Overview of Recent Advances in 3-Hydroxycoumarin Chemistry as a Bioactive Heterocyclic Compound

Coumarins or benzo-2-pyrone derivatives are one of the most significant families of natural compounds and are also important in synthetic organic chemistry. They have been widely used as starting materials or precursor molecules in the pharmaceutical, perfumery and agrochemical industries, etc. Hydroxycoumarins are an important class of coumarin compounds that possess several physical, chemical and biological properties. Among the hydroxycoumarins, 3-hydroxycoumarin seems to be the most important because of its numerous chemical, photochemical and biological properties. However, this compound remains less well known compared to others of the same class such as 7-hydroxycoumarin and 4-hydroxycoumarin. This study is therefore devoted to 3-hydroxycoumarin and its applications. The main purpose of this review is to summarize and document the recent advances on 3-hydroxycoumarin, concerning the main routes of its synthesis, its reactivity, its applications in different fields of biology. Several methods for the synthesis of 3-hydroxycoumarin have been described in the literature, most of which use salicylic aldehyde and 1-(2-hydroxyphenyl)ethanone as starting compounds. Other synthesis pathways exist, but they are based on intermediate synthesis compounds. Concerning the reactivity of 3-hydroxycoumarin, many heterocyclic compounds obtained from 3-hydroxycoumarin have been reported in the literature. Among these heterocycles are pyrido[2,3-c]coumarin derivatives, chromeno[4,3-e][1,3]oxazine derivatives, dihydropyrano[2,3-c] chromenes and 3-coumarinyl carboxylates. Various researches have also concerned the biological properties of this compound. It appears from these numerous studies that 3-hdroxycoumarin is used in fields such as genetics, pharmacology, microbiology, etc.


Introduction
Hydroxycoumarins natural or synthetic are of great interest, since many of them show prominent biological activity and photochemical characteristics. Hydroxycoumarins and their derivatives have been extensively examined in various fields like such as biology, medicine, physics and chemistry [1][2][3][4][5][6][7][8]. Specifically, 3-hydroxycoumarin 1 and their derivatives represent less known class of hydroxycoumarin compounds. This compound ( Figure  1) which known as 3-hydroxy-2H-chromen-2-one and 3-hydroxy-2H-1-benzopyran-2-one or 3-hydroxychromen-2-one in IUPAC system. Its structure contains two tautomeric keto-enol forms [6]. Also known as 3-hydroxychromenone, this compound represent nowadays, an important precursor in the realm of organic synthesis. Compounds possessing the 3-hydroxycoumarin nucleus are recently explore for their antioxydant activity [9], fluorescence and photopropecteur properties [6][7][8]. This review is not exhaustive, the objective is to enhance the title compound, its reactivity and its applications. Thus, we report in present paper, the synthesis and reactivity of 3-hydroxycoumarin. The biological properties of this compound will then be investigated.

3-Hydroxycoumarin Synthesis Using Salicylic Aldehyde
One of the earliest methods of compound 1 synthesis has been proposed by Trivedi and Sethna [10]. The reaction equations for the method of synthesis are as follows ( Figure  2). An equimolecular mixture of salicylic aldehyde 2 and acetylglycine 3 is heated for 1 hour in the presence of 1 equivalent of anhydrous sodium acetate 4 and 2 equivalents of acetic anhydride 5. The intermediate product of the reaction, 3-acetamidocoumarin 6 is then absorbed in a minimal amount of alcohol and heated under reflux with 3N hydrochloric acid for 3 to 4 hours. The 3-hydroxycoumarin 1 is isolated by cooling this reaction mixture. The reaction certainly takes place by esterification between the phenol function of salicylaldehyde 2 and the acid function of acetylglycine 3 in the presence of sodium acetate 4. Intramolecular condensation then occurs between the only active methylene of this reaction intermediate and the aldehyde function, under the combined effect of the base and acetic anhydride, a solvent known for its dehydrating character. 3-acetamidocoumarin 6 is then obtained. The last step in the reaction is the substitution of the acetamide function by a hydroxyl in the presence of hydrochloric acid (HCl). The acid then protonates the nitrogen and favours its substitution ( Figure 3).

Synthesis of Pyrido[2,3-c] Coumarin Derivatives
3-hydroxycoumarin 1 is widely used as a starting material in the synthesis of a number of oxygenated, nitrogenous and other heterocyclic molecules. This is the case of the pyrido[2, 3-c] coumarin derivatives. The pyrido [2,3-c]coumarin derivatives are structural analogues of santiagonamine 16 (Figure 8), an alkaloid isolated from Berberis Darwinii (Berberidacea). This compound has shown interesting properties for wound healing. Pave et al. [12] have developed a new method for the preparation of substituted derivatives of pyrido[2,3-c]coumarin 17 and its tetrahydro derivatives involving the condensation of 3-hydroxycoumarin 1 with β-aminoketone 18 followed by intramolecular cyclization (Figure 9). These compounds were synthesized to explore the different biological activities that they would contain.
The authors investigated beforehand the optimal conditions for this synthesis. The choice of the catalyst, the temperature, the kinetics of the reaction. Several catalysts were experimented in order to improve the yield of the specific synthesis. The results showed that when the reaction uses nano ZnO; it allowed to obtain the desired product with a yield of 91% in 2.5 h. When optimizing the reaction conditions, the effect of temperature was also monitored. The results showed that at 70°C, the product yield is maximum.
Crystallographic data of compound 30b

Antioxidant Properties
Bailly et al. [9] synthesized a series of hydroxylated  All of the compounds tested exhibited a variety of antioxidant activities ( Table 2). The results of the study established that the hydroxylated compounds on the C-6 and C-7 positions are the most active of the series with antioxidant powers comparable to those of quercetin and vitamin C. In addition, the introduction of a hydroxyl group at the C-3 position is sufficient to improve the extinguishing properties since coumarin did not react in all four tests. Substitution of the phenyl ring with another hydroxyl group resulted in a significant increase in antioxidant properties. A precise analysis of the results showed that the most effective compounds in the series were 33c and 33e. The authors also analyzed the behavior of these compounds in the radical scavenging mechanism. It appears from this investigation that these compounds form o-and p-quinonoid derivatives on radical scavenging. This suggests that they may serve as new lead compounds for pharmacological research.

3-Hydroxycoumarin Action on Tyrosinase
Human tyrosinase: tyrosinase is one of the key enzymes for the biosynthesis of melanin in mammals. Its decreased activity has been targeted for the prevention of skin hyperpigmentation disorders such as melasma and age spots. Work on the formulation of 3-hydroxycoumarin 1 loaded vesicles for topical applications by Schlicha et al. [52], showed that 3-hydroxycoumarin 1 has a strong ability to inhibit recombinant human tyrosinase. In vitro skin penetration and permeation studies have shown that these formulations effectively cross the barrier represented by the stratum corneum, delivering 3-hydroxycoumarin to the deep layers of the skin. The effect of applying the liquid and gel formulation at different times was also evaluated.
Mushroom tyrosinase: the structure-activity relationships and interactions of four hydroxycoumarins, including 3,4, 6,7-hydroxycoumarin ( Figure 22) with tyrosinase in the mushroom were also studied [53]. These different compounds showed different behaviours during the action of the enzyme. 3-Hydroxycoumarin was found to be a potent inhibitor of the enzyme compared to other hydroxylated coumarins. These results were compared with those obtained by in silico predictions to obtain potentially useful information for the synthesis of new coumarin inhibitors that resemble the structure of 3-hydroxycoumarin.

3-Hydroxycoumarin as Inhibitors of Moniliophthora Perniciosa Fungus
3-hydroxycoumarin is an in vitro, in vivo and in silico inhibitor of the fungus Moniliophthora perniciosa compared to the standard defense activator acibenzolar-S-methyl 37 and systemic fungicidal tebuconazole 38 [54]. Initially, in vitro tests for inhibition of basidiospore germination were performed using four different concentrations of 3-hydroxycoumarin, resulting in 100% inhibition at the concentration of 1000 ppm. Subsequently, this substance was used in vivo in four different treatments of cocoa plants of the SIC-23 genotype, with regard to the order of application. Data analysis showed greater inhibition when 3-hydroxycoumarin was applied after inoculation. In silico tests show that 3-hydroxycoumarin inhibits the production of chitin synthase by the fungus. Chitin synthase is a key enzyme in the chitin biosynthesis pathway. Therefore, the present study identifies a potential inhibitor of Moniliophthora perniciosa which is 3-hydroxycoumarin and suggests the best application methodology.

3-Hydroxycoumarin as New Matrix for DNA Analysis
The structure of 3-hydroxycoumarin contains a conjugated system consisting of a phenyl ring and a ketone group, which should have sufficient absorption for 337 nm. In addition, the hydroxyl group and the two carbonyl groups are considered important for a good matrix for time-of-flight mass spectrometry by laser desorption/ionization (MALDI-TOF MS) in DNA analysis [55][56]. Compared to conventional matrices of 3-hydroxypicolinic acid and 6-aza-2-thiothymine (ATT), 3-hydroxycoumarin has a significant improvement in resolution, S/N ratio, spot-to-spot-, and sample-to-sample reproducibility for the DNA segments analyzed. At present, despite extensive research, the matrices used in practice for DNA detection have been limited to 3-hydroxypicolinic acid 39 [57], picolinic acid 40 [58], 6-aza-2-thiothymine 41 [59], and 2,4,6-trihydroxyacetophenone 42 [60]. The introduction of 3-hydroxycoumarin as a template, initially used to analyze 67 m DNA, has greatly increased MALDI MS ability to analyze DNA.

Photoprotective Properties of 3-Hydroxycoumarin Against UVB Deleterious Effects
Many studies have shown the photoprotective properties of 3-hydroxycoumarin against the deleterious effects of UVB, as shown in the study by Goodwin and Pollock [61]. They reported on the UV-absorbing properties of 29 coumarin derivatives, including 3-hydroxycoumarin. Other recent work has also shown the properties of nucleus-bound coumarins. According to the various studies, the photoprotective effect of these compounds is linked to their ability to absorb UV radiation. These results are corroborated by experimental results on the photoprotective capacity of 3-hydroxycoumarin against UVB from sea urchin gametes and embryonic cells [14].

Human 15-LOX-1 inhibitors Based on 3-Hydroxycoumarin
Lipo-oxygenase enzymes are one of the causes of several diseases such as inflammation, cancer, asthma, allergies, strokes, etc. [62]. Because of their importance as therapeutic targets, work has been devoted to the discovery of pathways for the synthesis of new and potent inhibitors of this lipo-oxygenase. Several natural and synthetic derivatives of hydroxycoumarins have been reported as lipo-oxygenase inhibitors [63][64][65][66][67]. Most of them inhibit lipo-oxygenase pathways using the redox mechanism with their hydroxyl groups. Alavi et al. [66] analysed the lipo-oxygenase inhibitory power of monohydroxycoumarins against human 15-LOX-1 enzymes and their radical scavenging activity was comparatively observed. Among the coumarins mentioned, the 3-hydroxy derivative was the potent lipo-oxygenase inhibitor with an IC50 value of 9.5 µm. The authors showed that the replacement of 3-hydroxy with a 3-amino group led to the elimination of lipo-oxygenase inhibitory activity.

Conclusion
In this review, we discussed the synthesis, reactivity and biological properties of 3-hydroxycoumarin. About the synthesis of this compound, it is interesting to note that salicylaldehyde and 1-(2-Methoxyphenyl)ethanone are the oldest and most widely used starting compounds to our knowledge. Regarding reactivity, we have noticed that 3-hydroxycoumarin is already involved in the synthesis of some heterocycles sought for their multiple biological properties. We hope to have made the readers of this journal aware of the current interest of the scientific community in 3-hydroxycoumarin. It seems likely that 3-hydroxycoumarin will be a popular building block for the synthesis of heterocycles, and that other elegant and innovative developments and applications for this compound will emerge in the future.