural Activity Relationship-Based Studies and Meta-Analysis. International Journal of Molecular Sciences. 2022; 23(20):12605. https://doi.org/10.3390/ijms232012605
Chicago/Turabian StyleShamsudin, Nur Farisya, Qamar Uddin Ahmed, Syed Mahmood, Syed Adnan Ali Shah, Murni Nazira Sarian, Muhammad Muzaffar Ali Khan Khattak, Alfi Khatib, Awis Sukarni Mohmad Sabere, Yusnaini Md Yusoff, and Jalifah Latip. 2022. "Flavonoids as Antidiabetic and Anti-Inflammatory Agents: A Review on Structural Activity Relationship-Based Studies and Meta-Analysis" International Journal of Molecular Sciences 23, no. 20: 12605. https://doi.org/10.3390/ijms232012605