Comprehensive Review on Medicinal Applications of Coumarin-Derived Imine–Metal Complexes

Simple Summary This review is an attempt to gather, analyze, and systemize data about the antimicrobial, anticancer, antioxidant, anthelmintic, pesticidal, and nematocidal properties of coumarin-derived imine–metal complexes. With these properties is a discussion of the progress medicinal chemistry has made on these complexes, and the findings presented here show a promising future for this field. We hope that our review will provide medicinal chemists and biologists with a thorough and accurate review of coumarin-derived imine–metal complexes and encourage them to identify investigational new drug (IND) candidates. With those IND candidates there is the hope of biologically active drugs and a healthier, happier future for humanity. Abstract Coumarins are fused six-membered oxygen-containing benzoheterocycles that join two synthetically useful rings: α-pyrone and benzene. A survey of the literature shows that coumarins and their metal complexes have received great interest from synthetic chemists, medicinal scientists, and pharmacists due to their wide spectrum of biological applications. For instance, coumarin and its derivatives have been used as precursors to prepare a large variety of medicinal agents. Likewise, coumarin-derived imine–metal complexes have been found to display a variety of therapeutic applications, such as antibacterial, antifungal, anticancer, antioxidant, anthelmintic, pesticidal, and nematocidal activities. This review highlights the current synthetic methodologies and known bioactivities of coumarin-derived imine–metal complexes that make this molecule a more attractive scaffold for the discovery of newer drugs.


Introduction
The oxygen-containing benzo-fused heterocycles, such as coumarins (2H-chromen-2ones), are one of the most important and considered classes of compounds in medicinal chemistry because of their widespread pharmacological activities [1]. The simplest member of the coumarin family of compounds, "coumarin", was isolated by Vogel in the year 1920 and eventually prepared by Sir William Henry Perkin through the Perkin reaction in 1868 [2,3]. Over the last few decades, researchers have explored the coumarin derivatives for various important biological activities such as anti-inflammatory, antioxidant, antithrombotic, antiallergic, antiviral, and anticancer [4][5][6][7][8][9][10][11]. Medicinal chemists continue In recent years, Schiff bases have been used as multipurpose scaffolds to obtain biologically important molecules. Particularly, Schiff bases complexed with metal will have further enhanced biological activity. Therefore, the combination of Schiff base metal complexes with pharmacologically important small-molecule organic ligands such as coumarins is one of the important medicinal chemistry strategies to obtain ideal drug candidates. [17] (Figure 2). Coumarin pharmacophores are a part of several active drugs, such as the vitamin K antagonist, Warfarin. Because it can be assumed that coumarin-metal complexes will Molecules 2022, 27, 5220 3 of 30 have important medical applications, we have provided a chart ( Figure 3) that includes the articles published on these complexes indexed in Scopus for the past ten years (2012-2022). We recently reviewed medicinal applications of coumarins bearing azetidinone and thiazolidinone moieties [18]. In continuation of our effort on coumarin chemistry, we have mainly focused on its Schiff base-metal complexes as possible pharmacological agents in this review.
Coumarin pharmacophores are a part of several active drugs, such as the vitamin K antagonist, Warfarin. Because it can be assumed that coumarin-metal complexes will hav important medical applications, we have provided a chart ( Figure 3) that includes the ar ticles published on these complexes indexed in Scopus for the past ten years (2012)(2013)(2014)(2015)(2016)(2017)(2018)(2019)(2020)(2021)(2022) We recently reviewed medicinal applications of coumarins bearing azetidinone and thia zolidinone moieties [18]. In continuation of our effort on coumarin chemistry, we hav mainly focused on its Schiff base-metal complexes as possible pharmacological agents in this review.

Chemistry
Coumarins are therapeutically active members of the benzopyran-2-one family. Cou marins are extensively dispersed in nature and can be found in both naturally occurring and synthetic medicinally active compounds. In recent years there has been considerabl growth in the chemistry of coumarins as a keystone for the design and development of considerable number of compounds [19,20]. Nowadays, coumarin and its derivatives, es pecially Schiff bases derived from coumarins, belong to the most active classes of com pounds and possess a wide spectrum of biological activity [21,22]. On the other hand metal complexes derived from Schiff base ligands of coumarin show tremendous poten tial in numerous fields such as fluorescent probes, optical brighteners, antioxidants, anti microbials, anthelmintics, hypotensive, and inhibitors of platelet aggregation and cyto toxic activity [23][24][25][26][27][28][29][30]. Hence, the synthesis, structural identification, and biological activity evaluation of new derivatives of coumarin-derived imine-metal complexes continually pique research interest across the world.

Chemistry
Coumarins are therapeutically active members of the benzopyran-2-one family. Coumarins are extensively dispersed in nature and can be found in both naturally occurring and synthetic medicinally active compounds. In recent years there has been considerable growth in the chemistry of coumarins as a keystone for the design and development of a considerable number of compounds [19,20]. Nowadays, coumarin and its derivatives, especially Schiff bases derived from coumarins, belong to the most active classes of compounds and possess a wide spectrum of biological activity [21,22]. On the other hand, metal complexes derived from Schiff base ligands of coumarin show tremendous potential in numerous fields such as fluorescent probes, optical brighteners, antioxidants, antimicrobials, anthelmintics, hypotensive, and inhibitors of platelet aggregation and cytotoxic activity [23][24][25][26][27][28][29][30]. Hence, the synthesis, structural identification, and biological activity evaluation of new derivatives of coumarin-derived imine-metal complexes continually pique research interest across the world.

Antimicrobial Activity of Coumarin-Derived Imine-Metal Complexes
Farghaly et al. synthesized a Schiff base (Sbat) using 8-acetyl-7-hydroxy-4-methyl coumarin and 3-amion-1,2,4-triazole [31]. The reaction of the Schiff base with Ag(I) and Cu(II) metal ions produced the [Ag(Sbat)(NO 3 Figure 4). The antimicrobial properties of Gram-positive bacteria Staphylococcus aureus (S. aureus), Staphylococcus faecalis (S. faecalis), and Bacillus subtilis (B. subtilis) were evaluated using the standard agar diffusion test and Gram-negative bacteria used included Escherichia coli (E. coli), Neisseria gonorrhoeae (N. gonorrhoeae), and Pseudomonas aeruginosa (P. aeruginosa) ( Table 1). Antifungal activity against Aspergillus flavus (A. flavus) and Candida albicans (C. albicans) were also studied with the prepared complexes (Table 1). From the activity studies obtained, it was understood that the Schiff base had no activity against the two fungus species. Compounds 1 and 2 show no inhibitory action against the fungus. Sbat was found to be active against E. coli, N. gonorrhoeae, and S. faecalis. Also, 1 exhibited better antibacterial activity than the Schiff base. Complex 2 did not show any antibacterial activity against S. faecalis and N. gonorrhoeae. Against all microorganisms, 1 showed the maximum activity. The fact that the silver(I) complex was identified in a nanostructure might explain its biological activity because small silver nanoparticles with large surface area interact with bacteria better than larger ones. Also, it is worth noting that the reduced lipophilicity of 2 explains why it has weaker antibacterial activity than its parent ligands.   By condensing 3-formyl-4-hydroxycoumarin and oxalyldihydrazide in a 2:1 molar ratio, Linert et al. produced a hydrazone Schiff base ligand. In molar ratios of 1:1 or 2:1 (M:L), the Schiff base ligand interacted as a mono-, bi-, tri-, or even tetradentate ligand with metal cations to form mono-or binuclear complexes as keto or enol isomers, where M = Co(II), Ni(II), Cu(II), VO(IV), and Fe(III) (3-12) ( Figure 4) [32]. Both the Schiff base ligand and its metal complexes were tested against Gram-positive and Gram-negative bacteria along with one type of fungi. Against these microorganisms, the synthesized complexes showed modest antibacterial and antifungal activity (Table 1). Chelation tends to make the ligands much more effective and potent antibacterial agents, hence, complexes outperform the ligands in terms of activity. The results show that Cu (II), Fe (III), and VO 2+ complexes inhibited the growth of the selected bacteria and fungi the most. On the other hand, the Co(II) and Ni(II) complexes demonstrated modest activity. According to available data, binuclear complexes outperform acyclic complexes in terms of antibacterial activity, demonstrating that all these complexes are physiologically more efficient and implying that the chemical geometry of compounds is significant in explaining the complexes' biological activity.
Badami et al. prepared Schiff base (HL) from 8-formyl-7-hydroxy-4-methylcoumarin and benzylamine, which they subsequently used to synthesize complexes of Co(II) (13), Ni(II) (14), and Cu(II) (15) (Figure 4) [33]. The Schiff base metal complexes were investigated for their antibacterial (E. coli, P. aeruginosa, Klebsiella pneumoniae (K. pneumoniae), and S. aureus) and antifungal (Penicillium chrysogenum (P. chrysogenum), and Aspergillus niger (A. niger)) activities, and it was discovered that the metal complexes had a more deadly impact on bacteria and fungus development than their parent ligand (Table 1). Against all strains, compound 15 demonstrated potential antibacterial and antifungal action. Solubility, conductivity, dipole moment, and cell permeability factors are thought to be the probable causes for the enhancement in the activity.
In another report, Schiff base ligand 3-chloro-N-((7-hydroxy-4-methyl-2-oxo-2H-chromen-8-yl)methylene)benzo[b]thiophene-2-carbohydrazide and its Cu(II) (16), Co(II) (17), Ni(II) (18), and Zn(II) (19) (Figure 4) complexes with octahedral geometries were synthesized by Mruthyunjayaswamy et al. [34]. The compounds' antibacterial activity was evaluated in vitro against two Gram-negative bacteria (E. coli (MTCC 46) and Salmonella typhi (S. typhi) (MTCC 98)) and two Gram-positive bacteria (B. subtilis (MTCC 736) and S. aureus (MTCC 3160)) ( Table 1). C. albicans (MTCC 227), Cladosporium oxysporum (C. oxysporum) (MTCC 1777), and A. niger (MTCC 1881) ( Table 1) were tested for antifungal activity in vitro. All of the synthesized compounds showed antimicrobial capabilities in antimicrobial screening, and as expected, the metal complexes exhibited a greater inhibitory impact than their parent ligands and metal chlorides. Apart from the chelation theory, the increase in activity can be explained by the fact that most ligands have an azomethine link. Additionally, in metal complexes the positive charge of the metal ion is shared partially with the hetero donor atoms found in the ligand, and p-electron delocalization may occur throughout the chelating system. As a result, increasing the lipophilic character of metal chelates facilitates their passage through the lipoid layer of bacterial membranes and the blockage of metal binding sites in microorganism enzymes. Other factors that promote activity include conductivity, solubility, and the length of the link between the ligand and the metal ions.  Table 1). The agar plate antifungal activity of coumarin imine ligand and its metal complexes was evaluated against eight plant pathogenic fungi species (Alternaria alternata (A. alternate), A. flavus, Botrytis cinerea (B. cinerea), Fusarium verticillioides (F. moniliforme) and Verticillium albo atrum (V. alboatrum)) ( Table 1). The copper complex outperformed the three most commonly used antifungal drugs. It had 100% radial inhibition (RI) against the most susceptible fungus, A. flavus. The RI of the tetrahedral cadmium complex against A. alternata, A. flavus, F. moniliforme, and V. alboatrum was 90%. However, the octahedral 20 possessed a 95% RI against B. cinerea. The square planar 23 has antifungal activity of 57-80%, with the highest activity against A. flavus and F. moniliforme. The octahedral 21 had the least antifungal activity, comparable to the drug Nystatin. The antibacterial activity of the investigated compounds was evaluated against four Gram-positive bacteria (S. citrus, Streptococcus pneumoniae (S. pneumoniae), B. subtilis, and Micrococcus luteus (M. luteus)) and four Gram-negative bacteria (Enterobacter aerogenes (E. aerogenes), E. coli, P. aeruginosa, and S. typhi). Even though the complexes under examination stopped bacteria from growing, they had a stronger antibacterial impact against Gram-positive bacteria than Gram-negative strains. Also, antibacterial activity was lowest for 21. The antibacterial and antifungal activities increased with metal chelation. The square planar copper complex has excellent antibacterial activity, which can be attributed to its structure.
Linert et al. prepared two new mono and binuclear complexes with a Schiff base ligand obtained from the condensation of 3-acetylcoumarine and diethylenetriamine [36]. With cobalt(II), nickel(II), copper(II), zinc(II), and oxovanadium(II), the Schiff base ligand formed mono-or bi-nuclear cyclic or macrocyclic complexes, depending on the metal-to-ligand mole ratio and preparation method (25)(26)(27)(28)(29)(30)(31)(32)(33)(34) (Figure 4). The Schiff base, HL, ligand, and its metal complexes were investigated for antibacterial activity against Gram-positive and Gram-negative bacteria, as well as a pathogenic fungus, Fusarium oxysporum (F. oxysporum) ( Table 1). The findings were compared with the gram-negative and gram-positive antibiotics, chloramphenicol and cephalothin. The antifungal standard was cycloheximide. In vitro antibacterial and antifungal activity showed that complexes outperform ligands. The π-electron delocalization and partial sharing of the positive charge with a donor group lower the metal atoms polarity and this chelation might increase the metal atom's lipophilicity, allowing it to pass through the lipid layers of the cell membrane and block metal binding sites on enzymes. The results showed that Cu(II) complexes had the greatest growth inhibition against Gram-positive bacteria, Gram-negative bacteria, and fungi. Com The compounds were evaluated for antibacterial (E. coli and P. aeruginosa), and antifungal (Candida, A. niger, and Rhizopus) activities using the disc diffusion technique (Table 1). Only a few species had antibacterial activity, and 40 had the most. Compounds 39 and 40 outperformed the others in antifungal activity. Protein synthesis is an important phase in the development of microorganisms. Metal ions function as growth inhibitors for microorganisms by adsorbing on the outside surface of the cell wall and preventing respiration. This interrupts protein synthesis and kills the microorganism. The increased activity of chelates may be owing to the metal ion's decreasing polarity due to sharing its positive charge with donor groups, as explained by chelation theory.
Kinni  (Table 1). Coordination with metal ions clearly increased the ligand's efficacy and also lessened the metal ion's polarity by sharing its positive charge with donor groups inside the chelate ring system generated during coordination. Because of its high lipophilicity, the central metal atom may easily penetrate the lipid layer of bacteria, causing them to die.
Bajroliya et al. developed Mn(II) and Co(II) metal complexes from novel Schiff bases derived from 8-formyl-7-hydroxy-4-methylcoumarin and 3-substituted 4-amino-5-mercapto-1,2,4-triazole by using microwave irradiation as well as conventional methods (47)(48)(49)(50)(51)(52)(53)(54)(55)(56) (Figure 4) [39]. Compared with the traditional approach, the microwave irradiation procedure yielded higher yields with better selectivity. This study investigated the in vitro antimicrobial activity of synthesized Schiff bases and their metal complexes by measuring the zone of inhibition in mm. Assays were performed using gentamycin at a 100 g/mL concentration against five species of bacteria: E. coli, P. aeruginosa, S. typhi, S. aureus, and B. subtilis. Antifungal activities were assessed against A. niger and C. albicans at 100 g/mL using fluconazole as a reference drug. The metal complexes of all Schiff bases had stronger antibacterial activity than the Schiff bases alone against selected bacteria and fungi ( Table 1) (Table 1). In antibacterial experiments, the Schiff bases were found to be potentially active against E. coli and S. typhi, as well as moderately active against S. aureus. Compounds 71 and 72 had substantial antibacterial activity against E. coli, P. aeruginosa, and S. typhi and least activity against S. aureus. Compounds 73 and 74 were effective against E. coli, S. aureus, and S. typhi, but only modestly effective against P. aeruginosa. Compounds 75 and 76 had outstanding antibacterial activity against S. typhi but only fair activity against E. coli, P. aeruginosa, and S. aureus. All Schiff bases were active against fungi. However, as compared with the uncoordinated compounds, 71-76 exhibited significantly increased activity, notably with A. flavus. The findings show that activity relies on metal ion type and varies in the following order: Cu > Ni > Co.
The metal complexes (83-96) ( Figure 5) with Schiff bases derived from the condensation of 3-acetylcoumarine with ethylenediamine and orthophenylenediameine were developed by Akkasali et al. [44]. All the developed compounds (83-96) were screened for their possible antimicrobial activity against E. coli, P. aeruginosa, A. niger, and C. albicans. The prepared metal complexes (83-96) showed moderate to high activity against the tested organisms. Among the complexes, copper complex 93 showed a maximum zone of inhibition against P. aeroginosa and nickel complexes 85 and 92 displayed higher antifungal activity against A. niger. In addition, nickel complex 92 also revealed good activity against C. albicans. However, all the developed compounds were less active than the standard drugs ciprofloxacin and fluconazole and the data presented in this review could be a helpful guide for medicinal chemists who are working in the area. Dhumwad and co-workers have designed the synthesis of metal complexes (97-104) ( Figure 5) of Schiff bases formed through the condensation of 8-formyl-7-hydroxy-4-methyl-coumarin with 3-amino-pyridine and 3-amino-2-chloro-pyridine [45]. The synthesized metal complexes (97-104) were evaluated for their in vitro antibacterial potential against S. aureus and E. coli, and antifungal efficacy against two fungi, viz., A. niger and C. albicans. Among the metal complexes, copper complexes 99 and 103 are found to be most active against the tested bacteria with a MIC value of 1.56 µg/mL, which is almost equal to that of the standard drug, norfloxacin. Therefore, the prepared copper complexes 99 and 103 are found to be more effective bactericides than fungicides. The metal complexes (83-96) ( Figure 5) with Schiff bases derived from the condensation of 3-acetylcoumarine with ethylenediamine and orthophenylenediameine were developed by Akkasali et al. [44]. All the developed compounds (83-96) were screened for their possible antimicrobial activity against E. coli, P. aeruginosa, A. niger, and C. albicans. The prepared metal complexes (83-96) showed moderate to high activity against the tested organisms. Among the complexes, copper complex 93 showed a maximum zone of inhibition against P. aeroginosa and nickel complexes 85 and 92 displayed higher antifungal activity against A. niger. In addition, nickel complex 92 also revealed good activity against C. albicans. However, all the developed compounds were less active than the standard drugs ciprofloxacin and fluconazole and the data presented in this review could be a helpful guide for medicinal chemists who are working in the area. Dhumwad and coworkers have designed the synthesis of metal complexes (97-104) ( Figure 5) of Schiff bases formed through the condensation of 8-formyl-7-hydroxy-4-methyl-coumarin with 3amino-pyridine and 3-amino-2-chloro-pyridine [45]. The synthesized metal complexes (97-104) were evaluated for their in vitro antibacterial potential against S. aureus and E. coli, and antifungal efficacy against two fungi, viz., A. niger and C. albicans. Among the metal complexes, copper complexes 99 and 103 are found to be most active against the  (Table 1) [46]. From the MIC studies, it has been found that the metal complexes were more active against both bacterial and fungal species than parent ligands. Among the metal complexes, cobalt complex 105 and nickel complex 107 revealed high activity against E. coli, P. aeruginosa, and S. typhi. Furthermore, cobalt complex 105 and nickel complex 107 also had good antifungal activity against A. flavus, Cladosporium, and A. niger. Patil et al. have also designed and synthesized a series of cobalt(II), nickel(II), and copper(II) complexes (111-122) ( Figure 5) with newly derived biologically active ligands that are prepared from the condensation of 3-substituted-4-amino-5-hydrazino-1,2,4-triazole and 8-formyl-7-hydroxy-4-methylcoumarin [47]. All the metal complexes (111-122) were evaluated for their antibacterial efficacy against four bacterial strains, namely E. coli, S. aureas, S. pyogenes, and P. aeruginosa using Gentamycin as the standard. From the antibacterial studies, it was found that all the synthesized metal complexes (111-122) were more active compared with the corresponding parent Schiff bases. Metal complex 116 showed maximum inhibition against S. aureas and P. aeruginosa at 25 µg/mL. Furthermore, metal complex 118 showed maximum inhibition towards E. coli at 25 µg/mL. Also, metal complex 120 displayed highest inhibition against P. aeruginosa at 25 µg/mL, whereas metal complex 121 revealed maximum inhibition towards S. aureas and S. pyogenes at 25 µg/mL. The synthesized metal complexes 111-122 (Table 1) were also screened for their antifungal activities against A. Flavus, Cladosporium, and A. niger using the standard drug fluconazole. Metal complex 114 presented MIC 10 µg/mL against S. aureus and A. Niger, whereas metal complex 120 showed MIC 10 µg/mL against A. Flavus.
In the recent past, Modak et al. reported the synthesis of copper complex 135 ( Figure 5) with imine ligand 6-((quinolin-2-ylmethylene)amino)-2H-chromen-2-one achieved from derivatization of natural compound coumarin [50]. The potential antibacterial effect of copper complex 135 was assessed for Flavobacterium psychrophilum (F. psychrophilum) isolated 10094 and efficacy was IC 50 16.1 ± 0.9 µg/mL. However, MIC and MBC of the copper complex 135 were found to be lower (32 µg/mL) than the precursor (64 µg/mL). Novel classes of metal complexes (136-140) ( Figure 5) that are derived from 7-hydroxy coumarin hydrazone of s-triazine derivatives were evaluated for their in vitro antibacterial potency against tested pathogens by the research group of Jani [51]. Antibacterial activity was tested using the agar diffusion method against E. coli and S. aureus and A. niger was used for antifungal activity. From the zone of inhibition data, it was concluded that metal complex 136 exhibited higher inhibition towards S. aureus, E. coli, Aspergillus niger, and S. pyogenes, whereas the other metal complexes 136-140 revealed moderate activity. All metal complexes (136-140) were inactive against P. klebsiella (Table 1).
In 2016, Patil and co-workers reported the synthesis of a series of Co(II), Ni(II), and Cu(II)complexes (141-146) ( Figure 5) from the reaction 8-formyl-7-hydroxy-4-methylcoumarin/3chloro-8-formyl-7-hydroxy-4-methylcoumarin with 2,4-difluoroaniline/o-toluidine [52]. Antimicrobial activities of metal complexes 141-146 were carried out through the disc diffusion method against two bacterial strains (P. auregenosa and Proteusmirabilis) with gentamicin as the standard and two fungal strains (A. niger and R. oryzae) with antifungal drug fluconazole (Table 1). Among different halogenated metal complexes, copper complex 146 exhibited more activity against A. niger. Nickel complex 145 displayed a maximum zone of inhibition against P. auregenosa, whereas copper and nickel complexes 143, 145, and 146 revealed maximum inhibition against Proteusmirabilis. Copper complex 147 ( Figure 5) with a salen-type ligand derived from the condensation of 4-methyl-7-hydroxy-8-formylcoumarin with 3,4-diaminotoluene was screened for in vitro antibacterial activity by Sharma et al. through the broth dilution method against four bacterial strains: E. coli, S. aureus, P. aeruginosa, and K. pneumonia [53]. Compound 147 exhibited an MIC of 12.5-200 µg·mL −1 and appeared to be active against both Gram-positive and Gram-negative bacteria. Both experimental and theoretical calculations revealed that 147 has better antibacterial potential than the parent Schiff base ligand (Table 1).
A series of five new Cu (II), Zn (II), Pd (II), Ru (III), and Ag(I) complexes (148-152) ( Figure 5) derived from the 3-acetylcoumarin-2-hydrazinobenzothiazole Schiff base have been synthesized and characterized by Atlam et al. [54]. All metal complexes 148-152 were screened for their antifungal effect towards two fungal strains, G. recinaceum (GR33) and O. latemarginatus (EM26). Palladium complex 150 acts as the best antifungal agent for GR33 with a 60% reduction, whereas the silver complex 152 has a 79% reduction for O. latemarginatus (EM26). The ligninolytic activity of the complexes on fungi was found using Poly R-dye decolorization ability. Results suggest that complexes showed decolorization at lower concentrations depending on the fungi used. From the observed results, it can be concluded that both palladium and silver complexes 152 and 150, respectively, were used for antifungal preservatives, whereas copper, zinc, and ruthenium complexes 148, 149, and 151, respectively, can be used for lignolytic activity. Observed results were confirmed using computational studies and molecular docking studies help to provide a better understanding of binding interactions (Table 1).
Sawant et al. reported the synthesis, characterization and antimicrobial activity of novel transition metal complexes of 4-methyl-7-hydroxy 8-formyl coumarin. The prepared Schiff base acts as a bidentate ligand for the complexation with Cu(II), Ni(II), Co(II), and Zn(II) ions. The Schiff base and their transition metal complexes (153-156) ( Figure 6) were screened for their antimicrobial activity towards two strains, E. coli and A. niger, through the tube dilution method in order to examine the effect of metal ions upon chelation (Table 1). All the transition metal complexes 153-156 showed MIC values less than 20 µg/mL compared with the ligand, which has MIC values less than 200 µg/mL against both species. The results of antimicrobial activity indicate that the antimicrobial activity of the Schiff base was increased on complexation with metal ions [55]. In 2009, Creaven and co-workers reported the Cu(II) complexes (157-167) ( Figure 6) of coumarin-derived Schiff bases. A few of the Cu(II) complexes were characterized through X-ray crystallography technique to determine the structures. Furthermore, all Cu(II) complexes 157-167 were screened for their anti-Candida activity. All Cu(II) complexes displayed excellent anti-Candida activity comparable to that of commercially available drugs such as ketoconazole and amphotericin B (Table 1) [56].
Schiff base was increased on complexation with metal ions [55]. In 2009, Creaven and coworkers reported the Cu(II) complexes (157-167) (Figure 6) of coumarin-derived Schiff bases. A few of the Cu(II) complexes were characterized through X-ray crystallography technique to determine the structures. Furthermore, all Cu(II) complexes 157-167 were screened for their anti-Candida activity. All Cu(II) complexes displayed excellent anti-Candida activity comparable to that of commercially available drugs such as ketoconazole and amphotericin B (Table 1) [56].  (Table 1) [57].

Anticancer Activity of Coumarin-Derived Imine-Metal Complexes
It is well known that coumarin derivatives present important cytotoxic activity against several cell lines [18]. It is also known that coordination of bioactive molecules to transition metals display enhanced inhibitory activity [58]. In this regard, Aazam and Structural analyses of all new transition metal complexes 168-171 were conducted through infrared, ultraviolet-visible, cyclic voltammetry, EPR, magnetic property, and thermogravimetric techniques. Furthermore, all transition metal complexes 168-171 were tested for their antibacterial activity against bacterial species such as K. pneumoniae, E. coli, and S. aureus by the disc diffusion method. The biological activity results concluded that the Schiff base transition metal complexes 168-171 have more efficiency compared with standard streptomycin drug and the transition metal complexes 168-171 arrested the growth of bacterium (Table 1) [57].

Anticancer Activity of Coumarin-Derived Imine-Metal Complexes
It is well known that coumarin derivatives present important cytotoxic activity against several cell lines [18]. It is also known that coordination of bioactive molecules to transition metals display enhanced inhibitory activity [58]. In this regard, Aazam and coworkers prepared the first coumarin-derived imine-metal complex that has been evaluated for its anticancer activity. This complex was synthesized from the reaction of 4-methyl-7-(salicylideneamino)coumarin with Cu(OAc) 2 . Interestingly, single crystal X-ray diffraction studies exhibited that the complex crystallized as a dimeric copper coumarin complex, 172, as depicted in Figure 7 [59]. In 2009, Creaven and coworkers corroborated this observation when they also observed the same dimeric copper complex [57]. Nonetheless, Creaven and coworkers went further and prepared a total of eleven coumarin copper complexes (172-182) (Figure 7) (Table 2). Although, other complexes were crystallized (e.g., 179), only complex 172 was observed as dimeric copper complex [60]. A year later, Creaven et al. reported the cytotoxicity activity of the eleven complexes against two human cell lines: human colon cancer cells (HT29) and human breast cancer cells (MCF-7) using the methylthiazolyldiphenyl-tetrazolium bromide assay (MTT) [60]. Unfortunately, none of the complexes were cytotoxic against colon cancer cells and only complexes 180 and 182 showed cytotoxicity against breast cancer cells, with IC 50 values of 79.8 µM and 34.5 µM, respectively. Values that are comparable with the positive control mitoxantrone (IC 50 value of 44 µM) ( Table 2). In an attempt to try to increase the observed cytotoxicity, the authors reduced the coumarin shift bases to amines. Sadly, their respective copper complexes were not successfully synthesized [60]. In 2017, Tabassum et al. reported the synthesis of one coumarin-derived imine-metal complex, 183 (Figure 7), that has an appended imidazole (Figure 4) [59]. In vitro anticancer studies revealed that complex 183 has superior cytotoxicity towards the A549 adenocarcinoma cell line in comparison with the standard drug cisplatin (Tab 2), which is a very In 2017, Tabassum et al. reported the synthesis of one coumarin-derived iminemetal complex, 183 (Figure 7), that has an appended imidazole (Figure 4) [59]. In vitro anticancer studies revealed that complex 183 has superior cytotoxicity towards the A549 adenocarcinoma cell line in comparison with the standard drug cisplatin (Table 2), which is a very promising discovery as A549 is a cisplatin-resistant cell line [61] ( Table 2). The same year, Sahin and coworkers reported the synthesis, characterization, and anticancer activity of two coumarin-derived imine-metal complexes. Synthesis of complex 184 (Figure 7) used Na 2 PdCl 4 to incorporate palladium to the ligand, whereas K 2 PtCl 4 was used to install platinum into complex 185 (Figure 7) [62]. Both complexes were evaluated against three human cancer cell lines: prostate cancer cells (ATTC), colon carcinoma cells (LNCap), and breast cancer cells (MCF-7) using the MTT assay. The data from the in vitro antitumor activity showed that palladium complex 184 had the most prominent activity against the three screened cell lines, with an IC 50 of 18.15 µg/mL for MCF-7, an IC 50 of 10.05 µg/mL for LNCap, and an IC 50 of 15.98 µg/mL for ATTC. Values that are 3-to 5-fold better than the ligand starting material [60].
In 2020, Hurtado et al. reported nine tetradentate coumarin Schiff-based metal complexes (186-194) (Figure 7) [63]. Two coumarin ligands and the five metals (Zn(OAc) 2 , Co(OAc) 2 , Cu(OAc) 2 , Ni(OAc) 2 , and K 2 PtCl 4) were used to prepare the nine complexes ( Figure 4). A cytotoxicity activity was carried out using an MTT assay in the carcinogenic cell line HeLa (human cervical cancer cells), and, to make the study more relevant, two noncarcinogenic cell lines, HFF-1 (human foreskin fibroblast cells) and HaCaT (human keratinocytes) were screened. Data from this study showed that both ligands and seven of the screened complexes displayed higher IC 50 (Table 2). Thus, they have promising anticarcinogenic potential [64].  (Table 2) [64]. It is important to note that fluorinated complexes showed similar or lower antitumor activity.

Antioxidant Activity of Coumarin-Derived Imine-Metal Complexes
Following similar methodology as mentioned above, three new coumarin-derived imine-metal complexes were synthesized by Sinha et al. from the condensation of 6aminocoumarin and pyridine-2-carboxaldehyde to make a ligand [65]. The ligand was reacted with Cr(CO) 4 , Mo(CO) 4 , and W(CO) 4 to produce complexes (201-203) (Figure 7). The three complexes were tested for their antioxidant properties and their antioxidant activity (radical scavenging activity) was examined with reference to 1,1-diphenyl-2picrylhydrazyl (DPPH), hydroxyl radical (OH·), superoxide(O 2 − ), and nitroxyl radical (NO·). The data revealed that the complexes had a maximum percentage of inhibition at concentrations of 0.03 mg/mL, 0.3 mg/mL, and 0.01 mg/mL for [Cr(CO) 4 (L)], [Mo(CO) 4 (L)], and [W(CO) 4 (L)], respectively. Therefore, complex 203, having the heaviest element (W), shows the highest scavenging ability. In 2012, Halli and coworkers reported another series of coumarin-derived imine-metal complexes (41)(42)(43)(44)(45)(46) (Figure 4) [38]. In addition to the antimicrobial activity (reported above), an antioxidant assay (DPPH) was investigated for all the synthesized complexes, and the tabulated data in Table 3 shows that the top radical scavengers were complexes 42 (Ni), 44 (Cd), and 46 (Hg) ( Table 3) at a concentration of 100 µg/mL [66]. Similarly, Sharma et al. reported the synthesis, antibacterial, and antioxidant activity of complex 204 (Figure 7) [67]. Although complex 39 presented some scavenging ability (30%), it was lower in comparison with the standards gallic acid (90%) and quercetin (80%) at a concentration of 62.5 µg/mL. Finally, Creaven's group has also studied a series of coumarin-derived imine-copper complexes (205-211) ( Table 3) (Figure 7) [66]. Besides cytotoxicity studies (data not relevant) of those complexes, their antioxidant activity was studied in wild type cells (Saccharomyces cerevisiae). Interestingly, the survival rates for wild-type cells exposed to oxidative stress (with menadione) was excellent. For instance, wild-type cells treated with complexes 205-211 had a typical survival of around 90%, versus 15% for untreated cells. However, when the oxidative stress was induced with H 2 O 2 , none of the complexes were able to protect the cells, perhaps due to the lack of CAT enzymes in the selected wild-type cells [68]. In summary, it is safe to say that all the coumarin-derived imine-metal complexes present some scavenger activity, and that it is always superior to that of their respective coumarin ligands [68].   (Table 4). Specifically, metal complexes 37 and 40 displayed noticeable activity compared with the standard drug, albendazole, at a 10 µg/mL concentration [37].

Pesticidal and Nematicidal Activity of Coumarin-Derived Imine-Metal Complexes
Pests and nematodes inhabit numerous trophic levels and together disturb the entire ecological balance. They grow for centuries, causing diverse infections notoriously lethal to plants, humans, and animals. Due to this ever-present issue, it is vital to identify sustainable effective nematicides and insecticides. In 2011, Fahmi et al. reported pesticidal and nematocidal activities of lanthanide(III) complexes (129-131) ( Figure 5) with 3-formyl-4-chlorocoumarin hydrazinecarbothioamide and 3-formyl-4-chlorocoumarin hydrazinecarboxamide against Tribolium castaneum and Meloidogyne incognita. All the metal complexes exhibited good pesticidal activity compared with their corresponding ligands. Sm(III) complex 130 was especially effective as evidenced through the comparative study of their percentage mortality data with other metal complexes (129 and 131). The nematocidal activity displays that metal complexes 129-131 were more active in lowering the hatching of eggs than the corresponding ligands [46].

Enzyme Activity of Coumarin-Derived Imine-Metal Complexes
For the treatment of Alzheimer's disease (AD), cholinesterase inhibition is the only valid target used. Hence, there is a continuous need for the development and synthesis of new cholinesterase inhibitor molecules. Recently, Özdemir and co-workers reported palladium and platinum complexes derived from combining coumarin and thiazole with 3-tertiary butyl salicylaldehyde, a new Schiff base [67]. Metal complexes 212 and 213 ( Figure 8) were structurally characterized from various spectroscopic techniques. Additionally, the authors investigated the inhibitor potencies of metal complexes on three esterase enzymes, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and pancreatic cholesterol esterase activities (CEase). The anti-esterase activity results directed that metal complexes have good inhibition effects on the cholinesterase (AChE/BChE) and pancreatic cholesterol (CEase) enzymes. Particularly platinum complex 213 exhibited a high inhibition effect with lower IC50 values (12.0 µM for AChE, 23 µM for BChE, and 21.0 µM for CEase) compared with the reference drugs [67].

Conclusions and Future Perspective
Searching through drug banks for coumarin-derived clinically approved age yielded several important drugs, including a treatment for HIV that combines sev ferent compounds and includes calanolide A, a coumarin agent. Currently, a nu clinical trials are being conducted on several coumarin-based drugs alone or in co tion with other drugs to treat common disorders, such as thrombosis, coagulatio ders, stroke (Ischemic), liver fibrosis, protein C deficiency, atrial fibrillation, et these findings it can be seen that coumarin-based drugs have an important role in health and well-being and are continuously researched to discover more clinical u Coumarin scaffold has great potential in medicinal chemistry and is extensive in drug design and development because of its vast biological properties. This sca

Conclusions and Future Perspective
Searching through drug banks for coumarin-derived clinically approved agents has yielded several important drugs, including a treatment for HIV that combines several different compounds and includes calanolide A, a coumarin agent. Currently, a number of clinical trials are being conducted on several coumarin-based drugs alone or in combination with other drugs to treat common disorders, such as thrombosis, coagulation disorders, stroke (Ischemic), liver fibrosis, protein C deficiency, atrial fibrillation, etc. From these findings it can be seen that coumarin-based drugs have an important role in global health and well-being and are continuously researched to discover more clinical uses.
Coumarin scaffold has great potential in medicinal chemistry and is extensively used in drug design and development because of its vast biological properties. This scaffold is frequently used for designing small molecules with various biological activities. Metal complexes of Schiff bases with coumarin pharmacophores have played an important role in medicinal chemistry. Various coumarin-derived imine-metal complexes have been developed in the last three decades and most of them exhibited important pharmacological properties. Funding: The authors thank Jain University, India for financial support. The authors also acknowledge the ACSPRF-ND grant (58269-ND1) for financial support.