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Development of Agents with Biological Activities by Umbelliferone: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Anita Kornicka.

Umbelliferone (UMB), known as 7-hydroxycoumarin, hydrangine, or skimmetine, is a naturally occurring coumarin in the plant kingdom, mainly from the Umbelliferae family that possesses a wide variety of pharmacological properties. In addition, the use of nanoparticles containing umbelliferone may improve anti-inflammatory or anticancer therapy. Also, its derivatives are endowed with great potential for therapeutic applications due to their broad spectrum of biological activities such as anti-inflammatory, antioxidant, neuroprotective, antipsychotic, antiepileptic, antidiabetic, antimicrobial, antiviral, and antiproliferative effects.

  • umbelliferone
  • 7-hydroxycoumarin-based compounds
  • pharmacological properties
  • fluorescence probes

1. Introduction

Phytochemicals constitute a large group of bioactive compounds derived from natural resources, especially those of plant origin. Among them, coumarins containing a 2H-1-benzopyran-2-one core found in a wide range of plants demonstrate the broad spectrum of pharmacological properties, including anticancer, antimicrobial, antiviral, anticoagulant, antihypertensive, anti-inflammatory, and antioxidant or neuroprotective activities [1].
Umbelliferone (UMB) (Figure 1), also known as 7-hydroxycoumarin, hydrangine, or skimmetine, is one of the most common plant-based coumarins present as a secondary metabolite in the flowers, fruits, and roots of almost all higher plants, mainly from the Umbelliferae/Apiaceae family [2]. The potential therapeutic effects of UMB in diabetes, cardiovascular or neurodegenerative diseases, inflammatory disorders, various cancer types, and microbial infections [3,4,5][3][4][5] (Figure 1) have gained increasing interest in the development of its synthetic derivatives with beneficial pharmacological activities.
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Figure 1. Therapeutical potential of umbelliferone [3,4,5].
Therapeutical potential of umbelliferone [3][4][5].
In addition, an accessible scaffold for transformation into various biologically active functionalized 7-hydroxycoumarins (Figure 2) [3,4,6,7,8,9,10,11][3][4][6][7][8][9][10][11] along with the lack of oral toxicity within the dose range of 200 mg/kg [12,13,14][12][13][14] make umbelliferone an attractive platform for the development of bioactive 7-hydroxycoumarin-based compounds in drug design.
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Figure 2. Biologically active 7-hydroxycoumarins derived from umbelliferone [3,6,7,8,9,10,11].

2. Anti-Inflammatory Activity

2.1. Anti-Inflammatory Properties of Umbelliferone

Inflammation is part of a complex biological process in the human body caused by various stimuli including pathogenic microorganisms, cell damage, irritants, or immune reactions. Because this process is necessary to protect the body, it should lead to the removal of pathogens and allow the tissue to return to its physiological state. On the other hand, prolonged inflammation is associated with the development of minor-to-major diseases such as rheumatoid arthritis, chronic asthma, multiple sclerosis, inflammatory bowel disease, or psoriasis, as well as cancer [15,16].
Similar to other natural coumarins including scopoletin, visnadin, marmin, daphnethin, or esculetin, umbelliferone also exhibits a favorable anti-inflammatory effect via various inflammatory signaling pathways [3,5,17,18,19].
In allergic conditions, the increase in NO production is associated with the severity of allergic symptoms, and its generation is regulated by inducible nitric oxidase synthase (iNOS) genes [20,21]. In turn, Nrf2 (nuclear factor erythroid 2 (NEF)-related factor 2) is a key signaling pathway involved in the regulation of the endogenous antioxidant system formed by heme oxygenase-1 (HO-1), superoxide dismutase (SOD), catalase (CAT), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), as well as thioredoxin and it protects cells from the oxidative stress markers [22].
Biologically active 7-hydroxycoumarins derived from umbelliferone [3][6][7][8][9][10][11].

2. Anti-Inflammatory Activity

2.1. Anti-Inflammatory Properties of Umbelliferone

Inflammation is part of a complex biological process in the human body caused by various stimuli including pathogenic microorganisms, cell damage, irritants, or immune reactions. Because this process is necessary to protect the body, it should lead to the removal of pathogens and allow the tissue to return to its physiological state. On the other hand, prolonged inflammation is associated with the development of minor-to-major diseases such as rheumatoid arthritis, chronic asthma, multiple sclerosis, inflammatory bowel disease, or psoriasis, as well as cancer [15][16].
Similar to other natural coumarins including scopoletin, visnadin, marmin, daphnethin, or esculetin, umbelliferone also exhibits a favorable anti-inflammatory effect via various inflammatory signaling pathways [3][5][17][18][19].
In allergic conditions, the increase in NO production is associated with the severity of allergic symptoms, and its generation is regulated by inducible nitric oxidase synthase (iNOS) genes [20][21]. In turn, Nrf2 (nuclear factor erythroid 2 (NEF)-related factor 2) is a key signaling pathway involved in the regulation of the endogenous antioxidant system formed by heme oxygenase-1 (HO-1), superoxide dismutase (SOD), catalase (CAT), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), as well as thioredoxin and it protects cells from the oxidative stress markers [22].
It has been reported that intraperitoneal administration of 1, 10, and 50 mg/kg of umbelliferone in BALB/c mice significantly attenuated both acute histamine- and chronic picryl chloride-induced ear edema reducing the allergic symptoms and the oxidative stress by the induction of the Nrf2 expression on the one hand and downregulation of iNO expression on the other hand [24].
It has been reported that intraperitoneal administration of 1, 10, and 50 mg/kg of umbelliferone in BALB/c mice significantly attenuated both acute histamine- and chronic picryl chloride-induced ear edema reducing the allergic symptoms and the oxidative stress by the induction of the Nrf2 expression on the one hand and downregulation of iNO expression on the other hand [23].

2.2. Synthetic 7-Hydroxycoumarin-Based Compounds as Anti-Inflammatory Agents

Given its favorable anti-inflammatory activity, the umbelliferone framework has been used for chemical modification to identify original and effective compounds that can serve as anti-inflammatory agents [17,31].
Given its favorable anti-inflammatory activity, the umbelliferone framework has been used for chemical modification to identify original and effective compounds that can serve as anti-inflammatory agents [17][24].
Recently, 9,10-dihydrochromeno[8.7-
e][1,3]oxazin-2(8
][1][3]oxazin-2(8
H
)-one derivatives (
1
) were designed and synthesized as potential anti-inflammatory agents (
Figure 3) [32].
) [25].
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Figure 3. Anti-inflammatory 7-hydroxycoumarin-based compounds 1–4.
Among the compounds that showed anti-inflammatory activity, analogue
1a
has been found to exert the most potent biological effect, which was determined to be capable of decreasing the concentration of pro-inflammatory cytokines including TNF-α and IL-6 in lipopolysaccharide (LPS)-induced cytokine release in RAW264.7 mouse macrophages. It has been indicated that derivative
1a
can inhibit inflammatory responses by suppressing the MAPK (mitogen-activated protein kinase) and NK-
κB signaling pathways that play a pivotal role in the regulation of inflammatory cytokines [33]. 
B signaling pathways that play a pivotal role in the regulation of inflammatory cytokines [26]. 
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Figure 4. A 2D representation of docked ligand 1a in TNF-α.
The newly synthesized 2-[(2-oxo-2
H
-chromen-7-yl)oxy]acetamides of general formula
2
(
Figure 3) hybridized with substituted aniline or benzylamine moieties were also explored for their potential anti-inflammatory activity against LPS-induced IL-6 and TNF-α release in RAW264.7 cells [34].
) hybridized with substituted aniline or benzylamine moieties were also explored for their potential anti-inflammatory activity against LPS-induced IL-6 and TNF-α release in RAW264.7 cells [27].
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Figure 5. A 2D model of the interaction between 7-hydroxycoumarin derivative 2a with the active site of NF-κB p65.
Additionally, in 2021, Gao et al. used the Knoevenagel reaction and Pechmann condensation to develop a new series of 3-acetyl-7-hydroxycoumarin Mannich bases (
3
) and Betti bases (
4
) (
Figure 3) that were explored in vitro for their anti-inflammatory activity [35].
) that were explored in vitro for their anti-inflammatory activity [28].

3. Antioxidant Activity

3.1. Antioxidant Properties of Umbelliferone

Oxidative stress is implicated in a number of pathological conditions such as cardiovascular diseases, cancer, neurodegenerative diseases, diabetes mellitus, ischemia/reperfusion injury, or rheumatoid arthritis, as well as in the ageing process through multiple mechanisms, where free radicals contribute to cellular damage [36]. Therefore, there is a growing interest in antioxidant agents with therapeutic potential [37].
Oxidative stress is implicated in a number of pathological conditions such as cardiovascular diseases, cancer, neurodegenerative diseases, diabetes mellitus, ischemia/reperfusion injury, or rheumatoid arthritis, as well as in the ageing process through multiple mechanisms, where free radicals contribute to cellular damage [29]. Therefore, there is a growing interest in antioxidant agents with therapeutic potential [30].
In this line, the antioxidant potential of umbelliferone is also worth mentioning. As was nicely elaborated by Mazimba [3] and Lin et al. [5], its antioxidant properties are associated with the ability to scavenge free radicals as well as the inhibition of lipid peroxidation. 

3.2. Synthetic 7-Hydroxycoumarin-Based Compounds as Antioxidant Agents

With regards to the antioxidant activity of 7-hydroxycoumarin-based compounds, Al-Majedy et al. designed and synthesized two series of modified 7-hydroxycoumarins and evaluated them for their antioxidant potency [39,40]. Among them, the best radical scavenging properties were shown by 7-[(4-phenyl-5-thioxo-4,5-dihydro-1
With regards to the antioxidant activity of 7-hydroxycoumarin-based compounds, Al-Majedy et al. designed and synthesized two series of modified 7-hydroxycoumarins and evaluated them for their antioxidant potency [31][32]. Among them, the best radical scavenging properties were shown by 7-[(4-phenyl-5-thioxo-4,5-dihydro-1
H
-1,2,4-triazol-3-yl)methoxy]coumarin (
5
) and 5-{[(coumarin-7-yl)oxy]methyl}-1,3,4-thiadiazol-2(3
H
)-one (
6
) (
Figure 6), which exhibited the inhibition of 91% and 88% of free radicals, respectively, at a concentration of 250 µg/mL in the 2,2′-diphenyl-1-picrylhydrazyl radical assay (DPPH) [40].
), which exhibited the inhibition of 91% and 88% of free radicals, respectively, at a concentration of 250 µg/mL in the 2,2′-diphenyl-1-picrylhydrazyl radical assay (DPPH) [32].
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Figure 6. Antioxidant 7-hydroxycoumarin-based compounds 5–10.
In 2018, Kurt et al. evaluated novel coumarin carbamate derivatives (
7
) (
Figure 6) for their anticholinesterase, antioxidant, and anti-aflatoxigenic activities [41]. The synthesized compounds exhibited moderate-to-low radical scavenging ability (IC
) for their anticholinesterase, antioxidant, and anti-aflatoxigenic activities [33]. The synthesized compounds exhibited moderate-to-low radical scavenging ability (IC
50
= 23.15–>200 µM) in 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) analysis compared to
quercetin
(IC
50
= 15.49 µM) used as a standard compound. 
Regarding the antioxidant activity of 7-hydroxycoumarin-based compounds, some studies have been recently carried out showing the potential of coumarins linked with 1,2,3-triazoles [42,43]. Worth noting are coumarins of general formula
Regarding the antioxidant activity of 7-hydroxycoumarin-based compounds, some studies have been recently carried out showing the potential of coumarins linked with 1,2,3-triazoles [34][35]. Worth noting are coumarins of general formula
8
prepared by Joy et al. through the copper catalyzed azide-alkylene cycloaddition reaction (
Figure 6) [42].
) [34].
Moreover, Kaushik and Chacal synthesized two series of coumarin-1,2,3-triazole hybrid molecules using the click chemistry approach from the coumarin-based terminal alkynes and aromatic azides and tested their antioxidant activity via the DPPH method [43]. However, all compounds displayed lower DPPH-based radical scavenging activity (IC
Moreover, Kaushik and Chacal synthesized two series of coumarin-1,2,3-triazole hybrid molecules using the click chemistry approach from the coumarin-based terminal alkynes and aromatic azides and tested their antioxidant activity via the DPPH method [35]. However, all compounds displayed lower DPPH-based radical scavenging activity (IC
50
= 3.33–8.75 μg/mL) compared to the standard ascorbic acid (IC
50
= 1.23 μg/mL), and the presence of the electron-donating groups on the benzyl moiety in the structure of these compounds might contribute to increased antioxidant activity. In addition, the 7-hydroxycoumarin-based compounds generally evidenced higher activity than their 4-hydroxycoumarin-based counterparts. The best result was found for derivative
9
with an IC
50
value of 3.33 μg/mL (
Figure 6) [43].
) [35].
Most recently, a new 7-hydroxycoumarin derivative
10
(
Figure 6) was invented as a potential antioxidant agent [44]. Although the antioxidant activity of
) was invented as a potential antioxidant agent [36]. Although the antioxidant activity of
10
was lower than the standard BHT (
p
< 0.05), it was found that all used concentrations (0.03125–1 mg/mL) owed its ability to scavenge radicals in the DPPH assay. The experimental antioxidant properties of coumarin
10
were also supported by molecular docking analysis that revealed the possible interactions of derivative
10
with the active binding site of CYP450.

3.3. Metal Complexes with 7-Hydroxycoumarin-Based Compounds as Antioxidant Agents

Recently, it was demonstrated that the radical scavenging ability of novel 3-acetyl-7-methoxy-4

N-substituted thiosemicarbazones may be increased by ruthenium chelation [47]. The best radical scavenging properties have been shown by Ru(II) complex

-substituted thiosemicarbazones may be increased by ruthenium chelation [37]. The best radical scavenging properties have been shown by Ru(II) complex

11

(

Figure 7

), which displayed an antioxidant potency with about a fifteen-fold lower IC

50

value than standard vitamin C in the DPPH model (IC

50

= 5.28 µM vs. IC

50

= 98.72 µM). 

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Figure 7. Antioxidant 7-hydroxycoumarin-based metal complexes 11–13.
In 2020, Özdemir et al. synthesized a series of 7-oxy-3-ethyl-6-hexyl-4-methylcoumarin-substituted lutetium(III) phthalocyanine compounds, whose antioxidant properties were evaluated [48]. Complexes
In 2020, Özdemir et al. synthesized a series of 7-oxy-3-ethyl-6-hexyl-4-methylcoumarin-substituted lutetium(III) phthalocyanine compounds, whose antioxidant properties were evaluated [38]. Complexes
12
and
13
(
Figure 7) displayed much better 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS)-based radical cation scavenging activity compared with standard butylated hydroxyanisole (BHA), 120.344 mM troloxy/mg and 188.733 mM troloxy/mg vs. 52.63 mM troloxy/mg. On the other hand, the FRAP (Ferric Reducing Antioxidant Power) and CUPRAC (Cupric Reducing Antioxidant Capacity) analyses evidenced their lesser potency compared to BHT and vitamin C used as standards [48].
) displayed much better 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS)-based radical cation scavenging activity compared with standard butylated hydroxyanisole (BHA), 120.344 mM troloxy/mg and 188.733 mM troloxy/mg vs. 52.63 mM troloxy/mg. On the other hand, the FRAP (Ferric Reducing Antioxidant Power) and CUPRAC (Cupric Reducing Antioxidant Capacity) analyses evidenced their lesser potency compared to BHT and vitamin C used as standards [38].

4. Umbelliferone and 7-Hydroxycoumarin-Based Compounds Acting in the Central Nervous System (CNS)

4.1. Neurodegenerative Disorders

Umbelliferone and its simple derivatives—6-formylumbelliferone (14) from the plant Angelica decursiva, its isomeric analogue 8-formylumbelliferone (15), and umbelliferone 6-carboxylic acid (16) (Figure 8)—exhibit potent inhibitory activities towards acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and aspartic protease β-secretase 1 (BACE1) [52,53,54][39][40][41]. However, it should be noted that the data regarding the inhibitory activity of umbelliferone towards AChE and BuChE are contradictory.
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Figure 8. Umbelliferone derivatives 14–16 as potent AChE, BuChE, and BACE1 inhibitors for the treatment of neurodegenerative disorders. 
Numerous diseases can be caused by a defect of more than one biological target—an enzyme or receptor. Thus, such disorders cannot be adequately addressed by the classical ‘one target, one molecule’ approach [57][42]. A promising strategy to tackle multifactorial diseases, e.g., AD, consists in the design of multifunctional agents, known as ‘hybrid’ molecules. These complex molecules display stable chemical combinations of two drug moieties or pharmacophores acting at different targets. Such ‘dual-acting compounds’ combine two distinct chemical entities [58,59][43][44]. According to this, Hirbod et al. designed a 7-hydroxycoumarin hybrid bearing a heterocyclic framework—8-hydroxyquinoline 17 (Figure 9)—as a novel cholinesterase inhibitor [60][45].
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Figure 9.
Chemical structure of 7-hydroxycoumarin-based compound
17
as an AChE and BuChE inhibitor.
Numerous diseases can be caused by a defect of more than one biological target—an enzyme or receptor. Thus, such disorders cannot be adequately addressed by the classical ‘one target, one molecule’ approach [57]. A promising strategy to tackle multifactorial diseases, e.g., AD, consists in the design of multifunctional agents, known as ‘hybrid’ molecules. These complex molecules display stable chemical combinations of two drug moieties or pharmacophores acting at different targets. Such ‘dual-acting compounds’ combine two distinct chemical entities [58,59]. According to this, Hirbod et al. designed a 7-hydroxycoumarin hybrid bearing a heterocyclic framework—8-hydroxyquinoline 17 (Figure 9)—as a novel cholinesterase inhibitor [60].
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Figure 9. Chemical structure of 7-hydroxycoumarin-based compound 17 as an AChE and BuChE inhibitor.
Recently, Mzezewa et al. have described 3-substituted 7-hydroxycoumarin derivatives 18 and 19 as multifunctional anti-Alzheimer’s disease agents (Figure 10) [63][46].
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Figure 10. Chemical structures of 7-hydroxycoumarin-based compounds 18 and 19 as multifunctional anti-Alzheimer’s disease agents.
In addition, these compounds offer significant neuroprotective effects towards MPP+-compromised SH-SY5V neuroblastoma cells with no inherent cytotoxicity at 10 µM. Consequently, compounds 18 and 19 have been proposed for further studies to explore their neuroprotective potential in AD and related neurodegenerative diseases such as Parkinson’s disease. Although 7-hydroxycoumarins 18 and 19 exhibited weak cholinesterase inhibitory activity when compared with the reference denezepril (AChE and BuChE IC50 = >100 µM vs. AChE IC50 = 0.007 µM and BuChE IC50 = 4.40 µM), the tested compounds demonstrated selectivity towards MAO-B with IC50 values of 0.029 µM and 0.101 µM, respectively.

4.2. Neuropsychiatric Diseases

4.2.1. Synthetic 7-Hydroxycoumarin-Based Compounds Targeting Monoamine Oxidase (MAO) and D-Amino Acid Oxidase (DAAO)

Recently, Seong et al. reported 6-formylumbelliferone derivative 14 and its isomeric analogue 15, presented in Figure 8, as highly selective hMAO-A inhibitors [65][47]. The higher selectivity and inhibitory activity towards hMAO-A exhibited 7-hydroxy-2-oxo-2H-chromene-6-carbaldehyde (14) with an IC50 value of 3.23 μM for hMAO-A and an IC50 value of 15.31 μM for hMAO-B. Enzyme kinetic studies revealed that both 6-formylumbelliferone 14 and 8-formylumbelliferone 15 are competitive hMAO inhibitors. These investigations were supported by molecular docking studies. Data revealed that compounds 14 and 15 dock well into the active sites of recombinant human monoamine oxidase A and B. The formyl group of 14 interacts strongly with substrate binding site (SBS) residues Tyr444 and Tyr197 of hMAO-A via water-mediated hydrogen bonds, whereas Phe352 and Tyr407 residues are involved in hydrophobic noncovalent π-π T-shaped (perpendicular T-shaped) and π-π stacking interactions. Hydroxycoumarin derivatives 14 and 15 demonstrated a neuroprotective effect due to their antilipid peroxidation and anti-Aβ25–35 (amyloid β self-assembly) aggregation activity in rat brain tissue. 

In a study in 2018, Dhirman et al. investigated monoamine oxidase’s inhibitory effects on a series of umbelliferone-based compounds [66][48]. By substituting the coumarin scaffold at the C-7 position, MAO’s inhibitory potential was significantly increased. MAO inhibition studies have shown that hybrid compounds containing the 5-bromoisatin moiety 20 (Figure 11) exhibited a pronounced hMAO-A activity (IC50 = 7.47 μM), whereas incorporation of the 2-hydroxy-2-phenylacetate moiety into umbelliferone derivative 21 (Figure 11) resulted in significant hMAO-B blocking (IC50 = 10.32 μM). In the same studies, umbelliferone turned out to be less active than the tested compounds (hMAO-A IC50 = 18.08 μM and hMAO-B IC50 = 12.98 μM) [66][48].
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Figure 11.
Chemical structures of 7-hydroxycoumarin-based compounds
20
–
22
as MAO and DAAO inhibitors.
In 2022, Bester et al., as a result of their investigations, described the synthesis of 3-hydroxy-7-benzyloxy-2H-chromen-2-one (22) starting from 2,4-dihydroxybenzaldehyde, N-acetylglycine, and acetic anhydride (Figure 11) [69][49]. Compound 22 was identified as a potent, selective inhibitor of MAO-B (IC50 = 0.012 μM) and DAAO (IC50 = 1.86 μM). The results obtained were an improvement or comparable to those of the reference inhibitors: coumarin (MAO-B IC50 = 2.56 μM), isatin (MAO-B IC50 = 3.90 μM), and 3-methylpyrazole-5-carboxylic acid (DAAO IC50 = 1.88 μM).

4.2.2. Synthetic 7-Hydroxycoumarin-Based Compounds Targeting Serotonin Receptors

Recent studies have clearly demonstrated that umbelliferone-based compounds may interact with serotonin receptors. In 2021, among a series of 7-hydroxycoumarins bearing a piperazine moiety, 7-hydroxycoumarin derivatives 23 and 24 (Figure 12) showed high antagonistic activity against serotonin receptors [70][50].
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Figure 12.
Chemical structures of 7-hydroxycoumarin-based compounds
23
and
24
targeting 5-HT receptors.
In the paper, the authors claimed that the substitution pattern dictates the selectivity and affinity of tested compounds for 5-HT receptors. The structure–activity analysis showed that the presence of a five-carbon atom linker and 2-methoxyphenyl group attached to the piperazine moiety (compound 23) was the most beneficial for 5-HT1A antagonistic activity, whereas the (2,2-dichloro)piperazin-1-yl moiety is associated with a higher inhibition of the 5-HT2A receptor (compound 24).

4.3. Antiepileptic Agents

The antiepileptic effects of 7-hydroxycoumarin derivatives may be associated with the synergistic effect on γ-aminobutyric acid ionotropic receptors (GABAA). In the reaction of 7-hydroxycoumarin and 2-chloro-1-morpholinoethan-1-one, Yakovleva and collaborators synthesized umbelliferone derivative 25 (Figure 143) containing a morpholine-acetamide group at position C-7 [73][51]. Compound 25 showed pronounced antiepileptic activity in the corazole-GABAA receptor antagonist convulsion test. The effectiveness of 7-hydroxycoumarin derivative 25 is associated with the morpholine ring, which has an optimal lipophilic-hydrophilic profile. The antiepileptic effect of derivative 25 at a dose of 200 mg/kg was comparable to that of reference valproic acid at the same dose. A further increase in the dose to 300 mg/kg led to an increase in the anticonvulsant activity of 25 [73][51].
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Figure 143.
Chemical structure of 7-hydroxycoumarin-based compound
25
as an antiepileptic agent.

5. Umbelliferone and 7-Hydroxycoumarin-Based Compounds as Antidiabetic Agents

Extracts of widely cultivated plants, such as

Musa species (banana flower ethanolic extracts) containing umbelliferone, were identified as potential antidiabetic herbal remedies in the management of diabetes and associated complications. Isolated umbelliferone increased the activity of crucial enzymes involved in glucose utilization and the glycolytic activity of the liver in alloxan-induced diabetic rats [74]. 

Umbelliferone was also reported to be effective in diabetic cardiomyopathy (DCM) by suppressing Janus kinase2 (JAK2) and the signal transducer and activator of the transcription signaling pathway (STAT3) [77]. Moreover, umbelliferone in a type 2 diabetic rat model at doses of 10 and 30 mg/kg decreased levels of glucose, glycated hemoglobin (HbA1c), tumor necrosis factor (TNF-α), and interleukin-6 (IL-6).
In this context, it should be mentioned that 6-formylumbelliferone (

species (banana flower ethanolic extracts) containing umbelliferone, were identified as potential antidiabetic herbal remedies in the management of diabetes and associated complications. Isolated umbelliferone increased the activity of crucial enzymes involved in glucose utilization and the glycolytic activity of the liver in alloxan-induced diabetic rats [52]. 

Umbelliferone was also reported to be effective in diabetic cardiomyopathy (DCM) by suppressing Janus kinase2 (JAK2) and the signal transducer and activator of the transcription signaling pathway (STAT3) [53]. Moreover, umbelliferone in a type 2 diabetic rat model at doses of 10 and 30 mg/kg decreased levels of glucose, glycated hemoglobin (HbA1c), tumor necrosis factor (TNF-α), and interleukin-6 (IL-6).
In this context, it should be mentioned that 6-formylumbelliferone (
14
,
Figure 8
)—an example of a rare hydroxycoumarin derivative found in nature—is effective at reducing glucose levels. In 2022, Md Yousof Ali was the first who reported its antidiabetic properties isolated from
Angelica decursiva—a herb used in traditional Korean and Chinese medicine [78]. The antidiabetic effect of 6-formylumbelliferone (
—a herb used in traditional Korean and Chinese medicine [54]. The antidiabetic effect of 6-formylumbelliferone (
14
) has been attributed to the blocking of enzymes that play a crucial role in diabetes mellitus type 2 including protein tyrosine phosphatase 1B (PTP1B) (IC
50
= 1.13 μM), α-glucosidase (IC
50
= 58.36 μM), and human recombinant aldose reductase (HRAR) (IC
50
= 5.11 μM). Furthermore, this 7-hydroxycoumarin derivative showed promising antidiabetic potential inhibiting advanced glycation end-product (AGE) (IC
50 = 2.15 μM) formation and improving insulin sensitivity by promoting the glucose uptake in insulin-resistant C2C12 muscle cells [78].
= 2.15 μM) formation and improving insulin sensitivity by promoting the glucose uptake in insulin-resistant C2C12 muscle cells [54].
In 2017, Wang et al. reported novel coumarin-isatin derivatives as a novel class of α-glucosidase inhibitors [79]. The synthesized library of hybrids was composed of a 2-[(2-oxo-2
In 2017, Wang et al. reported novel coumarin-isatin derivatives as a novel class of α-glucosidase inhibitors [55]. The synthesized library of hybrids was composed of a 2-[(2-oxo-2
H
-chromen-7-yl)oxy]acetohydrazide fragment (7-hydroxycoumarin derivative) and a substituted isatin moiety. It was found that the introduction of electron-withdrawing groups at the C-5 position of the benzene ring of the isatin skeleton significantly increased their activity. Excellent inhibition was observed for compound
26
(
Figure 15) with an IC
4) with an IC
50
value of 2.56 μM when compared to the reference drug—
acarbose
(IC
50
= 817.38 μM). Further kinetic studies at different concentrations of compound
26
in the presence of
p
-nitrophenyl α-D-glucopyranose (
p
NPG) revealed that 7-hydroxycoumarin derivative
26
is a non-competitive inhibitor. Moreover, molecular docking simulations have confirmed a high binding affinity with
Saccharomyces cerevisiae
α-glucosidase through optimal hydrophobic and hydrogen interactions with the enzyme. Thus, compound
26 may serve as a leading structure in the development of novel α-glucosidase inhibitors that modulate postprandial hyperglycemia in type 2 diabetes [79].
may serve as a leading structure in the development of novel α-glucosidase inhibitors that modulate postprandial hyperglycemia in type 2 diabetes [55].
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Figure 154. Chemical structure of 7-hydroxycoumarin-based compound 26 as an α-glucosidase inhibitor.

6. Chemotherapeutic Activity

6.1. Antimicrobial Properties of Umbelliferone and 7-Hydroxycoumarin-Based Compounds

The search for 7-hydroxycoumarin-based compounds as antimicrobial agents has developed due to the rapid growth of the drug resistance of microbes. The antimicrobial activity of parent 7-hydroxycoumarin—umbelliferone of various origins—was reported several times in in vitro studies [14]. Pure 7-hydroxycoumarin showed activity against

Bacillus cereus

with a MIC and MBC value of 62.5 µg/mL. However, this coumarin exhibited rather moderate effectiveness against other enteropathogenic bacterial species of Gram-negative

Escherichia coli

,

Shigella sonnei,

and

Salmonella typhimurium

, as well as Gram-positive

Enterococcus faecalis

and

Staphylococcus aureus

. In addition, high concentrations were often required to inhibit the growth of most species tested (MIC = 500–1000 µg/mL) [14].

Recently, the 7-hydroxycoumarin moiety was explored for its ability to inhibit biofilm formation by pathogenic bacterial strains. Firstly, the biofilm inhibitory properties of umbelliferone were shown at a concentration of 50 µg/mL against uropathogenic

E. coli [83]. 

[56]. 

6.1.1. Synthetic 7-Hydroxycoumarin-Based Compounds as Antibacterial and Antifungal Agents

The design of novel synthetic 7-hydroxycoumarin-based compounds as antibacterial and antifungal agents was directed by a different substitution pattern of umbelliferone. However, the substitution at the C-8 position of the parent molecule was of great importance for biological activity. Thus, Manidhar Darla et al. described novel 8-substituted 7-hydroxycoumarins, which exhibited considerable activity against multi-drug-resistant bacteria
E. coli
,
S. aureus
, and
P. aeruginosa
as well as fungal strains
A. niger
and
C. albicans [88]. Among them, compounds
[57]. Among them, compounds
27
and
28
(
Figure 16) were selected as promising antibacterial and antifungal compounds because they were shown to be two-fold more potent than
5) were selected as promising antibacterial and antifungal compounds because they were shown to be two-fold more potent than
norfloxacin
with MIC values of 4–6 µg/mL vs. MIC = 10 µg/mL against
E. coli
,
S. aureus
, and
P. aeruginosa
. Both of them were also three-fold more effective against
A. niger
and
C. albicans
than the first-line antifungal agent—
fluconazole (MIC = 4–5 µg/mL vs. 12–14 µg/mL) [88].
(MIC = 4–5 µg/mL vs. 12–14 µg/mL) [57].
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Figure 165.
Chemical structures of 7-hydroxycoumarin-based compounds
27
–
33
as antibacterial and antifungal agents. The substitution pattern of the parent 7-hydroxycoumarin structure is indicated in color.
7-Hydroxycoumarin derivatives with an aliphatic or aryl moiety attached at the C-3 position of the coumarin skeleton directly or through various linkers were studied for their antimicrobial activity [89]. Among them, 7-hydroxy-4-methylcoumarin
7-Hydroxycoumarin derivatives with an aliphatic or aryl moiety attached at the C-3 position of the coumarin skeleton directly or through various linkers were studied for their antimicrobial activity [58]. Among them, 7-hydroxy-4-methylcoumarin
29
with a phenyl moiety directly attached at the C-3 position of the coumarin ring system (
Figure 16) was shown as a potential antibacterial agent against the
5) was shown as a potential antibacterial agent against the
methicillin
-resistant
S. aureus
(MIC = 16 µg/mL) and the
vancomycin
-resistant
E. faecium
(MIC = 32 µg/mL).
Preliminary screening of antimicrobial activity of the synthesized 7-
O-coumarinyl alkenoates showed that compounds with a hydroxyl group in the alkenyl side chain possess greater activity than those with a non-hydroxyl carboxylic chain [91]. In particular, compounds
-coumarinyl alkenoates showed that compounds with a hydroxyl group in the alkenyl side chain possess greater activity than those with a non-hydroxyl carboxylic chain [59]. In particular, compounds
30
and
31
(
Figure 16) displayed the highest activity against
5) displayed the highest activity against
B. subtilis
,
S. pyogenes
,
S. aureus
, and
E. coli
in the range of minimum inhibitory concentrations of 32–64 µg/mL comparable to the reference antibiotic—
chloramphenicol (
MIC
=
32 µg/mL). Moreover, all compounds exhibited inhibitory activity against the fungi
C. albicans
,
C. parapsilosis,
and
Cryptococcus neoformans.
Attempts at syntheses and testing of umbelliferone esters as antimicrobial agents led to the development of novel 7-hydroxycoumarin esters through the acylation reaction with different chain length vinyl esters catalyzed by the lipase Novozym 435 [92]. The bioactive assay revealed that compounds with alkyl chain lengths of 10 (7-decanoate umbelliferone ester
Attempts at syntheses and testing of umbelliferone esters as antimicrobial agents led to the development of novel 7-hydroxycoumarin esters through the acylation reaction with different chain length vinyl esters catalyzed by the lipase Novozym 435 [60]. The bioactive assay revealed that compounds with alkyl chain lengths of 10 (7-decanoate umbelliferone ester
32
) and 12 carbon atoms (7-laurate umbelliferone ester
33
) (
Figure 16) exert a powerful biological activity and may be considered as promising therapeutic candidates for the treatment of infectious disease. 
5) exert a powerful biological activity and may be considered as promising therapeutic candidates for the treatment of infectious disease. 
One of the highly explored coumarin hybrids is the combination of 7-hydroxycoumarin derivatives with the 1,2,3-triazole moiety using ether linker [95]. The study showed that coumarin-based hybrid compounds of general formula
One of the highly explored coumarin hybrids is the combination of 7-hydroxycoumarin derivatives with the 1,2,3-triazole moiety using ether linker [61]. The study showed that coumarin-based hybrid compounds of general formula
34
(
Figure 17) possess a potency to build good oral drug candidates for the treatment of infections especially in immunocompromised patients. Moreover, the structure–activity relationship analysis of this class of compounds revealed the importance of substitution of the phenyl moiety (R
6) possess a potency to build good oral drug candidates for the treatment of infections especially in immunocompromised patients. Moreover, the structure–activity relationship analysis of this class of compounds revealed the importance of substitution of the phenyl moiety (R
1
, R
2
) in the hybrid molecules on their antimicrobial properties. Therefore, the introduction of a substituent at the
para
position of the aromatic ring (R
2
) resulted in more efficient biological activity than the
meta
substituent (R
1
). The most beneficial for biological activity was the introduction of a nitro group at the aromatic ring. Thus, novel coumarin hybrid
34a
(
Figure 9
) showed promising inhibitory potency against Gram-positive bacteria such as
M. luteus
and
B. cereus
with a MIC value of 4 µg/mL, and it was fourfold more potent than the standard drug—
ampicillin
(MIC = 16 µg/mL). 
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Figure 176. General structure of 7-hydroxycoumarin-1,2,3-triazole hybrids (34) as antibacterial and antifungal agents.
It is worth noting that numerous coumarin-1,2,3-triazole hybrids are promising candidates for the treatment of infections caused by multi-drug-resistant pathogens. A series of 7-hydroxycoumarin-based compounds linked to various 4-alkyl- or 4-aryl-1,2,3-triazole units through a methylene bridge at the C-4 position of the coumarin skeleton have been found as high-potential antibacterial agents [96]. SAR analysis indicates that the presence of
It is worth noting that numerous coumarin-1,2,3-triazole hybrids are promising candidates for the treatment of infections caused by multi-drug-resistant pathogens. A series of 7-hydroxycoumarin-based compounds linked to various 4-alkyl- or 4-aryl-1,2,3-triazole units through a methylene bridge at the C-4 position of the coumarin skeleton have been found as high-potential antibacterial agents [62]. SAR analysis indicates that the presence of
para
-alkylphenyl, 2-chloro-4-fluorobenzenesulfonamide, or dithiocarbamate substituents at the C-4 position of the triazole ring favors high selectivity towards
Enterococcus
species that are considered formidable pathogens. Hence, the selected hybrids
35
–
38
(
Figure 18) were found to be superior in inhibiting the growth of clinically isolated
7) were found to be superior in inhibiting the growth of clinically isolated
vancomycin
-resistant (VRA)
E. faecium
(MIC = 8–64 µg/mL), while the most common antibiotics, e.g.,
ceftazidime
and
ciprofloxacin
, exhibited a lack of activity. Of special interest is hybrid
35
which was fourfold more potent than
ceftazidine
against VRA
E. faecium
and
E. faecalis (MIC = 8 µg/mL and 64 µg/mL vs. MIC = 256 µg/mL) [96].
(MIC = 8 µg/mL and 64 µg/mL vs. MIC = 256 µg/mL) [62].
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Figure 187. Chemical structures of 4-substituted 1,2,3-triazole-7-hydroxycoumarin hybrids 35–38 as antibacterial agents.
An expanded series of hybrids containing imidazole or 2- as well as 4-methyl substituted imidazole revealed a superiority to compounds with a 2-phenylimidazole moiety. Hence, compounds 39, 40, and 42 (
Figure 19) displayed remarkable efficacy against
8) displayed remarkable efficacy against
S. aureus
,
S. agalactiae,
and
F. columnare
(MIC = 2–16 µM and MBC = 8–128 µM) and significant FabK inhibitory activity (IC
50 = 1.13–3.59 µM) [97].
= 1.13–3.59 µM) [63].
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Figure 198. Chemical structures of 7-hydroxycoumarin-imidazole hybrids 39–43 as antibacterial agents targeting FabI and FabK.
Much attention has been paid to hybrid
40
(
Figure 19), which showed antimicrobial activity against the three mentioned bacterial strains that was higher than the reference drug—
8), which showed antimicrobial activity against the three mentioned bacterial strains that was higher than the reference drug—
norfloxacin
(MIC and MBC values of 2–16 µM and 8–128 µM vs. MIC and MBC values of 32–64 µM and 64–128 µM)—and comparable or lower than
enrofloxacin (MIC and MBC values of 2–16 µM and 8–128 µM vs. MIC and MBC values of 2–6 µM and 2–16 µM) [97]. In addition, compound
(MIC and MBC values of 2–16 µM and 8–128 µM vs. MIC and MBC values of 2–6 µM and 2–16 µM) [63]. In addition, compound
40
displayed the best FabK inhibition potency with an IC
50
value of 1.13 µM. It is worth noting that compounds with six linker carbon atoms displayed a more definitely improved activity against
E. coli
than the other lengths of linkers. Thus, derivatives
41
and
43
(
Figure 19) were found to exhibit high activity against
8) were found to exhibit high activity against
E. coli
(MIC = 8 µM and 16 µM, respectively, and MBC = 64 µM) and maintain favorable MIC and MBC values against
S. aureus
,
S. agalactiae,
and
F. columnare
(MIC = 16–32 µM, MBC = 32–256 µM) compared to
enrofloxacin
(MIC = 1–8 µM, MBC = 2–16 µM) and
norfloxacin
(MIC = 1–64 µM, MBC = 2–128 µM). Furthermore, compounds
41
and
43
showed pronounced FabI and FabK inhibitory properties with IC
50
values of 1.20–1.35 µM and 3.44–3.55 µM, respectively. According to the data, hybrids
41
and
43 could serve as promising lead compounds for development of novel drug candidates with a broad spectrum of antibacterial activity acting through enoyl-acyl carrier protein reductase inhibition [97].
could serve as promising lead compounds for development of novel drug candidates with a broad spectrum of antibacterial activity acting through enoyl-acyl carrier protein reductase inhibition [63].
Recently, the combination of 7-hydroxycoumarin derivatives with a chalcone moiety in one molecule linked through a simple oxyacetamide linker and their oxime-containing analogues has gained great interest [98]. This class of hybrid molecules constitutes an interesting group of compounds with potent antimicrobial activity against Gram-positive (
Recently, the combination of 7-hydroxycoumarin derivatives with a chalcone moiety in one molecule linked through a simple oxyacetamide linker and their oxime-containing analogues has gained great interest [64]. This class of hybrid molecules constitutes an interesting group of compounds with potent antimicrobial activity against Gram-positive (
S. aureus
and
P. aeruginosa)
and Gram-negative (
E. coli
and
K. pneumoniae)
bacteria with MIC values in the range of 1.15–260 µg/mL; however, their exact mechanism of action has not been determined yet. Numerous hybrids proved to be most effective against cultured
S. aureus
, possessing comparable or even stronger effects than the reference drug—
levofloxacin
(MIC = 45 µg/mL). Among them, compounds
44
(MIC = 9.8 µg/mL) and
45
(MIC = 1.15 µg/mL) (
Figure 20
) were 4.6- and 39.1-fold more potent than the standard antibiotic. The structure–activity relationship analysis revealed that the incorporation of the oxime group into the structure of hybrids resulted in the enhancement of the antibacterial activity against Gram-positive
S. aureus
but caused a dramatic reduction in the potency against Gram-negative
E. coli
and
K. pneumoniae
. Thus, the compounds containing a ketone group were more efficient towards Gram-negative bacteria than their oxime analogues. In this line, hybrid
46
(
Figure 20) turned out to be the most promising with the inhibitory potency MIC = 35.8 µg/mL and 9.6 µg/mL against Gram-positive (
19) turned out to be the most promising with the inhibitory potency MIC = 35.8 µg/mL and 9.6 µg/mL against Gram-positive (
S. aureus
) and Gram-negative (
E. coli
,
K. pneumonia) bacterial strains [98].
) bacterial strains [64].
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Figure 2019. Chemical structures of 7-hydroxycoumarin-chalcone hybrids 44–46 as antibacterial agents.
Remarkable examples of potent antimicrobial agents are 7-hydroxycoumarin-substituted crown ether
47
and its sodium complex
48
(
Figure 21) presented by Sahin Gül et al. [99]. The above compounds exhibited a good activity against opportunistic pathogens including Gram-positive bacteria
0) presented by Sahin Gül et al. [65]. The above compounds exhibited a good activity against opportunistic pathogens including Gram-positive bacteria
M. luteus
,
B. cereus,
and
S. aureus,
and they were equipotent towards Gram-negative bacteria such as
P. vulgaris
and
E. coli.
The antibacterial activity of these compounds was comparable to the effectiveness of the reference antibiotics:
ampicillin
,
nystatin
,
kanamycin
,
sulphamethoxazol,
and
amoxicillin
.
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Figure 210.
Chemical structures of 7-hydroxycoumarin-crown ether compounds
47
and
48 as antibacterial and antifungal agents.

6.1.2. Metal Complexes of 7-Hydroxycoumarin-Based Compounds as Antibacterial and Antifungal Agents

Intending to enhance the antimicrobial activity of umbelliferone and its derivatives, researchers are opting for the preparation of their metal complexes. Among them, trioorganotin(IV) [100], Co(II), Ni(II), or Zn(II) [101] complexes of 7-hydroxycoumarin-derived ligands have shown enhanced in vitro antimicrobial activity compared to the parent ligands with low toxicity. Worth noting are also copper(II) complexes
as antibacterial and antifungal agents.

6.1.2. Metal Complexes of 7-Hydroxycoumarin-Based Compounds as Antibacterial and Antifungal Agents

Intending to enhance the antimicrobial activity of umbelliferone and its derivatives, researchers are opting for the preparation of their metal complexes. Among them, trioorganotin(IV) [66], Co(II), Ni(II), or Zn(II) [67] complexes of 7-hydroxycoumarin-derived ligands have shown enhanced in vitro antimicrobial activity compared to the parent ligands with low toxicity. Worth noting are also copper(II) complexes
49
and
50
with 6-acetyl-7-hydroxycoumarin
HL1
and 8-acetyl-7-hydroxy-4-methylcoumarin
HL2
, whose antimicrobial properties were evaluated against Gram-positive and Gram-negative bacterial strains as well as fungal strains (
Figure 22) [102].
1) [68].
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Figure 221. Chemical structures of ligands HL1, HL2, and their copper(II)-complexes 49 and 50 as antibacterial and antifungal agents.
Sadeek et al. demonstrated that compounds based on octahedral mixed-ligand complexes of Zr(IV) with ciprofloxacin hydrochloride as the primary ligand and 7-hydroxy-4-methylcoumarin as the secondary ligand with different coordination modes (CIP-HMC, Figure 223) possess promising biological activity against Gram-positive bacterial strains, including B. subtilis (MIC = 0.50–0.75 µg/mL) and B. cereus (MIC = 0.25–0.75 µg/mL), as well as Gram-negative bacterial strains, including P. aeruginosa (MIC = 0.50–1.0 µg/mL), K. pneumoniae (MIC = 0.50–1.0 µg/mL), and E. coli (MIC = 0.50–1.0 µg/mL), compared to the free ciprofloxacin (CP: G + ve bacterial strains MIC = 0.50 µg/mL, G − ve bacterial strains MIC = 0.5–0.75 µg/mL) and 7-hydroxy-4-methylcoumarin (HMC: G + ve bacterial strains MIC = 0.25 µg/mL, G − ve bacterial strains MIC = 0.25–0.50 µg/mL). The chelation process accelerates the drug action, increasing the potency of both ciprofloxacin and coumarin molecules especially towards B. subtilis (diameter of inhibition zone: 48–66 mm vs. 18–26 mm) [103][69].
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Figure 232. New Zr(IV) complexes formed from the interaction of ciprofloxacin hydrochloride and 7-hydroxy-4-methylcoumarin (CIP-HMC) (L = DMF, Py, and Et3N) as antibacterial agents.

6.2. Synthetic 7-Hydroxycoumarin-Based Compounds as Antituberculosis Agents

The 7-Hydroxycoumarin skeleton has also been considered as a pharmacophore for searching for new antitubercular agents. Umbelliferone isolated from the whole plants of Fatoua pilosa exhibited potent activity against Mycobacterium tuberculosis H37Rv with a MIC value of 58.3 µg/mL [104][70]. Many coumarin-containing derivatives have been screened for their antitubercular properties. One study reported in recent years proved that 4-methyl-7-hydroxycoumarin-1,2,3-triazole hybrids with antibacterial activity (Figure 187) are a promising source of new mycobacterial cell wall-targeted candidates for the treatment of tuberculosis [96][62]. Some of the coumarin-based triazole derivatives exhibited improved efficacy against the M. tuberculosis H37Ra strain in comparison to the first-line drug—pyrazinamide—with IC50 values in the range from 1.8 µg/mL to 4.0 µg/mL vs. an IC50 value of 10 µg/mL. Among them, compound 51 (Figure 243) has been claimed to be the most potent antitubercular agent with an IC50 value of 1.8 µg/mL.
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Figure 243.
Chemical structure of 7-hydroxycoumarin
51 incorporating a triazole moiety as antitubercular agent.

6.3. Synthetic 7-Hydroxycoumarin-Based Compounds as Antimalarial Agents

A series of sulfonamide-based coumarin-1,2,3-triazole conjugates as potential antimalarial agents have been developed [106]. Among them, hybrid
incorporating a triazole moiety as antitubercular agent.

6.3. Synthetic 7-Hydroxycoumarin-Based Compounds as Antimalarial Agents

A series of sulfonamide-based coumarin-1,2,3-triazole conjugates as potential antimalarial agents have been developed [71]. Among them, hybrid
52
(
Figure 25) displayed significant activity against the
4) displayed significant activity against the
P. falciparum
3D7 strain, responsible for the most lethal form of malaria, at concentrations of IC
50
< 10 µM. In comparison with a drug used in the prevention and treatment of malaria—
chloroquine
(IC
50
= 0.066 µM)—the best result was found for compound
52b
with an IC
50 value of 3.64 µM [106].
value of 3.64 µM [71].
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Figure 254. Novel 7-hydroxycoumarin-triazole hybrids 52 and 53 as antimalarial agents.
Worth mentioning are also coumarin-1,2,3-triazole hybrids of general formula
53
, previously described as antioxidant agents, which were effective against
P. falciparum
at concentrations of IC50 values ranging from 2.20 to 0.38 µg/mL (
Figure 25) [43]. 

6.4. Umbelliferone and 7-Hydroxycoumarin-Based Compounds as Antiviral Agents

4) [35]. 

6.4. Umbelliferone and 7-Hydroxycoumarin-Based Compounds as Antiviral Agents

The 7-hydroxycoumarin-based compounds having the bicyclic pinane framework were effective in treating the influenza A virus. Of special interest is the derivative containing the (−)-myrtenol 54 (Figure 265) with a significant anti-influenza activity compared with the reference drug rimantadine (IC50 = 36 µM vs. IC50 = 9 µM) [110][72].
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Figure 265.
Chemical structure of 7-hydroxycoumarin-based compound
54
as an antiviral agent.
It was found that compound 54 exhibited the highest activity when added to the infected cell culture at the early stages of viral reproduction (1–2 h after infection). It has been suggested that the most likely targets of this molecule are the viral hemagglutinin or proton channel M2, a protein that leads to viral infection. Moreover, compound 54 is characterized by the highest selectivity index calculated as the ratio between the cytotoxicity and the active dose.
Another class of novel agents suitable for preventing or treating infectious diseases are the aforementioned 7-hydroxycoumarins connected with a nitrogen-containing heterocycle by a methylene bridge [97][63]. Worth mentioning is derivative 41 containing a 2-methylimidazole ring and a six-membered linker depicted in Figure 198 which showed activity against the infectious hematopoietic necrosis virus (IHNV) [111][73]. Compound 41 significantly inhibits IHNV replication in EPC cells with an IC50 value of 2.53 µM and a CC20 value of 17.13 µM.

6.5. Umbelliferone and 7-Hydroxycoumarin-Based Compounds as Anticancer Agents

6.5.1. Synthetic 7-Hydroxycoumarin-Based Compounds as Histone Deacetylase (HDAC) Inhibitors

In addition to genetic alterations, aberrant epigenetic modifications of gene expression may also be involved in tumor initiation and progression. Histone acetylation plays a pivotal role in the epigenetic regulation of gene transcription and expression through chromatin modification. The level of this process is balanced under physiological conditions by both histone acetyltransferases (HATs) and histone deacetylases (HDACs) [129][74]. HDACs were found to be overexpressed in various cancer types such as prostate, ovarian, breast, and colon cancer or leukemia, with the fateful result of gene transcription and expression deregulation influencing a variety of cellular functions, namely, proliferation and differentiation, angiogenesis, metastasis, cell death, autophagy, and metabolism [130][75].
7-Hydroxycoumarin-based HDACs inhibitors show huge structural diversity. However, the general pharmacophore consists of substituted 7-hydroxycoumarin combined with 2-aminobenzamide or hydroxamic acid via a hydrophobic linker. Firstly, coumarin-based compounds as potent histone deacetylase inhibitors and anticancer agents were developed based on the structural modification of the selective class 1 HDAC inhibitor entinostat (Figure 276). In this approach, Abdizadeh et al. described the activity of novel HDAC inhibitors bearing 7-O-substituted coumarin carboxamide instead of the benzyl carbamate moiety of entinostat [131][76]. Numerous designed compounds (Figure 276) exhibited significant antiproliferative activity with IC50 values in the range of 0.27 µM to 61.87 µM against various cancer cells, especially colon (HCT116) and ovarian cancer (A2780) cells, as well as lung (A549), prostate (PC3), breast cancer (MCF7), and leukemia (HL60) cells. Additionally, the variety and position of substituents on the O-benzyl group were also important for the inhibitory activity. Within the series, the most potent 7-hydroxycoumarin derivative against tested tumor cell lines, derivative 55 (Figure 276) (IC50 = 1.69–16.6 µM), showed higher antiproliferative properties towards the HCT116, A549, and HL60 cell lines than the known clinically studied entinostat (IC50 = 0.27–3.14 µM vs. IC50 = 2.03–4.53 µM).

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Figure 276.
Chemical structures of 7-hydroxycoumarin-based benzamides
55
–
58
as HDAC1 inhibitors with anticancer properties.
Furthermore, compounds 56–58 (Figure 276) also displayed promising cytotoxicity effects on human cancerous cells (IC50 = 0.53–48.86 µM) and enzymatic inhibitory HDAC activity (IC50 = 0.80–5.41 µM) with unique HDAC1 isoform selectivity (IC50 = 0.47–0.87 µM) comparable to entinostat (IC50 = 0.41 µM). Molecular docking studies of the mentioned coumarins showed that these compounds interact with the active site of HDCA1 through the coordination of the zinc ion, strong hydrophobic interactions, and the formation of the hydrogen bond (Figure 287).
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Figure 287.
A 2D representation of the interaction between compounds 56–58 in the crystal structure of HDAC1.
The promising results of coumarin-based benzamides as potent HDAC inhibitors with anticancer activity encouraged the design of coumarins containing a hydroxamate moiety as HDAC inhibitors based on the structure of an FDA-approved deacetylase inhibitor for the treatment of cutaneous T-cell lymphoma—vorinostat, also known as suberoylanilide hydroxamic acid (SAHA, Figure 298) [132][77]. The designed compounds possessed a hydroxamic acid group linked via a spacer (CH2)n to the C-4 position of the coumarin scaffold (Figure 298). SAR analysis proved that the HDAC1 inhibitory activity of novel compounds was linker-length-dependent and revealed that seven carbon spacers were sufficient for high activity. Thus, compounds 59 and 60 (Figure 298) were claimed to possess excellent inhibitory potency against HDAC1 (IC50 = 0.24 nM and 1.85 nM, respectively) [132][77].
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Figure 298. Chemical structures of 7-hydroxycoumarin-based hydroxamate derivatives 59–64 as HDAC1 inhibitors with anticancer properties.
According to the obtained results, coumarin-based hydroxamate 60 was considered as the lead structure to explore more coumarin-based HDAC inhibitors with better activities [133][78]. The modification of structure 60 consisted in replacing the methoxy group at the C-7 position of the coumarin core with a different alkoxy chain length or substituted benzyloxy group (Figure 298). A series of novel compounds were evaluated in vitro for their HDAC inhibitory activities. In general, the synthesized compounds were more active than the reference drug SAHA, and the alkoxy-substituted coumarins showed stronger inhibitory potency than the benzyloxy-substituted analogues. Furthermore, it was revealed that the potency of the alkoxy-substituted compounds improved with the appropriate elongation of the chain length, while the inhibitory effect of the benzyloxy-substituted ones depended significantly on the nature and position of the substituent at the benzyloxy group. Among them, 2-methoxyethoxy-substituted analogue 61 (Figure 298) was found to be the most potent HDAC1 inhibitor (IC50 = 0.30 nM) with significant growth inhibition against human MDA-MB-231, H157, and A549 cancer cell lines (IC50 = 0.36–2.79 µM), even better than SAHA (IC50 = 0.36–2.79 µM). Molecular docking proved the high binding potency of compound 61.  Exploring various novel SAHA analogues, it was evidenced that the introduction of a hydroxamate moiety at the C-7 position of the 7-hydroxycoumarin skeleton could effectively improve HDAC inhibitory activity. Thus, novel target compounds 63–64 (Figure 298) displayed higher inhibitory effects against HDAC1 than SAHA (IC50 = 6.88 nM and 8.71 nM vs. IC50 = 21.10 nM) [132][77]. A series of 7-hydroxycoumarin-3-carboxylic-based N-hydroxycinnamide derivatives have also been described as histone deacetylase inhibitors with anticancer activity [134][79]. Among them, 7-hydroxycoumarin derivative 65 depicted in Figure 3029 was identified as the most potent HDAC inhibitor (IC50 = 0.32 μM) with 26-fold selectivity for the HDAC1 isoform over the HDAC6 one (IC50 = 0.19 µM vs. 4.98 µM). These results were better than those of SAHA (HDAC IC50 = 0.48 µM; HDAC isoform selectivity: HDAC1 IC50 = 0.23 µM vs. HDAC6 IC50 = 0.22 µM) [134][79].
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Figure 3029. Chemical structure of 7-hydroxycoumarin-3-carboxylic-based N-hydroxycinnamide derivative 65 as an HDAC inhibitor with anticancer properties.

6.5.2. Synthetic 7-Hydroxycoumarin-Based Compounds as Androgen Receptor (AR) Antagonists

Anticancer therapy may utilize androgen receptor (AR) signaling pathway inhibition, which has been implicated in the carcinogenesis and metastasis of hormone-related tumors, e.g., prostate and breast cancer. Driven by the need to search for unique AR antagonists, the in silico screening of small-molecule libraries of 7-substituted umbelliferone derivatives was applied [135][80]. Using a combined virtual protocol, two molecules, 66 and 67, were identified (Figure 310) that interact with AR in a unique manner and act as pure AR antagonists [136][81].
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Figure 310. Chemical structures of 7-hydroxycoumarin-based compounds 66–71 as AR antagonists with anticancer properties.
Based on these findings, a novel series of umbelliferone derivatives varying in the terminal aromatic group of the ketone linkage at the C-7 position of the coumarin scaffold was designed and evaluated in in vitro studies for antiproliferative activity against the prostate 22Rv1 and breast MCF-7 cancer cell lines [138][82]. Within the series, compounds 68 and 69 (Figure 31) displayed remarkable antiproliferative activity against human prostate (22Rv1) and breast (MCF-7) cancer cells with IC50 values in the ranges of 0.93–22.27 μM and 0.47–43.21 μM. In turn, coumarins 70 and 71 (Figure 31) were superior in inhibiting the growth of 22Rv1 cells (IC50 = 22.27 μM and 20.37 μM, respectively) in comparison to clinically used drugs, including second-generation AR antagonist enzalutamide (IC50 = 31.76 μM) [138][82].
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Figure 321. The 2D putative binding modes of compounds 68 and 69 inside the antagonistic hAR-LBD showing hydrogen bond interactions with key amino acids: Arg752, Gln711, Thr877, and Asn705.

6.5.3. Synthetic 7-Hydroxycoumarin-Based Compounds as Inhibitors of the PIK3/Akt Signaling Pathway

Novel synthesized compounds bearing a pyridinylurea substituent attached to the coumarin core at the C-3 position were expected to show favorable interactions with the hinge region of PI3Ks through the formation of the critical hydrogen bond with the backbone residue of valine [144][83]. Molecular structure analysis revealed that the nature of the substituent and its position on the distal aryl ring may have a great influence on the interactions with the ATP-binding pocket and differential potency. Preliminary in vitro screening selected compound 72 (Figure 332) as the most promising candidate with considerable growth inhibitory effects on human cancer cell lines, including lung carcinoma A549, breast carcinoma MCF-7, leukemia K562, and cervical carcinoma HeLa (IC50 values ranging from 2.17 µM to 7.13 µM), that was able to inhibit 84.1% of PIK3K activity.
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Figure 332. Chemical structures of 7-hydroxycoumarin-based compounds 72–75 as inhibitors of the PI3K/Akt signaling pathway with anticancer properties.
In turn, Abdelnaby et al. investigated dual PI3K/Akt-acting hybrids bearing 7-hydroxycoumarin derivatives and a thiosemicarbazone moiety or its cyclic form, a thiazolidin-4-one ring, attached at the C-8 position of the coumarin ring [145][84]. Several of the synthesized compounds exhibited comparable or improved cytotoxicity against the breast MCF-7 cancer cell line compared with standard drug 5-fluorouracil (5-FU) (IC50 = 1.03–26.41 µM vs. IC50 = 27.81 µM). Within the coumarin-thiosemicarbazone series, compound 73 (Figure 332) displayed significant efficacy with an IC50 value of 5.13 µM, while hybrid 74 (Figure 332) was even 23-fold more potent than 5-FU (IC50 = 1.21 µM vs. IC50 = 27.81 µM) and demonstrated an excellent safety profile with a good selectivity index (SI = 16.61 vs. SI = 1.3) [145][84].
The structure–activity analysis of this class of compounds revealed that the cyclization strategy and substitution pattern of the thiazolidine ring are important for the anticancer activity [145][84]. Thus, within the coumarin-thiazolidine series, a cyclic analogue of benzoyl derivative 75 depicted in Figure 332 was found to induce the most remarkable cytotoxic effect against MCF-7 cells at a low concentration of IC50 = 1.03 µM in comparison to the non-cyclic analogue (IC50 = 47.32 µM).
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6.5.4. Monoterpene-Coumarin Hybrids as Tyrosyl-DNA Phosphodiesterase 1 (Tdp1) Inhibitors

Figure 34. Compound
The screening approach along with the oligonucleotide-based fluorescence assay have been successfully applied to identify 3-methoxybenzyl-7-hydroxycoumarin
75 in the active site of PI3K (left) and Akt-1 (right).

6.5.4. Monoterpene-Coumarin Hybrids as Tyrosyl-DNA Phosphodiesterase 1 (Tdp1) Inhibitors

The screening approach along with the oligonucleotide-based fluorescence assay have been successfully applied to identify 3-methoxybenzyl-7-hydroxycoumarin 76
annulated with the cyclohexane ring (
Figure 335) as a new structural type of Tdp 1 inhibitor with an IC
) as a new structural type of Tdp 1 inhibitor with an IC
50 value of 4.93 µM [152].
value of 4.93 µM [85].
Pharmaceuticals 16 01732 g035
Figure 353.
Monoterpene-coumarin hybrids
76
–
78
as Tdp1 inhibitors with anticancer properties.
The structural optimization revealed that the replacement of the phenyl group with a bulky monoterpenoid moiety at the C-7 position of the coumarin core could increase inhibitor potency. Thus, 7-hydroxycoumarin
77
(
Figure 35) containing a monoterpene substituent at the 7-hydroxy group was found to show Tdp-1 inhibition at a low concentration of IC
3) containing a monoterpene substituent at the 7-hydroxy group was found to show Tdp-1 inhibition at a low concentration of IC
50
= 0.675 µM. Interestingly, compound
77
exhibited negligible cytotoxicity (CC
50
> 100 µM) when tested against human cancer cells; however, it significantly enhanced the cytotoxic activity of the Top1 inhibitor—
camptothecin
—in cancer cells.
Novel hybrids bearing a 4-aryl-7-hydroxycoumarin core and monoterpenoid moieties were designed as potential tumor sensitizers for currently used antitumor drugs [153]. The synthesized compounds emerged as potent Tdp1 inhibitors with IC
Novel hybrids bearing a 4-aryl-7-hydroxycoumarin core and monoterpenoid moieties were designed as potential tumor sensitizers for currently used antitumor drugs [86]. The synthesized compounds emerged as potent Tdp1 inhibitors with IC
50
values in the submicromolar range. Of these, monoterpene-arylcoumarin hybrid
78
presented in
Figure 35 was selected for in vivo studies using the Marine Krebs-2 carcinoma model, which revealed its synergistic effect with a clinically important Topo1 inhibitor—
3 was selected for in vivo studies using the Marine Krebs-2 carcinoma model, which revealed its synergistic effect with a clinically important Topo1 inhibitor—
topotecan
—against Krebs-2 carcinoma. 

6.5.5. Synthetic 7-Hydroxycoumarin-Based Compounds as Carbonic Anhydrase (CA) Inhibitors

Recently, the search for antitumor drugs led to the discovery of novel carbonic anhydrase inhibitors represented by a 7-hydroxycoumarin derivative containing primary sulfonamide moiety
79
(
Figure 36) [161]. It has been demonstrated that compound
4) [87]. It has been demonstrated that compound
79
has a selective antiproliferation effect on the colorectal HT-29 cancer cell line, which has a high CA IX expression under ambient air (IC
50
= 17.01 µM for HT-29, IC
50
= 118.73 µM for embryonic kidney cell line HEK293T compared to the standard drug
doxorubicine
with IC
50
values of 5.38 and 1.051 µM, respectively). Compound
79
inhibits the proliferation and migration of HT-29 cells in a dose-dependent manner and acts as an inducer of apoptosis.
Pharmaceuticals 16 01732 g036
Figure 364. Chemical structures of 7-hydroxycoumarin-based compounds 79 and 80 as CA-IX and CA-XII inhibitors with anticancer properties.
In 2019, among a series of novel 7-hydroxycoumarin-3-carboxamides, Thacker et al. reported N-(4-chlorophenyl)-7-hydroxy-2-oxo-2H-chromene-3-carboxamide (80) (Figure 364) as exhibiting a submicromolar potency against tumor-associated, transmembrane-bound carbonic anhydrases hCA IX and hCA XII [162][88]. The concentration value required to produce half the maximum enzyme inhibition Ki for the designed small-molecule inhibitor 80 was calculated as 0.2 μM.
An interesting class of hybrid compounds—4-chloromethyl-7-hydroxycoumarins linked via the 1,2,3-triazole ring—has been reported to be effective as selective inhibitors of the tumor-associated isoform hCA IX [163][89]. The lowest in vitro inhibition constant was achieved by compound 81 (Figure 375) containing a para-substituted cyano group at the benzene ring (Ki = 32.7 nM); the calculated Ki constant for acetazolamide (AAZ) as a standard CA inhibitor equals 25.8 nM. Hence, 7-hydroxycoumarin derivative 81 could be taken as a lead compound for the further design and development of selective and potent hCA IX inhibitors [163][89].
Pharmaceuticals 16 01732 g037
Figure 375. Chemical structures of 4-substituted 1,2,3-7-hydroxycoumarin hybrids 81 and 82 as selective CA IX inhibitors with anticancer properties.
It was suggested that the introduction of the sugar moiety into the chemical structure of the designed carbonic anhydrase inhibitors can lead to a significant enhancement of their activity [164,165,166][90][91][92]. In this context, of great importance for the development of new chemotherapeutic agents are carbohydrate-based 7-hydroxycoumarin derivatives (82) (Figure 375) comprising a biocompatible covalent heterocyclic linker designed by Chu et al. [167][93].

6.5.6. Synthetic 7-Hydroxycoumarin-Based Compounds as Cyclooxygenase-2 (COX-2) and 5-Lipoxygenas (5-LOX) Inhibitors

The development of novel antitumor drugs based on the inhibition of cyclooxygenase-2 (COX-2) has been an important part of antitumor drug development, because COX has proven to be a promising target in the design of antitumor agents. There is a growing understanding that several inflammatory mediators, such as cytokines, chemokines, and growth factors, may promote cancer formation and progression by controlling the tumor microenvironment. 

Similar to COX-2, lipoxygenases (LOXs) are pro-inflammatory enzymes associated with arachidonic acid (AA) cascade. In this pathway, AA is transformed into hydroxyeicosatetraenoic acids derivatives (HETEs) and leukotrienes (LTs), which play a major key role in the development and progression of human cancers as a result of LOX activation. In particular, the overexpression of 5-LOX has been shown to have significant effects on the cell cycle, preventing apoptosis and stimulating angiogenesis.

In this line, Shen et al. designed a novel COX-2 and 5-LOX dual inhibitor composed of the 1-(4-sulfamoylphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-pyrazole and 7-hydroxycoumarin moieties [174][94]. A high selectivity level has been observed for compound 83 (Figure 38) towards enzyme subtypes based on its IC50 values of 0.23 µM for COX-2 and 0.87 µM for 5-LOX, making the tested compound superior to celecoxib as a positive control for COX-2 (IC50 = 0.41 µM) and zileuton for 5-LOX (IC50 = 1.35 µM).

6.5.7. Metal Complexes of 7-Hydroxycoumarin-Based Compounds as Anticancer Agents

In 2018, Hua et al. described cou-platin (84, Figure 396) composed of 7-hydroxycoumarin and a platinum(IV) moiety derived from cisplatin as more potent towards a variety of cancer cells than cisplatin (IC50 = 0.08–2.46 µM vs. IC50 = 1.86–9.34 µM) [176][95]. The mechanistic studies with the use of human colon carcinoma HCT116 cells revealed that new Pt-binding molecule 84 is able to inhibit cancer cell growth via activation of cell apoptosis and inhibition of the ERK/MAPK signaling pathway.

Pharmaceuticals 16 01732 g039
Figure 396.
Chemical structures of 7-hydroxycoumarin-based Pt(IV) complexes
84
and
85
as anticancer agents.
In turn, Pt(IV) conjugate 85 (Figure 396), composed of an AR-binding nonsteroidal cyanonilutamide unit, 7-hydroxycoumarin, and cisplatin moiety, represents the AR antagonist intended for castration-resistant prostate cancer treatment [177][96]. Malignancy-related inflammation is one of the factors contributing to the development and spread of many types of cancer; thus, Wang et al. have examined novel bifunctional platinum(IV) compounds with 7-hydroxycoumarin ligands arranged in axial positions, which were designed to have both antitumor and anti-inflammatory properties (86–89, Figure 4037) [178][97].
Pharmaceuticals 16 01732 g040
Figure 4037. Chemical structures of 7-hydroxycoumarin-based Pt(IV) complexes 86–89 as anticancer agents with a bi-functional mechanism of biological action. In fact, organometallic Ru(II)-arene compounds 92–94 containing a 7-hydroxycoumarin group showed stronger cytotoxic effects on cancer cell lines HCT-116 (colorectal cancer), HepG-2 (hepatocellur carcinoma), and A549 (non-small cell lung cancer) than ligand 90 and non-functionalized complex 91 (IC50 = 65.6–161.4 µM vs. IC50 > 500 µM) (Figure 4138).
Pharmaceuticals 16 01732 g041
Figure 4138.
Chemical structures of ligand
90
and Ru(II) complexes
91
–
94
as anticancer agents.
New NHC gold(I) complexes bearing a coumarin-type carbene ligand (96) and 1-thio-β-D-glucopyranosido groups as a second ligand (97 and 98) have been claimed as potential inhibitors of the TrxR enzyme by targeting the selenocysteine residue in the enzyme redox-active motif (Figure 4239) [184][98]. Notably, complex 97 containing the tetra-O-acetyl-1-thio-β-D-glucopyranosido ligand was found to be more efficient in ovarian carcinoma (A2780) and breast carcinoma (MCF-7) cell lines (IC50 = 11.6–12.9 µM) than ligand 95 and complex 96 (IC50 = 39.7–71.2 µM).
Pharmaceuticals 16 01732 g042
Figure 4239. Chemical structures of ligand 95 and 7-hydroxycoumarin-based Au(I) metal complexes 96–100 as TrxR inhibitors with anticancer properties. In turn, alkynyl-gold(I) complexes 99 and 100 (Figure 42) with a propargyl-functionalized coumarin derivative exhibited moderate-to-strong inhibitory potency against TrxR activity (IC50 values ranging from 0.044 µM to >1 µM) [185][99]. 

7. Umbelliferone and 7-Hydroxycoumarin-Based Compounds as Probes and Sensors

Levin et al. [188][100] synthesized novel dyad molecule 101 shown in Figure 430 composed of two different fluorophores: 1,2,4,5-tetraarylimidazole and 8-arylazomethinocoumarin. Because of the presence of both proton (hydrogen) donating/accepting groups in the structure, the designed molecule exhibits multiple fluorescence with maxima at 450 nm and 535 nm as a result of excited-state intramolecular proton transfer (ESIPT).

Pharmaceuticals 16 01732 g043
Figure 430.
Chemical structures of 7-hydroxycoumarin-based compounds
101
–
112
with fluorescent properties.
Recently, Xiao et al. focused on a series of 3-substituted umbelliferone derivatives in order to identify inhibitors of tautomerase of the macrophage migration inhibitory factor (MIF) with favorable physicochemical properties [189][101]. MIF is a pro-inflammatory cytokine which plays a pivotal role in the pathogenesis of many cancers. Its overexpression enhances angiogenesis, tumor growth, and progression. Hence, MIF enzymatic tautomerase activity has attracted considerable attention and displays a novel drug target for cancer treatment. The study demonstrated that selected 7-hydroxycoumarin derivative 102 (Figure 430) is a valuable tool in the advancement of MIF assays. In 2018, Shi et al. designed the switchable Förster resonance energy transfer (FRET) two-photon ratiometric probe (103) (Figure 430) for assaying γ-glutamyl transferase (GGT) activity, composed of 7-hydroxycoumarin that acts as an energy donor, a peptide derivative, and a 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (boron-dipyrromethene, BODIPY) moiety which is an energy acceptor [190][102].  A new ‘off-on’ pH-sensitive fluorescent probe (104) for water solutions was synthesized by Li et al. starting from 2-(1-phenyl-1H-phenanthro [9,10-d]imidazol-2-yl)aniline and 7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde (Figure 430) [191][103].
Shukla’s research group described the scalable synthesis of fluorinated 7-hydroxycoumarin-functionalized lysines which may find use in probing protein function in acidic environments [192][104]. Fluorinated lysine derivatives 105–107 shown in Figure 430 when excited at 360 nm exhibit fluorescence (Φf = 0.58–0.70) at pH values lower than 6 (pKa = 4.0–6.2).
In 2020, Gleason et al. demonstrated for the first time that fluorescent non-canonical amino acid (fNCAA) containing a 7-hydroxycoumarin moiety (108, Figure 430) can be used as an acceptor of Förster resonance energy transfer (FRET) in a single protein containing multiple tryptophan residues [193][105]. The fNCAA based on L-(7-hydroxycoumarin-4-yl)ethylglycine (108) due to its small size may be easily incorporated into versatile sites of proteins [194][106].
Recently, it was reported that sensors based on the oxidation of organic borates have superior selectivity for the detection of hydrogen peroxide than other ROS. In 2023, novel probe 109 (Figure 430) composed of 3-acetyl-7-hydroxy-2H-chromen-2-one and arylboronic acid for monitoring hydrogen peroxide levels in biological systems was synthesized in two steps by Wang et al. [201][107].
In 2018, Zhu et al. reported the synthesis of novel 7-hydroxycoumarin chemosensor 110 (Figure 430) in a straightforward manner by refluxing 8-formyl-7-hydroxycoumarin with nicotinohydrazide in ethanol [202][108]. 
Recently, Li et al. have reported 7-hydroxycoumarin-based carbonothioate derivative 111 (Figure 430) as a highly sensitive fluorescent probe for mercury ions with many practical applications [203][109]. 
Rojas-Montoya et al. designed a series of novel grafted photoluminescent polymers (112) (Figure 430) by gamma irradiation of polyethylene in the presence of acryloyl chloride, followed by an esterification reaction with a 7-hydroxycoumarin derivative functionalized with flexible chains of tetraethylene glycol [204][110]. 

8. Conclusions

Umbelliferone (UMB, 7-hydroxycoumarin) is a natural coumarin-derived compound with a diversity of bioactivities, including anti-inflammatory and antioxidant properties, disease prevention, cell growth modulation, and enzyme inhibition, among others. A large number of research groups have revealed that UMB possesses a promising pharmacological and safety profile, and it could be expected to treat various diseases such as inflammation, neurodegenerative disorders, neuropsychiatric diseases, diabetes, cancer, and microbial infections [3,4,5][3][4][5]. Additionally, the efficiency of the synthetic routes to obtain a wide range of functionalized 7-hydroxycoumarins with a variety of activities ensures that umbelliferone is an inspiring scaffold in drug design and development [3,6,7,8,205,206][3][6][7][8][111][112].

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