Coumarin Derivatives as Emerging Antidiabetic Agents: A Review of Synthetic Approaches and Biological Evaluation

The coumarin structure, also known as benzo-α-pyrone, is a naturally occurring chemical configuration that features a benzene ring fused with an α-pyrone ring. This arrangement is crucial in drug development because of its advantageous pharmacological characteristics. It creates a cyclic ester by joining a benzene ring with a lactone ring. The molecular formula is C₉H₆O₂. This structure acts as the foundational framework for a wide range of both natural and synthetic compounds[1].

The coumarin structure can be illustrated as a benzene ring where two adjacent hydrogen atoms are replaced by an unsaturated lactone ring, represented as −(CH)=(CH)−(C=O) −O−, categorized as a benzopyrone and falls under class of lactone group. This modification forms an additional six- membered heterocycle that shares two carbon atoms with the original benzene ring. Many natural and synthetic drugs incorporating the coumarin structure are well-known in medical practice[2]For example, hymecromone (4-methylumbelliferone) has been used to treat cholera and spasms. Scopoletin (6-methoxy-7-hydroxycoumarin), derived from various plant species, possesses antioxidant,  hepatoprotective,  anti-inflammatory,  and antifungal  properties[3]. Coumarin, initially identified in tonka beans (Dipteryx odoranta) in 1820, was also known by its French moniker, Coumarou. These substances are naturally occurring and are part of the 1,2- benzopyrone or 2H-1-benzopyran-2-one class of benzopyrones. The richest sources of coumarins include fruits like Bael fruits (Aegle marmelos)[4], Tetrapleura tetraptera TAUB (Mimosaceae)[5], bilberry, and cloudberry, as well as seeds such as tonka beans (Calophyllum cerasiferum Vesque and Calophyllum inophyllum Linn) [6], roots (Ferulago campestris) [7], leaves (Murraya paniculata) [8], Phellodendron amurense var. wilsonii [9], and in green tea and other items like chicory. They are also present in certain essential oils, including cinnamon bark oil [10], cassia oil [11], and lavender oil [8]. These compounds have been found in a diverse array of plant families [12]. To date, over 1,000 naturally occurring coumarin derivatives have been identified and systematically cataloged, highlighting their remarkable structural diversity and widespread occurrence in the plant kingdom [13]

Recent studies have shown the many biological functions of coumarins and their derivatives. These compounds have demonstrated significant promise in a variety of therapeutic domains, including anticancer [14], antibacterial [15], [16], anti-inflammatory [16], antiviral [17], anticonvulsant [18], antifungal [19], anticoagulant [20], antihyperglycemic [21], and antitubercular [22] properties. Their diverse bioactivity makes them interesting candidates for drug research and medical uses.

STRUCTURED DIVERSITY AND CLASSIFICATION

Coumarins can be classified broadly based on changes in their chemical structure, particularly substitutions and ring fusions on the benzopyran-2-one (chromen-2-one) core. Key subclasses include:

• Simple Coumarins: There are no extra ring systems; biological activity is commonly controlled by hydroxyl or methoxy groups.
• Furanocoumarins: containing a fused furan ring at positions 6, 7, or 8, have phototoxic and therapeutic applications.
• Pyranocoumarins: which include a fused pyran ring, have antibacterial characteristics.
• Phenylcoumarins and bis-coumarins: with phenyl substitutions or two connected coumarin moieties, have increased bioactivity.[23]

DIABETES MELLITUS: A THERAPEUTIC TARGET FOR COUMARINS

Diabetes mellitus (DM) is a global disease that affects more than 400 million people. T2DM, characterized by insulin resistance and β-cell dysfunction, is the most common kind [24]. Biguanides, thiazolidinediones, GLP-1 agonists, DPP-4 inhibitors, and SGLT2 inhibitors are among the currently available treatment medicines. However, constraints such as side effects and therapeutic resistance have prompted the quest for alternate pharmacological scaffolds [25]. Long-acting GLP-1 analogs (semaglutide, dulaglutide), dual PPARα/γ agonists (saroglitazar), advanced DPP-4 inhibitors (teneligliptin), and fixed-dose combinations have shown significant clinical promise in improving glycemic control while addressing cardiovascular risks [26]. Coumarin derivatives, which can influence carbohydrate-metabolizing enzymes and oxidative stress pathways, are emerging as promising options for antidiabetic medication development.

Synthetic Coumarin Derivatives As An Anti-Diabetic Agent

Coumarin-based compounds are being studied for their possible antidiabetic properties, specifically as inhibitors of α-amylase, α-glucosidase, and DPP-4. The following is a summary of notable findings:

Savankumar et al. (2024) synthesized a novel series of 2 -amino-7-(bis(2-hydroxyethyl)amino)-4H- chromene-3-carbonitrile derivatives and investigated their α-amylase inhibitory efficacy. Compound 1 had the strongest α-amylase inhibition, with an IC?? value of 3.60 ± 0.01 µg/mL. Molecular docking investigations validated these findings, revealing strong binding interactions with α-amylase residues including Ala145, Asp180, Phe181, and Arg183 [27].

Baccari W et al. (2024) synthesized arylidene-based sesquiterpene coumarins from coladonin and tested their inhibitory effect against α-amylase. Compound 2 had the strongest α-amylase inhibition (IC50=7.24 µM), outperforming the conventional acarbose (IC50=9.83 µM) [28].

El Behery et al. (2023) synthesized 8-methoxy-1-azacoumarin-3-carboxamide derivatives and evaluated their anti-diabetic potential through inhibition assay against α-glucosidase, α- amylase, and DPP-4 enzymes. Compound 3 showed the most potent activity, with IC50 values of 30.50 ± 2.67 µM for α-glucosidase and 19.98 ± 3.24 µM for α-amylase [29].

Patnagar et al. (2023) synthesized a variety of 8-benzimidazolyl coumarin-3-carboxamide derivatives and investigated their antioxidant and α-amylase inhibitory activities, targeting oxidative stress and type 2 diabetes. Compound 4a inhibited α-amylase the most, with an IC50 of 67.52 µM, outperforming the conventional metformin (IC50=54.13). Compound 4b exhibited the highest DPPH radical scavenging activity (IC50=89.67 µM) [30].

Khouzani et al. (2023) developed a new series of N-aryl-2-(4-((2-oxo-2H-chromen-4- yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)acetamide derivatives and tested their α-glucosidase inhibitory action for type 2 diabetes. Compound 5 had the highest α-glucosidase inhibition, with an IC50 of 3.5 ± 0.1 µM, exceeding the reference medication Acarbose (IC50=7.52 ± 2.0) [31]

Chun-Mei et al. (2022) created a series of coumarin-chalcone derivatives, with Compound 6 showing the strongest α-glucosidase inhibition (IC50=24.09). Molecular docking demonstrated 3t's significant binding contacts with important α-glucosidase residues, including Thr310, Arg315, Phe303, Asp307, and Asn350 [32].

Rina Soni et al. (2019) developed a series of 3,7-disubstituted chromen-2-one derivatives and investigated their DPP-4 inhibitory efficacy. Compound 7 displayed the strongest DPP-4 inhibition, showing 84.5% inhibition at 100 µM. Molecular docking investigations validated these findings, indicating strong binding interactions with critical DPP-IV residues such as Lys122, Gln123, and Tyr238, which are similar to the binding profile of the standard medication Vildagliptin [33].

Kenchappa R. et al. (2017) synthesized a series of 6-substituted-3-(1-(4-substituted).-4-((Z)- (5,6-dimethoxy-1-oxo-1H-inden-2(3H)-ylidene)methyl)-1H-pyrazol-3-yl)-2H-chromen-2- one derivatives were investigated for antioxidant and antihyperglycemic properties. Compound 8a exhibited the highest antioxidant activity, with a DPPH IC50 of 54.14 µg/mL, comparable to the standard BHT (IC50=46.95 µg/mL) [34].

Ghorbani H et al. created a series of coumarin-fused 4H-pyran derivatives (6a-o), with Compound 9 showing the strongest α-glucosidase inhibition (IC?? = 30.0 ± 0.5 µM), surpassing acarbose (IC?? = 750.0 µM). Furthermore, kinetic studies confirmed a competitive inhibition mechanism, while molecular docking and molecular dynamics simulations validated its strong and stable binding interactions with key enzyme residues (Asp214, Glu276, Asp349, Phe157, and Tyr344), highlighting its potential as an anti-diabetic agent [35].

Thabet et al. produced a series of 6-sulfonamide-2H-chromene derivatives (2-9), with Compound 10a exhibiting the strongest α-amylase inhibition (IC?? = 1.08 ± 0.02 mM), compared to Acarbose (IC?? = 0.43 ± 0.01 mM). Compound 10b inhibited α-glucosidase more effectively than Acarbose (IC?? = 0.604 ± 0.02 mg/mL). Molecular docking experiments revealed their high binding affinities with α-amylase, α-glucosidase, and PPAR-γ enzymes, indicating their anti-diabetic potential. Furthermore, in silico ADMET calculations showed high oral bioavailability, drug-likeness, and a low toxicity profile [36].

Umadevi et al. developed a range of coumarin derivatives and Ru(II) complexes with pyrazole rings as possible anti-diabetic drugs. The (CumAP)?Ru(II) complex had the highest anti- diabetic effect, considerably lowering blood glucose levels to 131.12 mg/dL, compared to the diabetic group (180.46 mg/dL). Compound 11 had the highest α-amylase inhibition (IC?? = 1.08 ± 0.02 mM) compared to Acarbose (IC?? = 0.43 ± 0.01 mM). It also showed considerable inhibition of α-glucosidase (IC?? = 2.44 ± 0.09 mg/mL) [37].

Basappa et al. produced a series of coumarin-triazole hybrids (8a-e). Compound 12a displayed the strongest α-amylase inhibition with an IC?? value of 5.43 µM, followed by Compound 12b (IC?? = 5.98 µM). Molecular docking investigations revealed substantial interactions with α-amylase (PDB ID: 4W93) and angiotensin-converting enzyme (ACE, PDB ID: 1O86), with docking scores of -3.42 kcal/mol and -5.60 kcal/mol, respectively [38].

Pan Y. et al. synthesized and studied coumarin compounds with anti-diabetic potential, focusing on α-glucosidase inhibition, AGE-RAGE pathway regulation, and oxidative stress reduction. Compound 13 (3-(4′-benzoylamino-phenyl) coumarin derivative) had the strongest α-glucosidase inhibition (IC?? < 65 μM). Molecular docking studies show strong binding interactions with α-glucosidase, indicating its potential as a treatment agent for diabetes [39].

Sahu et al. used molecular docking and molecular dynamics (MD) modeling to manufacture and screen 108 plant-derived coumarin derivatives for anti-diabetic properties. Compound 14 (Sanandajin) had the highest binding affinity (-12.7 kcal/mol) with AKT1, outperforming common medicines such as glimepiride and resveratrol [40].

Syeda et al. produced coumarin-based thiosemicarbazones (3a-3m), with Compound 15 showing the strongest α-glucosidase inhibition with an IC?? value of 2.13 ± 0.04 µM, beating the reference medication Acarbose (IC?? = 873.34 ± 1.67 µM). Molecular docking experiments demonstrated strong binding contacts of 3i with Asp352, Gln353, and His112 residues of α-glucosidase, confirming its potential as an anti-diabetic drug [41].

Tariq et al. produced a series of coumarin-hydrazone hybrids (7a-7i), and Compound 16 displayed the strongest α-glucosidase inhibition with an IC?? value of 2.39 ± 0.05 µM, greatly surpassing the conventional inhibitor Acarbose (IC?? = 873.34 ± 1.67 µM). Molecular docking experiments show strong hydrogen bonding interactions with Asp352, Asn350, and Gln353 residues in α-glucosidase's active region, indicating potential as an anti-diabetic drug [42].

Vawhal et al. developed a series of coumarin-based sulfonamide compounds as potential DPP- IV inhibitors. Compound 17 had the strongest DPP-IV inhibition, with an IC?? value of 10.98 ± 1 µM, followed by Compound 6j (IC?? = 10.14 ± 0.02 µM). Sitagliptin, the standard medication, demonstrated the most effective inhibition with an IC?? of 0.018 µM [43].

Elahabaadi et al. developed coumarin-dithiocarbamate hybrids (6a-6l) as possible α- glucosidase inhibitors for Type 2 Diabetes Mellitus. Compound 18 had the strongest α- glucosidase inhibition (IC?? = 85.0 ± 4.0 µM), outperforming the reference medication acarbose (IC?? = 750.0 ± 9.0 µM). Molecular docking revealed significant binding interactions,    with    His279    playing    an    important    role    [44].

Duong et al. produced a series of coumarin-pyrimidine hybrid compounds by combining 6- acetyl-5-hydroxy-4-methylcoumarin with guanidine. Compound 19a inhibited α-amylase more effectively than Acarbose (IC?? = 107.61 ± 1.12 μM), with an IC?? of 102.32 ± 1.15 μM. Compound 19b had the highest α-glucosidase inhibition (IC?? = 52.16 ± 1.12 μM), surpassing Acarbose (IC?? = 720.52 ± 11.13 μM) [45].

Rezapour et al. produced coumarin-indole hybrid compounds (4a-m) to inhibit α-glucosidase. Compound 20 (3-((1H-indol-3-yl)(3-phenoxyphenyl)methyl)-4-hydroxy-2H-chromen-2- one) displayed the strongest α-glucosidase inhibition (IC?? = 116.0 ± 0.7 μM), greatly surpassing    Acarbose    (IC??    =    750.0    ±    5.0    μM)    [46].

Anand-Krishna et al. investigated the Dipeptidyl Peptidase-IV (DPP-IV) inhibitory activity and antioxidant characteristics of quercetin and coumarin utilizing in silico, in vitro, and ex vivo methods. Quercetin (Compound 21) had the strongest DPP-IV inhibition (IC?? = 4.02 nmol/mL), slightly surpassing sitagliptin (IC?? = 5.49 nmol/mL), whereas coumarin showed moderate inhibition (IC?? = 54.83 nmol/mL) [47].

Mohammadi et al. studied the anti-hyperglycemic and toxicity of PTBAC and 2CTMBHC, two bis-coumarin derivatives used as α-glucosidase inhibitors. Among them, 2CTMBHC shown better in vivo anti-diabetic action than PTBAC and the conventional medication Acarbose. The oral starch tolerance test in diabetic mice revealed a considerable reduction in blood glucose levels, with 2CTMBHC at 10 mg/kg having the strongest impact [48].

Sharma et al. (2024) reviewed a broad range of 1,2,3- and 1,2,4-triazole-based derivatives for their α-amylase and α-glucosidase inhibitory activities in the management of type 2 diabetes. Compound 11c, a biscoumarin-1,2,3-triazole hybrid, showed the most potent α-glucosidase inhibition with an IC50 of 13 µM, significantly surpassing the standard drug acarbose (IC50 = 750 µM). Compound 35z, a 4-amino-1,2,4-triazole derivative, demonstrated strong dual inhibition against both α-amylase (IC50 = 2.01 µM) and α-glucosidase (IC50 = 2.09 µM), showing comparable efficacy to acarbose.

Channabasappa et al. (2021) synthesized a series of coumarin-tethered 1,2,3-triazole analogues via Cu(II)-catalyzed cyclization and evaluated their antimicrobial and α-amylase inhibitory activities. Among the series, compound 6g exhibited the most potent α-amylase inhibition with an IC?? of 4.11 µM, approaching the efficacy of the standard drug acarbose (IC?? = 2.66 µM). The compound also showed promising antimicrobial activity, especially against S. aureus, E. coli, and P. aeruginosa. Compound 6b also displayed good biological activity, though less potent than 6g in α-amylase inhibition (IC?? = 19.69 µM).

Chaabouni et al. (2024) synthesized a series of coumarin-3-carboxylic acid and iminocoumarin derivatives and evaluated their α-amylase inhibitory activity to explore their potential as antidiabetic agents. Among the tested compounds, compound 1b showed the most potent α-amylase inhibition with an IC₅? of 36 ± 1.04 µg/mL, outperforming compound 3c (IC?? = 50 ± 1.15 µg/mL) and compound 1c (IC?? = 66 ± 3.06 µg/mL). Molecular docking studies further validated the high binding affinity of compound 1b to the active site of α-amylase, indicating its potential as an anti-postprandial hyperglycemia agent [26].

Thuy Linh et al. (2025) isolated two new coumarin glycosides—Emberharin A and Emberharin B—along with eight known compounds from the aerial parts of Impatiens eberhardtii, and evaluated their α-glucosidase inhibitory activities to explore antidiabetic potential. Among the tested compounds, compound 7 (quercetin) exhibited the highest α-glucosidase inhibition with an IC?? of 157.7?±?5.9?µg/mL, outperforming kaempferol 3-O-α-L-rhamnopyranoside (6, IC?? = 170.6 ± 15.2?µg/mL) and kaempferol 3-O-β-glucopyranoside (5, IC?? = 181.6 ± 6.7?µg/mL). These results highlight the potential of flavonoid glycosides from I. eberhardtii as α-glucosidase inhibitors for type 2 diabetes treatment [26].

Mente?e et al. (2016) synthesized a novel series of quinazolinone–coumarin hybrid derivatives and investigated their α-glucosidase and pancreatic lipase inhibitory activities, targeting type 2 diabetes and obesity. Compound 7f exhibited the most potent α-glucosidase inhibition, with an IC?? of 6.11 ± 0.40 µM, significantly outperforming the standard drug acarbose (IC?? = 26.12 ± 2.38 µM). Compound 7g followed with an IC?? of 7.34 ± 0.37 µM. Both compounds also showed strong pancreatic lipase inhibition (IC?? = 3.52 ± 0.49 µM for 7f and 2.85 ± 0.27 µM for 7g), highlighting their potential as dual-action enzyme inhibitors [42].

Faryal et al. (2017) synthesized a novel series of hetarylcoumarin derivatives combining coumarin, pyrazole, and imidazole moieties via a multicomponent reaction catalyzed by p-toluenesulfonic acid, aiming to develop potent α-glucosidase inhibitors for type 2 diabetes. Among the synthesized compounds, compound 3f exhibited the most potent α-glucosidase inhibitory activity with an IC?? of 2.53?±?0.002?mM, showing approximately 15-fold greater potency than the standard drug acarbose (IC?? = 38.25 ± 0.12 mM). Compound 3j was the next most active (IC?? = 5.21 ± 0.006 mM), supporting the role of halogen substitutions in enhancing activity.

Yousof et al. (2016) isolated six coumarin derivatives from Angelica decursiva and investigated their antidiabetic potential by targeting α-glucosidase and protein tyrosine phosphatase 1B (PTP1B), key enzymes involved in type 2 diabetes. Among them, decursinol (compound 3) exhibited the strongest α-glucosidase inhibitory activity with an IC?? of 65.29 ± 0.81 µM, outperforming the standard acarbose (IC?? = 183.29 ± 1.02 µM). On the other hand, 4-hydroxy Pd-C-III (compound 1) showed the most potent PTP1B inhibition (IC?? = 5.39 ± 0.19 µM) and also effectively suppressed ONOO?-mediated tyrosine nitration, indicating antioxidant potential.

Gabr et al. (2018) synthesized a series of coumarin–benzothiazole hybrid derivatives and evaluated their antioxidant and α-glucosidase inhibitory activities to target oxidative stress and type 2 diabetes. Compound 5c demonstrated the most potent α-glucosidase inhibition with an IC?? of 6.32?±?0.51 µM, though slightly less active than the reference miglitol (IC?? = 0.39?±?0.02 µM). In antioxidant assays, compound 5c also showed the strongest DPPH radical scavenging activity (IC?? = 35.17?±?1.34 µM), compared to ascorbic acid (IC?? = 22.8?±?0.71 µM), suggesting its dual antidiabetic and antioxidant potential [30].

Ganjeh et al. (2024) synthesized a novel series of coumarin-linked 2-phenylbenzimidazole derivatives and evaluated their α-glucosidase inhibitory activity to address type 2 diabetes. Among the tested compounds, compound 5k, containing a 2-hydroxyphenyl moiety, showed the most potent α-glucosidase inhibition with an IC?? of 10.8?±?0.1?µM, significantly outperforming the standard acarbose (IC?? = 750.0?±?2.0?µM). Kinetic studies confirmed a competitive inhibition mechanism for 5k. Additionally, compound 5d (4-bromophenyl) also exhibited strong inhibition (IC?? = 22.9?±?0.2?µM).

Zhao et al. (2015) isolated a variety of mono-, di-, and trimeric coumarin derivatives from the flowers of Edgeworthia gardneri and evaluated their α-amylase and α-glucosidase inhibitory activities, targeting type 2 diabetes. Compound 4 exhibited the most potent dual inhibition, with an IC?? of 90 µg/mL against α-amylase and 86 µg/mL against α-glucosidase, surpassing the reference drug acarbose (IC?? = 465 µg/mL for α-glucosidase). Additionally, compound 3 demonstrated the strongest α-glucosidase inhibition (IC?? = 18.7 µg/mL) and acted via a noncompetitive mechanism, with binding driven by hydrophobic interactions [30].

Sherafati et al. (2020) synthesized a new class of phthalimide-Schiff base-coumarin hybrids and evaluated their α-glucosidase inhibitory potential to address type 2 diabetes. Among the series, compound 8a exhibited the most potent inhibition with an IC?? of 85.2 µM, showing approximately 9-fold stronger activity than the reference drug acarbose (IC?? = 750.0 µM). Compound 11d (IC?? = 94.2 µM) and 9d (IC?? = 104.5 µM) also showed significant inhibitory activity. Kinetic analysis revealed compound 8a acts via a competitive inhibition mechanism with a Ki of 80 µM. Docking studies confirmed that 8a, 11d, and 9d have higher binding affinities (−10.77, −8.65, and −8.66 kcal/mol respectively) to α-glucosidase than acarbose (−4.04 kcal/mol), primarily due to hydrogen bonding and hydrophobic interactions involving the phthalimide and coumarin moieties.

Ibrar et al. (2017) synthesized a novel series of coumarinyl iminothiazolidinone hybrids via a one-pot multicomponent method and evaluated their α-glucosidase and maltase-glucoamylase inhibitory potential to manage type 2 diabetes. Among the compounds, 6g exhibited the strongest α-glucosidase inhibition with an IC?? of 0.09 µM, surpassing the standard drug acarbose (IC?? = 38.2 µM) by over 400-fold. For maltase-glucoamylase, compound 6f showed the most potent activity (IC?? = 0.07 µM), on par with acarbose (IC?? = 0.06 µM). Both 6f and 6g were found to act via competitive inhibition, and docking studies revealed their binding is stabilized by hydrogen bonds and π–π interactions within the enzyme active site, particularly involving residues such as Arg212, His239, and Phe310.

Serry et al. (2025) synthesized a series of hybrid coumarin and chromone derivatives incorporating oxadiazole and pyrazoline moieties and evaluated their in vitro and in vivo α-glucosidase inhibitory activities for potential antidiabetic effects. Among the synthesized compounds, compound 11c demonstrated the most potent α-glucosidase inhibition with an IC?? of 119.7?±?4.3?μM, significantly outperforming the reference drug acarbose (IC?? = 300.9?±?10.9?μM). Molecular docking revealed that 11c had the best binding affinity (−9.1 kcal/mol) to the α-glucosidase active site, forming multiple hydrogen bonds and hydrophobic interactions.

Shao et al. (2010) synthesized a series of hydroxycoumarin derivatives and evaluated their α-glucosidase inhibitory activity targeting type 2 diabetes. Among them, compound 10 exhibited the most potent inhibition, with an IC?? of 0.86 µM, making it approximately 14 times more effective than genistein (IC?? = 12.36 µM) and significantly outperforming the standard drug deoxynojirimycin. Kinetic studies revealed that compound 10 acts as a noncompetitive inhibitor with a Ki of 0.589 µM, and its activity is time-dependent (slow-binding mechanism).

Muhammad et al. (2018) synthesized a series of 17 coumarin-based hydrazone derivatives and evaluated their α-glucosidase inhibitory activities in vitro. All compounds showed significant inhibition compared to the standard drug acarbose (IC?? = 39.45?µM). Compound 3 exhibited the strongest α-glucosidase inhibition, with an IC?? of 1.10?±?0.01 µM, outperforming acarbose by more than 35-fold. Molecular docking revealed that compound 3 binds deeply into the active site of α-glucosidase, stabilized by strong hydrophobic interactions and multiple hydrogen bonds, especially with residues Thr307 and Glu304. Compound 4 also showed potent inhibition (IC?? = 4.26?µM), but with slightly less favorable binding energy (−8.58 kcal/mol) compared to compound 3 (−9.19 kcal/mol). The enhanced activity of compound 3 is attributed to the ortho and meta hydroxyl substitutions on its benzylidene ring, facilitating additional hydrogen bonding and better positioning within the enzyme's active site.

Uzma Salar et al. (2016) synthesized 14 new 3-thiazolylcoumarin derivatives and evaluated their in vitro α-glucosidase inhibitory activities targeting type 2 diabetes. All compounds showed significant inhibition, with compound 14 exhibiting the most potent activity with an IC?? of 0.12?±?0.01?µM, outperforming the reference drug acarbose (IC?? = 38.25?±?0.12?µM) by over 300-fold. Molecular docking revealed that compound 14 binds strongly with the α-glucosidase active site, forming multiple key interactions, including arene-arene and polar contacts with residues Phe300, Arg312, and Asn241, driven by electronic effects of dichloro and hydroxyl substituents.

Alim Alsukor et al. (2025) synthesized sixteen coumarin sulfonamide derivatives and evaluated their in vitro α-glucosidase inhibitory activities to address type 2 diabetes. Among them, compound 16, bearing a 2,4,5-trichlorobenzene substituent, exhibited the most potent activity, with an IC?? of 40.6?±?1.49?µM, showing over 80-fold greater potency than acarbose (IC?? = 3410?±?1.54?µM). Molecular docking revealed that compound 16 formed multiple stabilizing interactions—including hydrogen bonds with Thr215 and His245, π–π stacking with Phe157, and π–anion interactions with Asp349 and Glu276—driven by the chlorine substituents’ electronic effects. Additionally, compound 10 (IC?? = 131.4?µM) demonstrated notable inhibitory activity, with interactions centered on the coumarin and sulfonamide moieties. These findings underscore the importance of halogen substitutions, especially chlorine at para/meta positions, in enhancing binding affinity and inhibitory efficacy.

Sahin (2023) investigated the in-vitro anti-diabetic, anti-Alzheimer, anti-tyrosinase, and antioxidant activities of four commercial coumarin derivatives (esculetin, esculin monohydrate, umbelliferone, scoparone) and four isolated 3-phenyl-3,4-dihydroisocoumarin derivatives (thunberginol C, scorzocreticoside I, scorzocreticoside II, scorzopygmaecoside). Thunberginol C exhibited the most potent α-glucosidase inhibition with an IC?? of 94.76?µM, outperforming the reference drug acarbose (IC???=?1036.2?µM), suggesting potential for type 2 diabetes management. It also showed significant dual inhibition against AChE (IC???=?82.41?µM) and BChE (IC???=?137.25?µM), and notable tyrosinase inhibition (IC???=?90.25?µM), although weaker than kojic acid (IC???=?15.72?µM). Antioxidant assays revealed esculetin as the most potent compound, with thunberginol C also demonstrating strong radical scavenging activity (DPPH EC???=?126.38?µM, ABTS?=?17.69?µM, CUPRAC?=?62.22?µM).

Kalfagianni and Hadjipavlou-Litina (2024) reviewed recent patents (2017–2024) on coumarin derivatives and their therapeutic applications, including anti-cancer, anti-diabetic, antioxidant, and neuroprotective effects. Among anti-diabetic candidates, 3-aryl-coumarin compound M-270 exhibited the strongest α-glucosidase inhibitory activity with an IC?? of 0.37 µg/mL, significantly outperforming standard treatments. Additionally, compound M-254 was the most potent inhibitor of AGE (advanced glycation end-product) formation (IC?? = 0.36 µg/mL), and compound M-286 demonstrated the highest DPPH radical scavenging activity (IC?? = 1.90 µg/mL). The coumarin-oxazole-ethylene hybrids also showed strong α-glucosidase inhibition with low toxicity, acting by delaying carbohydrate absorption. These findings support coumarin scaffolds as promising leads for developing multi-target anti-diabetic agents with added antioxidant benefits.

Ichale et al. (2024) synthesized a novel series of coumarin–thiazole hybrid derivatives and evaluated their α-glucosidase inhibitory activities as a therapeutic approach for type 2 diabetes. Among 15 derivatives, compound 18 exhibited the most potent inhibition, with an IC?? of 0.14 µM, significantly outperforming the reference drug acarbose (IC?? = 6.32 µM). Molecular docking studies with the α-glucosidase enzyme (PDB ID: 3TOP) revealed that compound 18 engaged in strong π–π stacking, hydrogen bonding, and π-sulfur interactions within the enzyme’s active site. Molecular dynamics simulations over 100 ns confirmed the stability of the ligand–enzyme complex, with hydrophobic interactions contributing more than electrostatic interactions to binding stability.

Xu et al. (2020) synthesized two series of cinnamic acid–coumarin hybrid derivatives (compounds 5a–i and 6a–i) and evaluated their α-glucosidase inhibitory activities for potential application in type 2 diabetes treatment. Among these, compound 5b showed the most potent inhibition with an IC?? of 12.98 µM, surpassing the positive control ursolic acid (IC?? = 11.38 µM). Compound 5a also demonstrated strong activity (IC?? = 19.64 µM). Kinetic analysis revealed that both compounds acted via reversible, mixed-type inhibition mechanisms. Molecular docking of compound 5b indicated its ability to bind within the active site of α-glucosidase, forming hydrogen bonds with LYS293 and engaging in hydrophobic and van der Waals interactions.

Younes and Mustafa (2024) isolated four novel isofraxetin-based phytocoumarins (Natural-B1 to B4) from green sweet bell pepper (GSBP) seeds using a novel kinetic thermomagnetic extraction method. The isolated compounds were evaluated for their antioxidative, anticancer, anti-inflammatory, and antidiabetic properties. In antidiabetic assays, Natural-B4 exhibited the most potent dual enzyme inhibition with an IC?? of 498.14 µg/mL against α-amylase and 512.34 µg/mL against α-glucosidase, showing moderate activity compared to acarbose (IC?? = 261.67 µg/mL and 283.22 µg/mL, respectively). Additionally, Natural-B4 demonstrated the highest oxidative stress mitigation (MF% = 81.48%) and cytotoxicity (IC?? = 46.76 µg/mL against HeLa cells), and was the most effective COX-2/5-LOX dual inhibitor among the series (IC?? = 3.74 µg/mL for COX-2 and 14.58 µg/mL for 5-LOX).

Table: Selected Coumarin Derivatives with Antidiabetic Activity

Compound	Structure	Observed Effect	Activity	Reference
1		α-amylase inhibition	IC??= 3.60 ± 0.01 µg/mL	Savankumar et al. (2024)
2		α-amylase inhibition	IC?? = 7.24 µM	Baccari W et al. (2024)
3		α-amylase inhibition	IC?? = 19.98 ± 3.24 µM	El Behery et al. (2023)
4a		α-amylase inhibition	IC?? = 67.52 µM	Patnagar et al.
4b		DPP-IV Inhibition	IC50= 89.67 µM	Patnagar et al.
5		α-glucosidase inhibition	IC?? = 3.5 ± 0.1 µM	Khouzani M.A. et al.
6		α-glucosidase inhibition	IC?? = 24.09 ± 2.36 µM	Chun-Mei et al. (2022)
7		DPP-IV inhibition	84.5% at 100 µM	Rina Soni et al. (2019)
8		Antihyperglycemic effect	Blood glucose = 115 mg/dL	Kenchappa R. et al. (2017)
9		α-glucosidase inhibition,	IC?? = 30.0 ± 0.5 µM	Ghorbani H et al.
10a		α-amylase in	IC?? = 1.08 ± 0.02 mM	Thabet et al.
10b		α-glucosidase	IC?? = 0.548 ± 0.02 mg/mL	Thabet et al.
11		Aldose reductase inhibition	Blood glucose = 131.12 ± 7.13 mg/dL	Umadevi et al.
12		α-amylase inhibition and ACE inhibition	IC??=5.43 µM	Basappa et al.
13		α-glucosidase inhibition	IC?? < 65 μM	Pan Y. et al.
14		inhibition of AKT1, GLUT1, α-amylase		Sahu, P.R., et al.
15		α-glucosidase inhibition	IC??= 2.13 ± 0.04 µM	Syeda et al.
16		α-glucosidase inhibition	IC??=2.39 ± 0.05 µM	Tariq et al.
17		DPP-IV inhibition	IC??=10.98 ± 1 µM	Vawhal et al.
18		α-glucosidase inhibition	IC?? = 85.0 ± 4.0 µM	Elahabaadi et al.
19a		α-amylase inhibition	IC?? = 102.32 ± 1.15 µM	Duong et al.
19b		α -glucosidase inhibition	IC?? = 52.16 ± 1.12 µM	Duong et al.
20		α-glucosidase inhibition	IC?? = 116.0 ± 0.7 µM	Rezapour et al.
21		DPP-IV inhibition	IC?? = 4.02 nmol/mL	Anand-Krishna et al.
22		α-glucosidase inhibition	IC?? = 13.0 µM	Mohammad et al.
23		α-glucosidase inhibition	IC50 =13 µM	Sharma et al. (2024)
24		α-amylase inhibition	IC??=4.11 µM	Channabasappa et al. (2021)
25		α-amylase inhibition	IC5036 ± 1.04 µg/mL	Chaabouni et al. (2024)
27		α-glucosidase inhibition	IC??= 157.7?±?5.9?µg/mL	Thuy Linh et al. (2025)
28		α-glucosidase inhibition	IC??= 6.11 ± 0.40 µM,	Mente?e et al. (2016)
29		α-glucosidase inhibition	IC??= 2.53?±?0.002?mM,	Faryal et al. (2017)
30		α-glucosidase inhibition	IC??= 65.29 ± 0.81 µM	Yousof et al. (2016)
31		α-glucosidase inhibition	IC??= 6.32?±?0.51 µM	Gabr et al. (2018)
32		α-glucosidase inhibition	IC??= 10.8?±?0.1?µM	Ganjeh et al. (2024)
33		α-glucosidase inhibition	IC?? = 465 µg/Ml for	Zhao et al. (2015)
34		α-glucosidase inhibition	IC??= 85.2 µM	Sherafati et al. (2020)
35		α-glucosidase inhibition	IC??= 0.09 µM	Ibrar et al. (2017)
36		α-glucosidase inhibition	IC??= 20.0 µM	Maryam et al. (2025)
37		α-glucosidase inhibition	IC??= 119.7?±?4.3?μM	Serry et al. (2025)
38		α-glucosidase inhibition	IC??= 0.86 µM	Shao et al. (2010)
39a		α-glucosidase inhibition	IC??= 1.10?±?0.01 µM	Muhammad et al. (2018)
39b		α-glucosidase inhibition	IC?? = 4.26?µM	Muhammad et al. (2018)
40		α-glucosidase inhibition	IC??= 0.12?±?0.01?µM	Uzma Salar et al. (2016)
41		α-glucosidase inhibition	IC??= 40.6?±?1.49?µM	Alsukor et al. (2025)
42		α-glucosidase inhibition	IC?? of 94.76?µM,	Sahin (2023)
43a		α-glucosidase inhibition	IC??= 0.37 µg/mL	Litina (2024)
43b		α-amylase inhibition	IC?? = 0.36 µg/mL	Litina (2024)
44		α-glucosidase inhibition	IC??= 0.14 µM	Ichale et al. (2024)
45		α-glucosidase inhibition	IC??= 12.98 µM	Xu et al. (2020)
46		α-glucosidase inhibition	IC??= 512.34 µg/mL	Mustafa (2024)