Design and synthesis of new coumarin-1,2,3-triazole hybrids as new antidiabetic agents: In vitro α-amylase, α-glucosidase inhibition, anti-inflammatory, and docking study European Journal of Chemistry 15 (3) (2024) 205-219 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2024 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. https://dx.doi.org/10.5155/eurjchem.15.3.205-219.2541 European Journal of Chemistry View Journal Online View Article Online Design and synthesis of new coumarin-1,2,3-triazole hybrids as new antidiabetic agents: In vitro α-amylase, α-glucosidase inhibition, anti-inflammatory, and docking study Vinayaka Chandrappa Barangi 1,2, Lokesh Anand Shastri 1,*, Prakasha Kothathi Chowdegowda 2, Rohini Sangappanavar 2, Karthik Inamdar 2, Nagarjuna Prakash Dalbanjan 3, Delicia Avilla Barretto 4, and Vinay Sunagar 5 1 Department of Chemistry, Karnatak University, Dharwad-580003, Karnataka, India 2 Department of Chemistry, Karnatak Lingayat Education, Parappa Channappa Jabin Science College, Hubballi-580031, Karnataka, India 3 Department of Biochemistry, Karnatak University, Dharwad, Karnataka 580003, India 4 School of Chemical Sciences, Goa University, Taleigao Plateau-403206, Panaji, Goa, India 5 Department of Chemistry, Govindram Seksaria Science College, Belagavi, Karnataka 590006 India * Corresponding author at: Department of Chemistry, Karnatak University, Dharwad-580003, Karnataka, India. e-mail: drlashastri@kud.ac.in (L.A. Shastri). 10.5155/eurjchem.15.3.205-219.2541 Received: 29 February 2024 Received in revised form: 24 April 2024 Accepted: 28 June 2024 Published online: 30 September 2024 Printed: 30 September 2024 The current study focuses on the synthesis of coumarin-triazole hybrids (7i-t) starting from 4-hydroxy benzaldehyde or 4-hydroxyacetophenone (1a-b) and propargyl bromide. On the other hand, coumarin derivatives (5c-h) were prepared by Pechmann cyclization and treated with sodium azide to give the corresponding 3-azido methyl coumarins (6c-h). Finally, 1,3- dipolar cycloaddition between compounds 6c-h and terminal alkyne 2a-b produces coumarin-triazole hybrids (7i-t) utilizing click chemistry approaches that are high yielding, wide in scope and simple to perform. The structural proofs of the newly synthesized coumarin-triazole hybrids (7i-t) are proved by various spectroscopic techniques, including IR, 1H NMR, 13C NMR, and LC-MS. The synthesized new coumarin triazole hybrids (7i-t) were explored for their antihyperglycemic potential and therefore evaluated for α-glucosidase and α-amylase inhibitory activities along with anti-inflammatory. The results suggest that among the series, compound 7l showed excellent activity with an IC50 value of 0.67±0.014 mg/mL and 0.72±0.012 mg/mL for α-amylase, and α-glucosidase inhibitory potential while compound 7o showed promising anti-inflammatory activity with IC50 value of 0.54±0.003 mg/mL. To support the above findings, molecular docking studies were performed, which confirmed the interaction of the synthesized molecules 7i-t with an effective binding energy of -9.0 to -10.6 kcal/mol at the active site of the enzyme human pancreatic α-amylase (PDB ID: 1B2Y). Therefore, these scaffolds have the potential to function as lead candidates for antidiabetic and anti-inflammatory activities. Diabetes Triazoles Coumarins Inflammation alpha-Amylase alpha-Glucosidase Cite this: Eur. J. Chem. 2024, 15(3), 205-219 Journal website: www.eurjchem.com 1. Introduction Chronic hyperglycemia is the hallmark of a group of meta- bolic diseases known as diabetes and is caused by abnorma- lities in insulin secretion. A person with diabetes has a body that cannot create enough insulin or will not respond to it. Based on how the body reacts to insulin and vice versa, diabetes is divided into two types. Type 1 diabetes, an autoimmune reaction in which the body restricts insulin production and requires daily insulin doses for proper functioning and survival; and type 2 diabetes, also known as hyperglycemia, in which high blood sugar occurs due to inadequate insulin secretion or insulin resistance in the body. Type 2 diabetes affects 90-95% of diabetics and poses a global health risk. This metabolic disorder leads to many complications including cardiovascular [1], neuropathy [2], retinopathy [3], and nephropathy [4] diseases. Biologically, carbohydrates are the main source of energy that is subsequently broken down into oligosaccharides, disaccharides, and simpler glucose by endocrine and exocrine enzymes present in our body, like α-amylase secreted by the pancreas, which breaks polysaccharides into oligosaccharides and disaccharides. α-Glucosidase enzyme secreted by the small intestine breaks it further into glucose, which ultimately increases the blood sugar level, which is further assimilated by cells in response to insulin production by the pancreas. This diabetes can be controlled by reducing postprandial hyper- glycemia [5] by delaying glucose absorption of glucose through the inhibition of enzymes such as α-amylase and α-glucosidase [6]. In recent years, a wide range of studies have shown the effectiveness of coumarin and its derivatives in regulating enzymes like α-amylase and α-glucosidase [7]. ABSTRACT RESEARCH ARTICLE KEYWORDS https://dx.doi.org/10.5155/eurjchem.15.3.205-219.2541 https://www.eurjchem.com/ https://dx.doi.org/10.5155/eurjchem.15.3.205-219.2541 mailto:drlashastri@kud.ac.in http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.15.3.205-219.2541&domain=pdf&date_stamp=2024-09-30 206 Barangi et al. / European Journal of Chemistry 15 (3) (2024) 205-219 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.3.205-219.2541 Figure 1. Some of the antidiabetic and anti-inflammatory compounds comprise coumarin and triazole moieties. Most diabetes treatment focuses on the management of hyperglycemia [8], which is a protocol centered on the reduction of oxidative stress, which is an effective approach for the treatment of diabetes and its related complications. Due to oxidative stress, the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and these free radicals are harmful to living systems [9] resulting inflame- mation and other effects. Furthermore, oxidative stress and inflammation are closely related, and several studies indicate that vascular inflammation is caused by arterial diseases. However, the accumulation of ROS at the site of inflammation occurs due to the fact that most cells and leukocytes are produced, leading to a respiratory damage [10]. The dangers associated with the inflammatory process make it difficult for medicinal chemists to develop more effective anti-inflam- matory drugs. A significant number of known anti-inflam- matory substances, particularly those with clinically demonst- rated efficacy, are acidic in character. Non-steroidal anti- inflammatory drugs (NSAIDs) are a prominent family of drugs used to treat inflammation. They operate in affected tissues by blocking the cyclooxygenase (COX) involved in the manufacture of prostaglandins [11-13]. With decades of history and future potential, heterocyclic chemistry has dominated the discipline and is essential for the synthesis of new medications. Coumarins and triazoles have attracted considerable interest among heterocycles due to their widespread natural occurrence and significant biological activity [14]. The glycoside derivatives of naturally occurring coumarins are helpful in medicine [15]. Coumarins are widely used as anticancer [16,17], antidiabetic [18], anti-inflammatory [19,20], antioxidant [21], anticonvulsant [22], antimicrobial [23,24], and antiviral [25] agents. Coumarin scaffolds are well-known structural motifs that are typically found in plants and a few microorganisms. They were revealed to exhibit a broad range of bioactivities and have emerged as leading candidates for therapeutic applications [26]. Since the development of click chemistry [27], triazoles have been highly yielding, wide in scope, and proven to be potent bioactive pharmacophores [28] that tend to exhibit various biochemical uses, drawing researchers in several disciplines [29]. Despite its unique and broad pharmacological characteristics, extensive efforts have not been made to develop coumarin-triazole-based antidiabetic drugs. However, recent literature findings emphasize the anti-diabetic efficacy of coumarin-moored triazole compounds [14,30], encouraging researchers to synthesize and investigate novel molecular hybrids with improved therapeutic value against α-amylase and α-glucosidase inhibitors. Structures of some of the reported coumarin and triazole moieties possessing good α-amylase inhibitors [31-33], α-glucosidase inhibitors [33-35] and anti- inflammatory agents [36,37] are shown in Figure 1. In an effort to find novel, potential active pharmacophores with promising α-glucosidase inhibitors, α-amylase inhibitors, we have synthesized 12 hybrid scaffolds with good antidiabetic agents Barangi et al. / European Journal of Chemistry 15 (3) (2024) 205-219 207 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.3.205-219.2541 O H RO Br O RO 1a,b 2a,b DMF, RT, 4 h R = H, CH3 Scheme 1. Synthesis of acetylenic dipolorophile, 2a,b. and further display better anti-inflammatory activity; they may turn out to be leading candidates for drug development studies. However, five-membered heterocycles, in particular 1,2,3- triazoles, play a crucial role in medicinal chemistry. 1,2,3- Triazoles were produced using a [3+2] cycloaddition method. Triazoles are widely used as antiviral [38], antimicrobial [39], anti-neuroinflammatory [40], anti-inflammatory [41], anti- plasmodial [42], antidiabetic [43], and anticancer agents [44]. When new or additional pharmacophore quality is added to existing molecules of coumarin derivatives, new structural entities that increase activity with the fewest negative effects may be produced. Various coumarin-triazole-linked derivatives have shown excellent antidiabetic properties [45-49]. The structural similarity between coumarin derivatives and the strong α-glucosidase inhibitor genistein prompted us to investigate the inhibitory activity of coumarin and triazole hybrids as potential candidates in our search for new, easily available, and chemically stable α-glucosidase inhibitors. 2. Experimental 2.1. Material and methods All starting materials and reagents were analytical grade, obtained from commercial suppliers (Sigma Aldrich, S.D. Fine, Alfa Aesar, and Spectrochem), and used without additional purification. All melting points were determined using a Coslab Scientific melting point device and are unadjusted. Thin layer chromatography (TLC) was used to track reaction rates on precoated Merck silica gel 60F254 plates using an appropriate solvent system and spots were identified using UV light (λ = 254 nm). IR spectra were collected using potassium bromide (KBr) pellets on a Nicolet 170 SX FTIR spectrometer; the frequencies are reported in cm−1. With a Bruker Avance FT NMR spectro- meter with tetramethylsilane as probe, nuclear magnetic resonance (1H NMR, 400 MHz and 13C NMR, 100 MHz) spectra were collected using TMS as an internal standard, using CDCl3 and DMSO-d6 as a solvent. Shimadzu GCMSQP2010S and ESI/APCI-hybrid quadrupole, time-of-flight, and LC/MS mass spectrometers were used to record mass spectra (Synapt G2 HDMS ACQUITY UPLC). A Heraeus Carlo Erba 1180 CHN analyzer was used to perform elemental studies (C, H and N). 2.2. General synthetic procedure 2.2.1. Synthesis of terminal alkynes, 2a,b The p-hydroxyarylcarbonyl compound (1 equiv.) was disintegrated in DMF and potassium carbonate (1.5 equiv.) was added. Propargyl bromide (1.2 equiv.) was injected dropwise into this solution and the reaction components were stirred at room temperature for 24 h. After the completion of the reaction, which was scrutinized by TLC, it was discharged onto smashed ice, the precipitate was filtered to obtain the product (Scheme 1) [50]. 2.2.2. Preparation of 4-(azidomethyl)-2H-chromen-2-ones, 6c-h 4-Bromomethyl coumarin (5c-h) (0.010 mol) was taken in acetone (20 mL) in a round-bottom flask. Sodium azide (0.012 mol) in water (3.00 mL) was added dropwise with stirring, which was continued for 10 h. The reaction mixture was then poured into ice-cold water. The separated solid was filtered and recrystallized from ethanol to obtain the compound 6c-h using the reported method (Scheme 2) [51]. 2.2.3. Synthesis of 1,2,3-triazolyl-methyl-2H-chromen-2- ones, 7i-t The reaction mixture was prepared by taking acetylenic dipolorophile (compounds 2a-b, 0.1 mol) in THF:H2O mixture (1:1 ratio), followed by the addition of CuSO4·5H2O (0.015 mol), and sodium ascorbate (0.03 mol). The reaction mixture was stirred at room temperature for half an hour and subsequently 4-(azidomethyl)-2H-chromen-2-ones (6c-h) (0.1 mol) were added. The consequential reaction mixture was stirred for one hour, and the completion of the reaction was monitored by TLC. The reaction mixture was then poured into ice cold water. The separated solid was filtered, washed with water and recrystallized with ethyl acetate to obtain the desired product (7i-t) (Scheme 2). 4-([4-([4-Acetylphenoxy]methyl)-1H-1, 2, 3-triazol-1-yl]met hyl)-6-methyl-2H-chromen-2-one (7i): Color: White. Yield: 91%. M.p.: 114-116 °C. FT-IR (KBr, ν, cm-1): 1731 (Coumarin, C=O), 1668 (Ketone, C=O). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.37 (s, 3H, CH3), 2.51 (s, 3H, C(O)CH3), 5.30 (s, 2H, coumarin-C4- CH2), 5.78 (s, 1H, coumarin-C3-H), 5.98 (s, 2H, O-CH2), 6.77 (d, 1H, J = 8.8 Hz, ArH), 7.14 (d, 1H, J = 8.8 Hz, ArH), 7.35 (d, 1H, J = 8.8 Hz, ArH), 7.49 (d, 1H, J = 8.4 Hz, ArH), 7.66 (s, 1H, coumarin- C5-H), 7.78 (d, 1H, J = 8.8 Hz, ArH), 7.92 (d, 1H, J = 8.8 Hz, ArH), 8.42 (s, 1H, ArH). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 20.44, 26.42, 61.27, 85.20, 108.59, 113.69, 114.64, 116.56, 116.62, 117.13, 120.81, 125.95, 130.40, 130.46, 133.46, 133.56, 163.21, 167.55, 178.03, 184.44, 196.4. LC-MS (m/z): 390.89 [M+1] 392.89 [M+2]. Elem. anal. calcd. for C22H19N3O4 (%): C, 67.86; H, 4.92; N, 10.79; Found: C, 67.81; H, 4.94; N, 10.75. 4-([4-([4-Acetylphenoxy]methyl)-1H-1, 2, 3-triazol-1-yl]met hyl)-7-methyl-2H-chromen-2-one (7j): Color: Buff. Yield: 93%. M.p.: 124-126 °C. FT-IR (KBr, ν, cm-1): 1730 (Coumarin, C=O), 1672 (Ketone, C=O). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.41 (s, 3H, CH3), 2.51 (s, 3H, C(O)CH3), 5.29 (s, 2H, coumarin-C4- CH2), 5.79 (s, 1H, coumarin-C3-H), 5.97 (s, 2H, O-CH2), 7.14 (d, 2H, J = 8.8 Hz, ArH), 7.22 (d, 1H, J = 8.4 Hz, ArH), 7.28 (s, 1H, coumarin-C5-H), 7.74 (dd, 1H, J = 8.0, 8.8, 14.0 and 14.8 Hz, ArH), 7.92 (d, 2H, J = 8.8 Hz, ArH), 8.41 (s, 1H, ArH). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 21.05, 26.40, 61.26, 112.86, 114.62, 116.85, 124.44, 125.66, 125.85, 130.20, 130.44, 142.82, 150.0, 159.57, 161.73, 194.0, 196.34. LC-MS (m/z): 390.98 [M+1], 392.98 [M+2]. Elem. anal. calcd. for C22H19N3O4 (%): C, 67.86; H, 4.92; N, 10.79; Found:C, 67.90; H, 4.95; N, 10.82. 208 Barangi et al. / European Journal of Chemistry 15 (3) (2024) 205-219 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.3.205-219.2541 Scheme 2. Schematic depiction of coumarinyl-triazoles, 7i-t. 4-([4-([4-Acetylphenoxy]methyl)-1H-1, 2, 3-triazol-1-yl]met hyl)-2H-benzo[h]chromen-2-one (7k): Color: Brown. Yield: 88%. M.p.: 118-120 °C. FT-IR (KBr, ν, cm-1): 1731 (Coumarin, C=O), 1655 (Ketone, C=O). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.48 (s, 3H, C(O)CH3), 5.29 (s, 2H, coumarin-C4-CH2), 5.95 (s, 1H, coumarin-C3-H), 6.09 (s, 2H, O-CH2), 7.13 (d, 2H, J = 8.8 Hz, ArH), 7.72-7.75 (m, 2H, ArH), 7.82-7.92 (m, 4H, Ar-H), 8.03-8.06 (m, 1H, ArH), 8.36-8.39 (m, 1H, ArH), 8.43 (s, 1H, ArH). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 26.4, 49.6, 61.2, 112.8, 113.4, 114.6, 120.3, 121.7, 122.2, 124.3, 125.9, 127.7, 128.0, 129.1, 130.2, 130.4, 150.1, 150.8, 159.3, 161.7, 189.4, 196.3. LC-MS (m/z): 426.15 [M+1] 428.15 [M+2]. Elem. anal. calcd. for C25H19N3O4 (%): C: 70.57; H, 4.55; N, 9.88; Found: C, 70.62; H, 4.45; N, 9.82. 1-([4-([4-Acetylphenoxy]methyl)-1H-1, 2, 3-triazol-1-yl]met hyl)-3H-benzo[f]chromen-3-one (7l): Color: Peach. Yield: 92%. M.p.: 130-132 °C. FT-IR (KBr, ν, cm-1): 1735 (Coumarin, C=O), 1668 (Ketone, C=O). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.49 (s, 3H, C(O)CH3), 5.29 (s, 2H, coumarin-C4-CH2), 5.47 (s, 1H, coumarin-C3-H), 6.46 (s, 2H, O-CH2), 7.11 (d, 2H, J = 8.4 Hz, ArH), 7.58-7.69 (m, 3H, ArH), 7.87 (d, 2H, J = 8.4 Hz, Ar-H), 8.09 (d, 1H, J = 8.0 Hz, ArH), 8.25 (d, 1H, J = 8.8 Hz, ArH), 8.37 (s, 1H, ArH), 8.43 (d, 1H, J = 8.4 Hz, Ar-H). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 26.5, 53.3, 61.3, 112.5, 113.0, 114.7, 117.5, 125.9, 128.6, 129.8, 130.5, 134.7, 143.0, 152.7, 154.4, 159.1, 161.8, 196.5. LC- MS (m/z): 426.15 [M+1], 425.19 [M+]. Elem. anal. calcd. for C25H19N3O4 (%): C, 70.58; H, 4.50; N, 9.88; Found: C, 70.63; H, 4.49; N, 9.90. 4-([4-([4-Acetylphenoxy]methyl)-1H-1, 2, 3-triazol-1-yl]met hyl)-6-methoxy-2H-chromen-2-one (7m): Color: Peach. Yield: 78%. M.p.:150-152 °C. FT-IR (KBr, ν, cm-1): 1712 (Coumarin, C=O), 1694 (Ketone, C=O). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.49 (s, 3H, C(O)CH3), 3.78 (s, 3H, OCH3), 5.28 (s, 2H, coumarin-C4-CH2), 5.86 (s, 1H, coumarin-C3-H), 6.0 (s, 2H, O- CH2), 7.12 (d, 2H, J = 8.0 Hz, ArH), 7.23-7.27 (m, 2H, ArH), 7.38 (d, 1H, J = 8.8 Hz, ArH), 7.90 (d, 2H, J = 8.0 Hz, ArH), 8.41 (s, 1H, ArH). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 26.4, 49.3, 55.8, 61.2, 107.7, 114.4, 114.6, 117.5, 117.9, 119.6, 125.9, 130.2, 130.4, 147.4, 149.7, 155.6, 159.5, 161.7, 196.3. LC-MS (m/z): 406.03 [M+1], 405.03 [M+]. Elem. anal. calcd. for C22H19N3O5 (%): C, 65.18; H, 4.72; N, 10.37; Found: C, 65.21; H, 4.74; N, 10.35. 4-([4-([4-Acetylphenoxy]methyl)-1H-1, 2, 3-triazol-1-yl]met hyl)-5,7-dimethyl-2H-chromen-2-one (7n): Color: Light brown. Yield: 92%. M.p.: 142-144 °C. FT-IR (KBr, ν, cm-1): 1735 (Coumarin, C=O), 1657 (Ketone, C=O). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.43 (s, 3H, CH3), 2.59 (s, 3H, C(O)CH3), 2.76 (s, 3H, CH3), 5.17 (s, 1H, coumarin-C3-H), 5.40 (s, 2H, coumarin- C4-CH2), 6.25 (s, 2H, O-CH2), 7.14 (s, 1H, ArH), 7.21-7.24 (m, 3H, ArH), 8.00 (d, 2H, J = 8.8 Hz, ArH), 8.40 (s, 1H, ArH). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 20.6, 23.3, 26.4, 52.2, 61.3, 114.5, 114.6, 115.6, 126.0, 129.8, 130.2, 130.4, 133.6, 134.1, 136.5, 137.1, 154.6, 159.1, 196.3. LC-MS (m/z): 404.12 [M+1], 405.12 [M+2]. Elem. anal. calcd. for C23H21N3O4 (%): C, 68.47; H, 5.25; N, 10.42; Found: C, 68.50; H, 5.21; N, 10.45. 4-([1-([6-Methyl-2-oxo-2H-chromen-4-yl]methyl)-1H-1, 2, 3- triazol-4-yl]methoxy)benzaldehyde (7o): Color: Cream. Yield: 75%. M.p.: 154-156 °C. FT-IR (KBr, ν, cm-1): 1731 (Coumarin, C=O), 1686 (Aldehyde, C=O). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.25 (s, 3H, CH3), 5.22 (s, 2H, coumarin-C4-CH2), 5.67 (s, 1H, coumarin-C3-H), 5.87 (s, 2H, O-CH2), 7.12 (d, 2H, J = 8.8 Hz, ArH), 7.24 (d, 1H, J = 8.4 Hz, ArH), 7.37 (d, 1H, J = 8.4 Hz, ArH), 7.55 (s, 1H, coumarin-C5-H), 7.75 (d, 2H, J = 8.8 Hz, ArH), 8.32 (s, 1H, ArH), 9.76 (s, 1H, CHO). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 20.4, 49.1, 61.4, 113.7, 115.23, 116.6, 116.8, 124.4, 126.0, 129.9, 131.8, 133.4, 133.9, 142.7, 150.0, 151.2, 159.5, 162.8, 191.3. LC-MS (m/z): 376.11 [M+1], 375.11 [M+]. Elem. anal. calcd. for C21H17N3O4 (%): C, 67.19; H, 4.56; N, 11.19; Found: C, 67.21; H, 4.54; N, 11.15. 4-([1-([7-Methyl-2-oxo-2H-chromen-4-yl]methyl)-1H-1, 2, 3- triazol-4-yl]methoxy)benzaldehyde (7p): Color: Tan. Yield: 91%. M.p.: 178-180 °C. FT-IR (KBr, ν, cm-1): 1721 (Coumarin, C=O), 1671 (Aldehyde, C=O). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.41 (s, 3H, CH3), 5.32 (s, 2H, coumarin-C4-CH2), 5.80 (s, 1H, coumarin-C3-H), 5.97 (s, 2H, O-CH2), 7.21 (m, 3H, J = 8.8 Hz, ArH), 7.29 (s, 1H, coumarin-C5-H), 7.73 (d, 1H, J = 8.0, 8.8, 14.0 and 14.8 Hz, ArH), 7.85 (d, 2H, J = 8.8 Hz, ArH), 8.42 (s, 1H, ArH), 9.87 (s, 1H, CHO). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 21.1, 49.2, 61.4, 112.9, 114.7, 115.3, 116.9, 124.5, 125.7, 126.0, 129.9, 131.8, 142.7, 143.6, 150.0, 153.2, 156.5, 162.9, 191.4. LC-MS (m/z): 376.11 [M+1], 378.11 [M+2]. Elem. anal. calcd. for C21H17N3O4 (%): C, 67.19; H, 4.56; N, 11.19; Found: C, 67.20; H, 4.55; N, 11.22. 4-([1-([2-Oxo-2H-benzo[h]chromen-4-yl]methyl)-1H-1, 2, 3- triazol-4-yl]methoxy)benzaldehyde (7q): Color: Peach. Yield: 92%. M.p.: 136-138 °C. FT-IR (KBr, ν, cm-1): 1723 (Coumarin, C=O), 1670 (Aldehyde, C=O). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 5.29 (s, 2H, coumarin-C4-CH2), 5.95 (s, 1H, coumarin-C3- H), 6.09 (s, 2H, O-CH2), 7.13 (d, 2H, J = 8.8 Hz, ArH), 7.72-7.75 (m, 2H, ArH), 7.82-7.92 (m, 4H, Ar-H), 8.03-8.06 (m, 1H, ArH), 8.36-8.39 (m, 1H, ArH), 8.43 (s, 1H, ArH), 9.87 (s, 1H, CHO). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 49.7, 61.4, 112.8, 115.3, Barangi et al. / European Journal of Chemistry 15 (3) (2024) 205-219 209 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.3.205-219.2541 120.3, 121.7, 124.4, 126.1, 127.8, 128.1, 129.2, 130.0, 131.8, 134.5, 149.3, 150.9, 158.9, 158.4, 162.9, 175.7, 183.7, 191.5. LC- MS (m/z): 412.16 [M+1], 414.16 [M+2]. Elem. anal. calcd. for C24H17N3O4 (%): Calcd. C, 70.07; H, 4.17; N, 10.21; Found: C, 70.10; H, 4.15; N, 10.25. 4-([1-([3-Oxo-3H-benzo[f]chromen-1-yl]methyl)-1H-1, 2, 3- triazol-4-yl]methoxy)benzaldehyde (7r): Color: Buff. Yield: 89%. M.p.: 128-130 °C. FT-IR (KBr, ν, cm-1): 1736 (Coumarin, C=O), 1687 (Aldehyde, C=O). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 5.35 (s, 2H, coumarin-C4-CH2), 5.51 (s, 1H, coumarin-C3-H), 6.49 (s, 2H, O-CH2), 7.23 (d, 2H, J = 8.8 Hz, ArH), 7.62-7.72 (m, 3H, ArH), 7.85-7.88 (m, 2H, Ar-H), 8.10-8.13 (dd, 1H, J = 1.0, 1.2, 6.8 and 8.0 Hz, ArH), 8.28 (d, 1H, J = 9.2 Hz, ArH), 8.40 (d, 2H, J = 8.8 Hz, Ar-H), 9.88 (s, 1H, CHO). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 53.1, 61.4, 112.4, 112.9, 115.2, 117.4, 125.4, 125.8, 126.1, 128.5, 129.7, 131.7, 134.5, 152.6, 154.3, 158.9, 162.8, 170.3, 191.3. LC-MS (m/z): 412.13 [M+1], 413.14 [M+2]. Elem. anal. calcd. for C24H17N3O4 (%): C, 70.07; H, 4.16; N, 10.21; Found: C, 70.03; H, 4.19; N, 10.20. 4-([1-([6-Methoxy-2-oxo-2H-chromen-4-yl]methyl)-1H-1, 2, 3-triazol-4-yl]methoxy)benzaldehyde (7s): Color: Light pink. Yield: 64%. M.p.: 136-138 °C. FT-IR (KBr, ν, cm-1): 1716 (Coumarin, C=O), 1635 (Aldehyde, C=O). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 3.72 (s, 3H, OCH3), 5.25(s, 2H, coumarin-C4- CH2), 5.82 (s, 1H, coumarin-C3-H), 5.93 (s, 2H, O-CH2), 7.14-7.21 (m, 3H, ArH), 7.33 (d, 1H, J = 8.8 Hz, ArH), 7.79 (d, 3H, J = 8.4 Hz, ArH), 8.36 (s, 1H, ArH), 9.79 (s, 1H, CHO). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 49.5, 55.7, 61.3, 106.3, 110.0, 114.2, 115.1, 117.7, 119.4, 125.6, 131.6, 136.6, 148.8, 155.6, 159.3, 164.2, 196.6. LC-MS (m/z): 392.02 [M+1], 391.03 [M+]. Elem. anal. calcd. for C21H17N3O5 (%): C, 64.45; H, 4.38; N, 10.74; Found: C, 64.41; H, 4.34; N, 10.75. 4-([1-([5, 7-Dimethyl-2-oxo-2H-chromen-4-yl]methyl)-1H-1, 2,3-triazol-4-yl]methoxy)benzaldehyde (7t): Color: Buff. Yield: 95%. M.p.: 152-154 °C. FT-IR (KBr, ν, cm-1): 1720 (Coumarin, C=O), 1672 (Aldehyde, C=O). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.42 (s, 3H, CH3), 2.75 (s, 3H, CH3), 5.18 (s, 1H, coumarin- C3-H), 5.42 (s, 2H, coumarin-C4-CH2), 6.24 (s, 2H, O-CH2), 7.13 (s, 1H, ArH), 7.20 (s, 1H, ArH), 7.31 (d, 2H, J = 8.8 Hz, ArH), 7.94 (d, 2H, J = 8.8 Hz, ArH), 8.41 (s, 1H, ArH), 9.94 (s, 1H, CHO). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 20.62, 23.3, 61.4, 83.6, 111.5, 115.3, 115.6, 126.1, 129.8, 129.9, 131.8, 136.5, 148.6, 153.0, 154.6, 162.8, 179.4, 191.3. LC-MS (m/z): 391.19 [M+2], 390.98 [M+1], 389.98 [M+]. Elem. anal. calcd. for C22H19N3O4 (%): C, 67.86; H, 4.92; N, 10.79; Found: C, 67.90; H, 4.91; N, 10.75. 2.3. Experimental method for biological evaluation 2.3.1. In vitro α-amylase inhibition assay In humans, starch is first partially digested by salivary amylase, resulting in the degradation of polymeric substrates into shorter oligomers. Once the oligomers reach the gut, they are further hydrolyzed by pancreatic α-amylase into maltose, maltotriose, and small malto-oligosaccharides. Dietary starch (maltose) is hydrolyzed by the digestive enzyme (α-amylase), which breaks down into glucose prior to absorption. Inhibition of α-amylase can lead to a reduction in postprandial hyper- glycemia in diabetic conditions. Thus, in vitro antidiabetic activity was examined by α-amylase inhibition potential using the 3,5-dinitro salicylic acid method [52]. Various concentra- tions of synthesized compounds were preincubated for half an hour with 1% α-amylase. This was considered a test; the negative control or blank was maintained without α-amylase but with distilled water. The positive control was maintained with distilled water and α-amylase. Starch (1%, 1 mL) was added and incubated at 37 °C for 10 min. 1 mL DNSA reagent was added to all test tubes. The test tubes were then incubated in a boiling water bath for 5 min. The OD was taken at 540 nm after cooling the tubes. Acarbose was a standard antidiabetic drug. The experiment was carried out in triplicate. The percentage inhibition of α-amylase activity was determined using the following formula: Inhibition (%) = [1 − B A ] × 100 (1) where A = Absorbance of the control reaction mixture (negative control) and B = Absorbance of the test reaction mixture. 2.3.2. In vitro α-glucosidase inhibition assay The evaluation of p-nitrophenoxide, which is produced from nitrophenol in basic media, is the core of the α-glucosidase inhibition assay [53]. The enzyme glucosidase releases p- nitrophenol from p-NPG (p-nitrophenyl-α-D-glucopyranoside). The percentage of inhibition (drop of the light absorption species, p-nitrophenoxide) was evaluated in the presence and absence of an inhibitory substance (negative control, 100% of enzyme activity). This percentage of inhibition was considered as the method's response. The experiment was carried out in triplicate. The following equation was used in each case to determine the percentage of inhibition. Inhibition (%) = [1 − B A ] × 100 (2) where A = Control reaction mixture absorbance and B = Test reaction mixture absorbance. 2.3.3. In vitro anti-inflammatory activity by denaturation of bovine serum albumin method The anti-inflammatory effect of compound 7i-t derivatives was evaluated using the denaturation of bovine serum albumin methodology, as described by Mizushima et al. [54] and Sakat et al. [55]. The test sample contains the test chemical and a 1% aqueous solution of bovine albumin, and the pH of the reaction mixture was adjusted to 7.4 using appropriate stripping solutions. The test samples were incubated at 37 °C for 20 minutes before being heated to 51 °C for 20 minutes. After being cooled to room temperature, the turbidity of the sample was measured at 660 nm with a UV-visible spectrophotometer. The experiment was carried out in triplicate, with diclofenac sodium serving as the control medication. The percentage inhibition of protein denaturation was determined using the following formula. Inhibition (%) = [1 − B A ] × 100 (3) where A = Absorbance of the control reaction mixture (negative control) and B = Absorbance of the test reaction mixture. 2.4. Molecular docking The 3D structure of the synthesized compounds in .pdb and .pdbqt formats was prepared using Avogadro software in the optimized geometrical conformations and by applying MMFF94 force field using Open Babel software [56]. The newly synthesized compounds and acarbose were docked against the hypothesized enzyme human pancreatic α-amylase in complex with the carbohydrate inhibitor acarbose (PDB code: 1B2Y) [57]. The protein preparation, including the removal of bound ligands and water molecules that were heteroatoms, the addition of polar hydrogens, the computation of Kollman and Gasteiger charges, and the assignment of other miscellaneous parameters was performed using ADT [58]. Molecular docking was performed using the AutoDock Vina.exe file, with ten modes in four energy ranges in a grid size of 40 Å × 40 Å × 40 at the active site of the enzyme (x: 18.909389, y: 5.790370, z: 47.006148) [59]. 210 Barangi et al. / European Journal of Chemistry 15 (3) (2024) 205-219 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.3.205-219.2541 Table 1. Optimization of reaction conditions. Entry CuSO4·H2O (mol %) Solvent Time (h) Yield (%) 1 10 DMSO 16 18 2 10 Acetonitrile 15 28 3 10 DMF 22 12 4 10 Ethanol 20 45 5 10 Methanol 20 54 6 10 Ethanol:H2O (1:1) 20 63 7 10 Ethanol:H2O (2:1) 20 69 8 10 THF:H2O (1:1) 4 88 9 15 THF:H2O (1:1) 4 90 10 20 THF:H2O (1:1) 4 90 7i (90%) 7j (92%) 7k (90%) 7l (88%) 7m (90%) 7n (88%) 7o (89%) 7p (88%) 7q (86%) 7r (85%) 7s (90%) 7t (90%) O O N N N O O O O N N N O O O O N N N O O O O N N N O O O O N N N O O O O O N N N O O O O N N N O H O O O N N N O H O O O N N N O H O O O N N N O H O O O N N N O H O O O O N N N O H O Figure 2. Synthesized coumarinyl-triazoles (7i-t) and their corresponding yields. 3. Results and discussion 3.1. Chemistry A number of 1,2,3-(triazol-4-yl)-2H-chromen-2-ones (7i-t) were successfully synthesized by a multistep process. In the present study, we intend to report the click-chemistry-tethered regioselective synthesis of 1,2,3-triazolyl-2H-chromen-2-one (7i-t) with high yields and purity in short reaction times (Scheme 1). 4-Hydroxy acetophenone/benzoaldehyde was used as the starting material, which upon treatment with propargyl bromide gives terminal alkynes (2a-b). On the other hand, 3-azido methyl coumarins (6c-h) were obtained by the reaction of 3-bromomethyl coumarin with sodium azide in aqueous acetone at room temperature. This was followed by the azide-alkyne cycloaddition of the 3-azido methylcoumarins (6c- h) and acetylenic dipolarophiles (2a-b) (Scheme 2), for which we optimized the reaction conditions using various catalytic amounts of CuSO4.5H2O in various solvents, as tabulated in Table 1. The structures of the synthesized compounds 7i-t were verified by 1H NMR, 13C NMR, mass spectroscopic studies, and elemental analysis. The structures of the synthesized coumarinyl-triazoles (7i-t) and their corresponding yields are given in Figure 2. Barangi et al. / European Journal of Chemistry 15 (3) (2024) 205-219 211 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.3.205-219.2541 Table 2. IC50 value for inhibition of the α-amylase activity of the synthesized compounds 7i-t *. Compounds IC50 value (mg/mL) 7i 1.29±0.027 7j 0.92±0.023 7k 0.89±0.017 7l 0.67±0.014 7m 1.10±0.016 7n 0.77±0.023 7o 1.69±0.008 7p 1.16±0.012 7q 0.98±0.013 7r 1.73±0.006 7s 2.31±0.005 7t 0.87±0.009 Acarbose 1.84±0.002 * Values are expressed as mean±SD, n = 3. Table 3. IC50 value of α-glucosidase inhibition of the synthesized compounds 7i-t. Compounds IC50 value (mg/mL) 7i 1.69±0.023 7j 0.99±0.026 7k 0.96±0.013 7l 0.72±0.012 7m 1.38±0.017 7n 0.81±0.021 7o 1.97±0.009 7p 1.30±0.014 7q 1.20±0.015 7r 2.28±0.007 7s 3.27±0.004 7t 0.99±0.006 Acarbose 1.41±0.005 * Values are expressed as mean±SD, n = 3. Solvent optimization was performed using various protic and aprotic solvents. Some commonly used solvents such as DMSO, ACN, DMF, ethanol, methanol, and THF, and a combination of these solvents are also used under reflux conditions to get products. Initially, DMSO, ACN, and DMF were used to obtain the products, but the yields were initially very low with the use of a 10 mol% catalyst, that is, (Table 1, Entries 1-3). The reaction was further extended and performed in protic solvents such as ethanol, methanol, and THF, and a mixture of water solvents. In the case of ethanol and methanol (Table 1, Entrys 4,5) and with water mixtures (Table 1, Entrys 6,7) here we noticed the formation of the product. But the reaction was completed after prolonged time and the isolated yields are 45-70%. Later, we increased the catalyst concent- ration to 15 mol%; the product resulted in a 90% yield (Table 1, Entry 8). When the catalyst concentration increased by 20 mol%, isolated yield changes were not found (Table 1, Entry 10). Some reactions were performed at ambient temperature; the result was found to be poor. We observed that the percentage yield of the products (7i-t) was higher in the alcohol and water mixture compared to the solvent alone. Then we decided to perform the reaction in THF with a water mixture; surprisingly, the product formation and completion of the reaction occurred in a short time, and the isolated yield is more than 85%. 3.2. Biological studies 3.2.1. Inhibition of α-amylase activity To investigate the pharmacological significance of these synthesized molecules, all hybrids were evaluated for their antidiabetic ability [60]. Therapeutic investigation to treat diabetes is to reduce postprandial hyperglycemia. This can be done by suppressing the absorption of glucose via inhibition of the sugar hydrolysing enzymes, particularly α-amylase [46] and α-glucosidase [53] in the digestive system [61]. Table 2 provides IC50 data of the findings of the study on α- amylase inhibition. Interestingly, the synthesized compound 7i- t exhibited a large impact on starch utilization and IC50 results of the compounds with the standard drug acarbose. Compounds 7l and 7n demonstrated excellent inhibition with values of 0.67±0.014 and 0.77±0.023 mg/mL, respectively. While compounds 7o, 7r, and 7s showed a moderate amount of α- amylase inhibition with IC50 values of 1.69±0.008, 1.73±0.006, and 2.31±0.005 mg/mL, respectively. Compound 7l exhibited the highest inhibition of the enzyme among all derivatives. From the study, we conclude that most synthesized compounds have more effectively shown inhibition of α-amylase compared to the standard drug. 3.2.2. In vitro α-glucosidase inhibition activity All compounds were screened for α-glucosidase inhibition profile with the help of p-NPG, the percentage inhibition was calculated and the IC50 values were determined [62]. All compounds exhibit excellent inhibition profiles except compounds 7r and 7s compared to the standard drug acarbose. Table 3 reveals that compound 7l showed significant glucosidase inhibition potency with the IC50 value of 0.72±0.012 mg/mL among all synthesized 7i-t compounds. 3.2.3. In vitro anti-inflammatory activity Synthesized 7i-t derivatives were evaluated for their anti- inflammatory efficacy using the protein denaturation inhibition technique with diclofenac sodium as the reference medication. The percentage inhibition of the synthesized compounds was measured using different concentrations ranging from 20 to 100 mg/mL. Table 4 lists the results of the IC50 values. Among the synthesized compounds, 7o, 7r, 7p, and 7q possessed excellent anti-inflammatory efficiencies with IC50 values of 0.54±0.003, 0.55±0.008, 0.57±0.85, and 0.60±0.011 mg/mL, respectively. Compounds 7i, 7j, 7k, 7l, 7m, 7n, 7s, and 7t exhibited moderate inhibition profiles with IC50 values of 0.70±0.021, 0.99±0.023, 1.11±0.017, 0.86±0.011, 0.77±0.013, 0.73±0.024, 1.41±0.006, and 1.72±0.007 mg/mL, respectively. 212 Barangi et al. / European Journal of Chemistry 15 (3) (2024) 205-219 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.3.205-219.2541 Table 4. IC50 anti-inflammatory activity of the synthesized compounds 7i-t *. Compounds IC50 value (mg/mL) 7i 0.70±0.021 7j 0.99±0.023 7k 1.11±0.017 7l 0.86±0.011 7m 0.77±0.013 7n 0.73±0.024 7o 0.54±0.003 7p 0.57±0.015 7q 0.60±0.011 7r 0.55±0.008 7s 1.41±0.006 7t 1.72±0.007 Diclofenac 0.67±0.004 * Values are expressed as mean±SD, n = 3. 3.3. Computational studies 3.3.1. Molecular docking studies The use of molecular docking is an emerging method in structure-based drug discovery to evaluate the binding conformation of tiny ligands to the appropriate protein target binding site. They proposed a possible mechanism of α-amylase activity and detailed intermolecular interactions between the synthesized compounds and the postulated protein. The docking studies produced a possible picture of drug-receptor interactions, with nine potential interactions for each compound with the protein. The best possible interaction with the lowest binding energy is visualized using the BIOVIA Discovery Studio 2021 visualizer (Figures 3 and 4). Details such as the binding energy, type of interactions, bond distance, and type of bonding of the possible interactions are listed in Table 5. It is clearly observed in Figures 3 and 4, the compounds 7k and 7q bearing benzo substitution on the coumarin ring showed the highest interaction with amylase protein than acarbose. The compound 7k forms three conventional hydrogen bonds (GLN63: H–O1; TYR151: OH–O4), one C-H bond, one π-anion electrostatic interaction, nine hydrophobic interactions (six π- πstacked, one π-πT shaped, two π-alkyl) with a binding energy of -10.6 kcal/mol. Compound 7q forms two conventional hydrogen bonds (GLN63: H–O1; TYR151: OH–O4), one C-H bond, one π-anion electrostatic interaction, eleven hydrophobic interactions (six π-πstacked, two π-π T shaped, three π-alkyl) with a binding energy of -10.3 kcal/mol. However, the standard drug acarbose forms 18 conventional hydrogen bonds, three π- donar hydrogen bond interactions, one hydrophobic π-alkyl interaction with a binding energy of -9.9 kcal/mol. This implies that the molecules docked, despite their difference in biological activity, have shown good results with respect to the standard drug. In addition, compounds 7i, 7j, 7l and 7r also showed good interaction comparable to the standard drug acarbose. Compound 7i forms two conventional hydrogen bonds (GLN63: H–O1; TYR151: OH–O4), one π-anion electrostatic interaction, ten hydrophobic interactions (one π-sigma, four π-π stacked, one π-π T shaped, four with π-alkyl) with a binding energy of - 9.8 kcal/mol similarly, compound 7j forms two conventional hydrogen bonds (GLN63: H–O1; TYR151: OH–O4), one π-anion electrostatic interaction, eleven hydrophobic interactions (five π-π stacked, one π-π T shaped, five with π-alkyl) with a binding energy of -9.8 kcal/mol, while compound 7l forms two conventional hydrogen bonds (GLN63: H–O1; TYR151: OH–O4), two C-H bonds, one π-anion electrostatic interaction, nine hydrophobic interactions (four π-π stacked, one π-π T shaped, two π-alkyl and one π-donar hydrogen bond) with a binding energy of -9.9 kcal/mol. Compound 7r forms two conventional hydrogen bonds (GLN63: H–O1; TYR151: OH–O4), one π-donar interaction, one π-sigma interaction, eleven hydrophobic interactions (two π-π stacked, one π-π T shaped, five with π- alkyl) with a binding energy of -9.8 kcal/mol whereas compounds 7m, 7n, 7o, 7p, 7s, and 7t showed less interaction compared to standard drugs. Compound 7m forms two conventional hydrogen bonds (GLN63: H–O1; TYR151: OH–O4), one C-H bonds, one π-anion electrostatic interaction, eleven hydrophobic interactions (four π-π stacked, two π-π T shaped, four with π-alkyl) with binding energy of -9.5 kcal/mol. Although compound 7n forms two conventional hydrogen bonds (GLN63: H–O1; TYR151: OH–O4), one C-H bond, two π- anion electrostatic interactions, one π-donor hydrogen bond interaction, eleven hydrophobic interactions (three π-sigma bonds, two π-π stacked, two π-π T shaped, four with π-alkyl) with binding energy of -9.5 kcal/mol. Compound 7o forms one conventional hydrogen bond (GLN63: H–O1; TYR151: OH–O4), one C-H bonds, one π-anion electrostatic interaction, nine hydrophobic interactions (three π-sigma bonds, four π-π stacked, one π-π T shaped, four π-alkyl) with binding energy of -9.4 kcal/mol. Similarly, compound 7p forms two conventional hydrogen bonds (GLN63: H–O1; TYR151: OH–O4), one C-H bonds, one π-anion electrostatic interaction, ten hydrophobic interactions (three π-sigma bonds, four π-π stacked, two π-π T shaped, four π-alkyl) with binding energy of -9.4 kcal/mol. Compound 7s forms two conventional hydrogen bonds (GLN63: H–O1; TYR151: OH–O4), one C-H bond, one π-anion electrostatic interaction, eleven hydrophobic interactions (five π-π stacked, two π-π T shaped, four π-alkyl) with a binding energy of -9.1 kcal/mol. Compound 7t forms two conventional hydrogen bonds (GLN63: H–O1; TYR151: OH–O4), one π-anion interaction, one π-sigma interaction, and four hydrophobic interactions (three π-π stacked, one with π-alkyl) with a binding energy of - 9.0 kcal/mol. These studies might be initiated to promote the development of the most potent drug molecule against targeting α-amylase and α-glucosidase. As depicted in Figure 4, all synthesized compounds were properly placed in the active site pocket of the α-amylase protein, showing more than ten strong contacts with excellent binding energy compared to the drug acarbose. 4. Structure activity relationship studies Observing the antihyperglycemic data (Tables 2 and 3), it can be seen that the keto derivatives (7i-n) are more potent molecules than the aldehydic derivatives (7o-t) molecular hybrids. However, it is clearly proven that substitution in the coumarin ring has a substantial effect on the α-amylase and α- glucosidase activity, 6-methyl (7i,o), methoxy substitution (7m, s) has decreased the potency, while substitution of 7-methyl (7j, p), dimethyl (7n, t) and benzo (7k, l, q, r) substitution have proved to be necessary for good. When comparing antidiabetic and anti-inflammatory activity with respect to aldehydic 7o-t and keto substitution, it was clear that keto 7i-n has a strong antidiabetic tendency whereas aldehydic derivatives have shown a strong anti- inflammatory effect (Table 4). Furthermore, the substitution of 6-methyl (7o,p), (7q,r) benzo in the coumarin ring has resulted Barangi et al. / European Journal of Chemistry 15 (3) (2024) 205-219 213 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.3.205-219.2541 Table 5. Details of the best possible interaction of compound 7i-t, newly synthesized compounds, and acarbose (Ac) with the enzyme human pancreatic α- amylase (1B2Y). Inhibitor Binding energy (kcal/ mol) Interactions Distance (Å) Bonding Types of bonding 7i -9.8 (GLN63) H – O1 2.28632 Hydrogen Conventional (TYR151) OH – O4 3.36470 Hydrogen Conventional (ASP300) O – π (N1-C12) 3.39924 Pi-Anion Electrostatic (LEU162) C – π (C14-C19) 3.93218 Pi-Sigma Hydrophobic π (TRP59) – π (C1-C6) 3.87733 Pi-Pi Stacked Hydrophobic π (TRP59) – π (C4-O1) 4.93615 Pi-Pi Stacked Hydrophobic π (TRP59) – π (C1-C6) 3.81425 Pi-Pi Stacked Hydrophobic π (TRP59) – π (C4-O1) 5.03580 Pi-Pi Stacked Hydrophobic π (N1-C12) – π (TYR62) 4.91665 Pi-Pi T-shaped Hydrophobic π (TRP59) – C22 4.01571 Pi-Alkyl Hydrophobic π (TRP59) – C22 4.47553 Pi-Alkyl Hydrophobic π (HIS305) – C22 4.95912 Pi-Alkyl Hydrophobic π (C14-C19) – (ALA198) 5.14104 Pi-Alkyl Hydrophobic 7j -9.8 (GLN63) H – O1 2.28129 Hydrogen Conventional (TYR151) H – O4 2.28352 Hydrogen Conventional (ASP300) O – π (N1-C12) 3.44223 Electrostatic Pi-Anion π (TRP59) – C22 3.89332 Hydrophobic Pi-Pi Stacked π (TRP59) – π (C1-C6) 4.86930 Hydrophobic Pi-Pi Stacked π (TRP59) – π (C1-C6) 3.79364 Hydrophobic Pi-Pi Stacked π (TRP59) – π (C4-O1) 4.94750 Hydrophobic Pi-Pi Stacked π (N1-C12) – π (TRP58) 5.10755 Hydrophobic Pi-Pi Stacked π (N1-C12) – π (TYR62) 4.92972 Hydrophobic Pi-Pi T-shaped π (TRP59) – C10 4.07646 Hydrophobic Pi-Alkyl π (TRP59) – C22 4.48723 Hydrophobic Pi-Alkyl π (HIS305) – C22 5.06349 Hydrophobic Pi-Alkyl π (C14-C19) – (LEU162) 4.56941 Hydrophobic Pi-Alkyl π (C14-C19) – (ALA198) 5.11186 Hydrophobic Pi-Alkyl 7k -10.6 (GLN63) H – O1 2.40121 Hydrogen Conventional (LYS200) H – O4 3.00452 Hydrogen Conventional (LYS200) H – O3 2.85598 Hydrogen Conventional C13 – H (GLU233) 3.55294 Carbon Hydrogen C H Bond (ASP300) – π (N1-C12) 3.50353 Electrostatic Pi-Anion (TRP59) – π (C2-C25) 3.86331 Hydrophobic Pi-Pi Stacked (TRP59) – π (N1-C12) 4.54653 Hydrophobic Pi-Pi Stacked (TRP59) – π (C2-C25) 5.06708 Hydrophobic Pi-Pi Stacked (TRP59) – π (C2-C25) 4.11828 Hydrophobic Pi-Pi Stacked (TRP59) – π (C4-O1) 3.67030 Hydrophobic Pi-Pi Stacked (TRP59) – π (N1-C12) 5.27908 Hydrophobic Pi-Pi Stacked (HIS201) – π (C14-C19) 4.91165 Hydrophobic Pi-Pi T-shaped π (C14-C19) – (LEU162) 4.80230 Hydrophobic Pi-Alkyl π (C14-C19) – (ALA198) 5.05869 Hydrophobic Pi-Alkyl 7l -9.9 (LYS200) H – O4 2.65835 Hydrogen Conventional (ILE235) H – O4 2.49055 Hydrogen Conventional (GLY306) H – N3 2.59004 Carbon Hydrogen C H Bond C10 – H(ASP300) 3.60089 Carbon Hydrogen C H Bond (HIS305) H – π (N1-C12) 3.18329 Hydrogen Pi-Donor Hydrogen Bond π (TRP59) – π (C1-C25) 5.60961 Hydrophobic Pi-Pi Stacked π (TRP59) – π (C1-C6) 4.04262 Hydrophobic Pi-Pi Stacked π (TRP59) – π (C1-C25) 5.83991 Hydrophobic Pi-Pi Stacked π (TRP59) – π (C1-C6) 4.28353 Hydrophobic Pi-Pi Stacked π (HIS201) – π (C14-C19) 4.79521 Hydrophobic Pi-Pi T-shaped π (C1-C6) – (LEU165) 5.30003 Hydrophobic Pi-Alkyl π (C14-C19) – (LEU162) 4.80556 Hydrophobic Pi-Alkyl π (C14-C19) – (ILE235) 5.39262 Hydrophobic Pi-Alkyl 7m -9.5 (GLN63) H – O1 2.35929 Hydrogen Conventional (TYR151) H – O4 2.27798 Hydrogen Conventional (HIS305) H – O3 2.68643 Carbon Hydrogen C H Bond (ASP300) O – π (N1-C12) 3.39505 Electrostatic Pi-Anion π (TRP59) – π (C4-O1) 3.86449 Hydrophobic Pi-Pi Stacked π (TRP59) – π (C1-C6) 4.96672 Hydrophobic Pi-Pi Stacked π (TRP59) – π (N1-C12) 3.90701 Hydrophobic Pi-Pi Stacked π (TRP59) – π (C4-O1) 5.12486 Hydrophobic Pi-Pi Stacked π (HIS201) – π (C14-C19) 5.08556 Hydrophobic Pi-Pi T-shaped π (N1-C12) – π (TYR62) 4.86631 Hydrophobic Pi-Pi T-shaped π (TRP59) – C22 4.22427 Hydrophobic Pi-Alkyl π (TRP59) – C22 4.46808 Hydrophobic Pi-Alkyl π (C14-C19) – (LEU162) 4.61837 Hydrophobic Pi-Alkyl π (C14-C19) – (ALA198) 5.04773 Hydrophobic Pi-Alkyl 7n -9.5 (GLN63) – O4 2.39519 Hydrogen Conventional (THR163) – O2 2.36131 Hydrogen Conventional C12 – (ASP300) 3.75949 Carbon Hydrogen C H Bond (ASP197) O – π (N1-C12) 3.70862 Electrostatic Pi-Anion (GLU233) O – π (N1-C12) 4.33018 Electrostatic Pi-Anion (TYR151) H – π (C1-C6) 3.02542 Hydrogen Pi-Donor Hydrogen Bond (LEU162) H – π (C4-O1) 2.39213 Hydrophobic Pi-Sigma C21 – π (TRP59) 3.90543 Hydrophobic Pi-Sigma C13 – π (TRP59) 3.70491 Hydrophobic Pi-Sigma π (TRP59) – π (C14-C19) 5.08035 Hydrophobic Pi-Pi Stacked π (TYR151) – π (C1-C6) 5.54510 Hydrophobic Pi-Pi Stacked 214 Barangi et al. / European Journal of Chemistry 15 (3) (2024) 205-219 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.3.205-219.2541 Table 5. (Continued). Inhibitor Binding energy (kcal/ mol) Interactions Distance (Å) Bonding Types of bonding 7n -9.5 π (HIS201) – π (C1-C6) 4.99780 Hydrophobic Pi-Pi T-shaped π (N1-C12) – π (TYR62) 5.60432 Hydrophobic Pi-Pi T-shaped π (TYR151) – C23 4.01717 Hydrophobic Pi-Alkyl π (N1-C12)– (ALA198) 4.85305 Hydrophobic Pi-Alkyl π (C4-O1) – (LEU162) 5.47430 Hydrophobic Pi-Alkyl π (C4-O1) – (ILE235) 5.02353 Hydrophobic Pi-Alkyl 7o -9.4 (GLN63) H – O1 2.31575 Hydrogen Conventional (ASP300) O – π (N1-C12) 3.38018 Electrostatic Pi-Anion (TRP59) – π (C4-O1) 3.90422 Hydrophobic Pi-Pi Stacked (TRP59) – π (C1-C6) 5.01531 Hydrophobic Pi-Pi Stacked (TRP59) – π (C4-O1) 3.85749 Hydrophobic Pi-Pi Stacked (TRP59 – π (C1-C6) 5.13778 Hydrophobic Pi-Pi Stacked π (N1-C12) – (TYR62) 4.95463 Hydrophobic Pi-Pi T-shaped π (TRP59) – C21 3.96179 Hydrophobic Pi-Alkyl π (TRP59) – C10 4.42755 Hydrophobic Pi-Alkyl π (HIS305) – C21 4.94644 Hydrophobic Pi-Alkyl π (C14-C19) – C (ILE235) 5.16866 Hydrophobic Pi-Alkyl 7p -9.4 (GLN63) H – O1 2.33823 Hydrogen Conventional (LYS200) H – O4 2.75495 Hydrogen Conventional C13 – (ASP197) 3.79620 Carbon Hydrogen C H Bond (ASP300) O – π (N1-C12) 3.44066 Electrostatic Pi-Anion (TRP59) – π (C4-O1) 3.89214 Hydrophobic Pi-Pi Stacked (TRP59) – π (C1-C6) 4.92557 Hydrophobic Pi-Pi Stacked (TRP59) – π (C4-O1) 3.91536 Hydrophobic Pi-Pi Stacked (TRP59) – π (C4-O1) 5.07707 Hydrophobic Pi-Pi Stacked (HIS201) – π (C14-C19) 4.99984 Hydrophobic Pi-Pi T-shaped π (C14-C19) – (TYR62) 4.86139 Hydrophobic Pi-Pi T-shaped (TRP59) – C21 4.81070 Hydrophobic Pi-Alkyl (TRP59) – C2 3.93727 Hydrophobic Pi-Alkyl π (C14-C19) – (LEU162) 4.64906 Hydrophobic Pi-Alkyl π (C14-C19) – (ALA198) 5.00874 Hydrophobic Pi-Alkyl 7q -10.3 (GLN63) H – O1 2.41250 Hydrogen Conventional (LYS200) H – O4 2.84496 Hydrogen Conventional C13 – (GLU233) 3.49525 Carbon Hydrogen C H Bond π (ASP300) – π (N1-C12) 3.46588 Electrostatic Pi-Anion π (TRP59) – π (C1-C6) 3.88158 Hydrophobic Pi-Pi Stacked π (TRP59) – π (C4-O1) 4.55721 Hydrophobic Pi-Pi Stacked π (TRP59) – π (C1-C25) 5.06047 Hydrophobic Pi-Pi Stacked π (TRP59) – π (C4-O1) 4.13392 Hydrophobic Pi-Pi Stacked π (TRP59) – π (C1-C6) 3.67432 Hydrophobic Pi-Pi Stacked π (TRP59) – π (C1-C25) 5.28316 Hydrophobic Pi-Pi Stacked π (HIS201) – π (C14-C19) 4.83253 Hydrophobic Pi-Pi T-shaped π (N1-C12) – (TYR62) 4.80416 Hydrophobic Pi-Pi T-shaped π (C14-C19) – (LEU162) 4.99288 Hydrophobic Pi-Alkyl π (C14-C19) – (ALA198) 5.09360 Hydrophobic Pi-Alkyl π (C14-C19) – (ILE235) 5.25722 Hydrophobic Pi-Alkyl 7r -9.8 (THR163) H – C12 2.80093 Carbon Hydrogen C H Bond C20 – (HIS299) 3.38207 Carbon Hydrogen C H Bond (TYR151) – π (C1-C25) 2.76766 Hydrogen Pi-Donor (ILE235) – π (C1-C6) 2.61306 Hydrophobic Pi-Sigma (TYR62) – π (C14-C19) 4.23699 Hydrophobic Pi-Pi Stacked (TYR151) – π (C1-C25) 4.68755 Hydrophobic Pi-Pi Stacked (HIS201) – π (C1-C6) 4.63528 Hydrophobic Pi-Pi T-shaped π (C1-C6) – (LYS200) 5.37394 Hydrophobic Pi-Alkyl π (C1-C6) – (ILE235) 5.43290 Hydrophobic Pi-Alkyl π (C4-O1) – (LEU162) 4.71975 Hydrophobic Pi-Alkyl π (C4-O1) – (ALA198) 4.87821 Hydrophobic Pi-Alkyl π (C14-C19) – (LEU162) 4.83850 Hydrophobic Pi-Alkyl 7s -9.1 (GLN63) H – O1 2.34111 Hydrogen Conventional (TYR151) H – O4 2.45881 Hydrogen Conventional (HIS305) H – C21 2.76795 Hydrogen C H Bond π (ASP300) – π (N1-C12) 3.40185 Electrostatic Pi-Anion π (TRP59) – π (C1-C6) 3.85899 Hydrophobic Pi-Pi Stacked π (TRP59) – π (C4-O1) 4.95810 Hydrophobic Pi-Pi Stacked π (TRP59) – π (C1-C6) 3.86331 Hydrophobic Pi-Pi Stacked π (TRP59) – π (C4-O1) 5.09627 Hydrophobic Pi-Pi Stacked π (N1-C12) – π (TRP58) 5.29984 Hydrophobic Pi-Pi Stacked π (HIS201) – π (C14-C19) 4.99122 Hydrophobic Pi-Pi T-shaped π (N1-C12) – π (TYR62) 4.97009 Hydrophobic Pi-Pi T-shaped π (TRP59) – C21 4.44170 Hydrophobic Pi-Alkyl π (TRP59) – C21 4.59693 Hydrophobic Pi-Alkyl π (C14-C19) – (LEU162) 4.84764 Hydrophobic Pi-Alkyl π (C14-C19) – (ALA198 4.95460 Hydrophobic Pi-Alkyl 7t -9.0 (GLN63) H – O4 2.19103 Hydrogen Conventional (THR163) H – O2 2.69678 Hydrogen Conventional (GLU233) O – π (N1-C12) 4.01980 Electrostatic Pi-Anion C22 – π (TYR151) 3.78505 Hydrophobic Pi-Sigma π (TYR62) – π (C14-C19) 4.87241 Hydrophobic Pi-Pi Stacked π (TYR151 – π (C1-C6) 4.18966 Hydrophobic Pi-Pi Stacked π (TYR151 – π (C4-O1) 5.63588 Hydrophobic Pi-Pi Stacked π (C4-O1) – (LEU162) 5.20264 Hydrophobic Pi-Alkyl Barangi et al. / European Journal of Chemistry 15 (3) (2024) 205-219 215 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.3.205-219.2541 Table 5. (Continued). Inhibitor Binding energy (kcal/ mol) Interactions Distance (Å) Bonding Types of bonding Acarbose -9.9 (GLN63) – O6 2.92098 Hydrogen Conventional (GLN63) – O5 2.96298 Hydrogen Conventional (ARG195) – O2 2.77415 Hydrogen Conventional (LYS200) – O2 2.45335 Hydrogen Conventional (LYS200) – O3 2.87745 Hydrogen Conventional (HIS305) – O2 2.95637 Hydrogen Conventional O2 – (GLU240) 3.19011 Hydrogen Conventional O2 – (HIS20) 2.63086 Hydrogen Conventional O3 – (GLU233) 2.75598 Hydrogen Conventional N4 – (GLU233) 2.92776 Hydrogen Conventional O2 – (GLU233) 3.32628 Hydrogen Conventional O2 – (ASP300) 2.66732 Hydrogen Conventional O3 – (HIS299) 2.70233 Hydrogen Conventional O6 – (ASP197) 2.83914 Hydrogen Conventional O6 – (TRP59) 2.51729 Hydrogen Conventional O4 – (THR163) 3.10358 Hydrogen Conventional O3 – (TYR62) 3.50463 Hydrogen Pi-Donor O2 – (TRP59) 3.84471 Hydrogen Pi-Donor O2 – (TRP59) 3.67806 Hydrogen Pi-Donor C6 – (LEU165) 4.31121 Hydrophobic Alkyl Figure 3. 3D interactions of the best binding modes with the least binding energy of newly synthesized compounds 7i-t at the active site pocket of the enzyme human pancreatic α-amylase (1B2Y). 216 Barangi et al. / European Journal of Chemistry 15 (3) (2024) 205-219 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.3.205-219.2541 Figure 4. 2D diagram showing the interactions of the best binding modes of newly synthesized compounds 7(i-t) at the active site of the enzyme human pancreatic α-amylase (1B2Y). 7i-t O O N N N O R O R' Coumarin backbone highly biologically active scaffold Bridging junction Triazole moiety Improves the potency Arylcarbonyl group enhnace the activity Figure 5. Representation of structure-activity relationship of synthesized compounds for biological activity. Barangi et al. / European Journal of Chemistry 15 (3) (2024) 205-219 217 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.3.205-219.2541 in enhanced anti-inflammatory behaviour compared to the substitution of methoxy 7s and dimethyl 7t in keto derivatives. Overall, it can be concluded that 7o, p, q, r was shown to be more effective anti-inflammatory activity by showing lower IC50 values than the standard drug diclofenac. The relevance of coumarin, traizole and arylcarbonyl moieties in the synthesised compounds for α-amylase inhi- bition has been well validated by docking studies, which have revealed numerous strong interactions inside the active site of the amylase protein. The coumarin moiety's ring oxygen formed strong hydrogen bonds with the GLN 63 residue, but the aromatic ring exhibited π-π stacking interactions with TRP 59 residue. The methyl, methoxy and benzo substitutions on coumarin resulted in additional π-alkyl, hydrogen, and pi-pi stacked interactions, respectively. The triazole moiety exhibited π-anion electrostatic contact with ASP 300, π-π T- shaped interaction with TYR 62, and additional scattering interactions that improved Trp 59. The superior activity of keto derivatives is supported by a strong hydrogen bonding of the keto group with protein residues TYR 151, which are absent in their respective aldehydic counterparts. General observation of the structure-activity relationship of the synthesized com- pounds as depicted (Figure 5). 5. Conclusions In summary, a series of novel 1,2,3-(triazol-4-yl)-2H- chromen-2-ones were synthesized and characterized using contemporary spectroscopic approaches. Furthermore, compared to the IC50 value of the standard drug acarbose, all compounds synthesized have shown an outstanding in vitro antihyperglycemic action with two to five times higher IC50 values in α-amylase and α-glucosidase inhibition assays compared to standard acarbose. Among the synthesized hybrids, compound 7l exhibited an outstanding α-amylase and α-glucosidase inhibitory potential, with IC50 values of 0.67±0.014 mg/mL and 0.72±0.012 mg/mL in addition to that compound 7o has exhibited the best anti-inflammatory activity with IC50 values of 0.54±0.003 mg/mL. Furthermore, molecular docking studies have substantiated the presence of strong molecular interaction synthesising hybrids with binding sites of human pancreatic α-amylase (PDB ID: 1B2Y) than that of a conventional ligand acarbose with an effective binding energy of -9.0 to -10.6 kcal/mol. Our novel effort to incorporate aromatic carbonyl in the coumarin-triazole scaffold has resulted in better antidiabetic potency compared to the existing library of coumarin derivatives in the literature. Since the synthesized compound 7l has shown excellent antihyper- glycemic activity, it can be evaluated for use as a lead drug in an antidiabetic drug development program. Acknowledgements One of the authors, Vinayaka Chandrappa Barangi, acknowledges the University’s Grant Commission for providing Council of Scientific and Industrial Research-University Grant Commission (CSIR-UGC) fellowship (Ref. No.: 151674 Roll. No. DEC: 2018-2019). The authors also thank the University Scientific Instrumentation centre (USIC) and the Sophisticated Analytical Instrument Facilities-Department of Science and Technology (SAIF-DST) of Karnatak University, Dharwad, India for spectral analyses. The authors also thank Karnatak University, Dharwad, India for financial support as seed grant for the research program. Disclosure statement Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: All ethical guidelines have been adhered. Sample availability: Samples of the compounds are available from the author. CRediT authorship contribution statement Conceptualization: Lokesh Anand Shastri, Vinayaka Chandrappa Barangi; Methodology: Vinayaka Chandrappa Barangi; Software: Nagarjuna Prakash Dalbanjan; Validation: Vinay Sunagar; Formal Analysis: Delicia Avilla Barretto; Investigation: Lokesh Anand Shastri; Resources: Rohini Sangappanavar, Karhik Inamdar; Data Curation: Prakasha Kothathi Chowdegowda; Writing - Original Draft: Vinayaka Chandrappa Barangi; Writing - Review and Editing: Lokesh Anand Shastri; Visualization: Prakasha Kothathi Chowdegowda; Supervision: Lokesh Anand Shastri. ORCID and Email Vinayaka Chandrappa Barangi vcbarangi41@gmail.com https://orcid.org/0009-0004-9918-0570 Lokesh Anand Shastri drlashastri@kud.ac.in https://orcid.org/0000-0002-5672-8442 Prakasha Kothathi Chowdegowda dr.kcprakash@gmail.com https://orcid.org/0000-0003-4888-4434 Rohini Sangappanavar rbsangappanavar@gmail.com https://orcid.org/0009-0008-2170-4038 Karthik Inamdar karthikrinamdar151947@gmail.com https://orcid.org/0009-0004-9947-136X Nagarjuna Prakash Dalbanjan dnp.biochem@gmail.com https://orcid.org/0000-0003-1053-6610 Delicia Avillia Barretto delicia@unigoa.ac.in https://orcid.org/0000-0001-9122-0663 Vinay Sunagar vinaysunagar@gssbgm.edu.in https://orcid.org/0000-0001-9804-7330 References [1]. Soni, R.; Durgapal, S. D.; Soman, S. S.; Georrge, J. J. Design, synthesis and anti-diabetic activity of chromen-2-one derivatives. Arab. J. Chem. 2019, 12, 701–708. [2]. Powell, H. C.; Mizisin, A. P. Diabetic neuropathy. In Encyclopedia of Neuroscience; Elsevier, 2009; pp. 511–516. 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The full terms of this license are available at https://www.eurjchem.com/index.php/eurjchem/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution, or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (https://www.eurjchem.com/index.php/eurjchem/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). https://www.eurjchem.com/index.php/eurjchem/terms http://creativecommons.org/licenses/by-nc/4.0 https://www.eurjchem.com/index.php/eurjchem/terms 1. Introduction 2. Experimental 2.1. Material and methods 2.2. General synthetic procedure 2.2.1. Synthesis of terminal alkynes, 2a,b 2.2.2. Preparation of 4-(azidomethyl)-2H-chromen-2-ones, 6c-h 2.2.3. Synthesis of 1,2,3-triazolyl-methyl-2H-chromen-2-ones, 7i-t 2.3. Experimental method for biological evaluation 2.3.1. In vitro α-amylase inhibition assay 2.3.2. In vitro α-glucosidase inhibition assay 2.3.3. In vitro anti-inflammatory activity by denaturation of bovine serum albumin method 2.4. Molecular docking 3. Results and discussion 3.1. Chemistry 3.2. Biological studies 3.2.1. Inhibition of α-amylase activity 3.2.2. In vitro α-glucosidase inhibition activity 3.2.3. In vitro anti-inflammatory activity 3.3. Computational studies 3.3.1. Molecular docking studies 4. Structure activity relationship studies 5. Conclusions Acknowledgements Disclosure statement CRediT authorship contribution statement ORCID and Email References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField16: PrintField17: PrintField18: PrintField19: PrintField110: PrintField111: PrintField112: PrintField113: PrintField114: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: PrintField26: PrintField27: PrintField28: PrintField29: PrintField210: PrintField211: PrintField212: PrintField213: PrintField214: