A review on synthesis of coumarin derived Schiff’s base metal complexes and their control over E. coli bacterium

Abstract

Nowadays, the dilemma of drug resistance to antibacterial strains is of huge concern. Among the bacteria, Escherchia coli (E. coli) is the major pathogen, which is found in human and other animals. It is responsible for variety of severe diseases. A variety of commonly used antibiotics such as amoxicillin, gentamycin, etc and fluid replacement method are the suggested treatments for the infections caused by E. coli. In a study, it was established that the metal-based heterocyclic drugs demonstrated a different mode of action compared to the commonly used heterocyclic antibacterial drugs. Coumarin, an oxaheterocycle, is a privileged scaffold in medicinal chemistry. Metal complexes of coumarin-derived Schiff’s bases exhibit a broad range of pharmacological activities. Therefore, in the present review article, we have focused on the synthesis of metal complexes of coumarin derived Schiff’s bases as well as their respective Schiff’s base ligands and their antibacterial activities against the gram-negative bacterium E. coli.

Keywords

Antibacterial coumarin minimum inhibitory concentration schiff’s base

1 Introduction

The antimicrobial resistance against the gram-negative pathogen E. coli is a matter of huge concern in the field of pharmaceutical chemistry [1]. In 1885, Theodore von Escherich discovered E. coli as one of the common infecting organism in the family of enterobacteriaceae. It is a rod shaped anaerobic and facultative bacteria of ∼2 μm in length and 0.5 μm width and grows between 10–40deg temperatures. It is mostly found in the intestines of humans and cattle including chickens, deer, sheep and pigs. It can also be found in contaminated water and meat which may cause infection in humans [2]. Also, certain strains of the bacterium can cause infant diarrhoea and gastroenteritis. In rare cases, it is responsible for bowel necrosis, pneumonia [3], septicaemia, peritonitis, mastitis and hemolytic-uremic syndrome [4]. To determine the presence of E. coli, MacConkey agar is inoculated with test organisms using streak plate technique and incubated the plate at 37deg for one day (24 h). Appearance of pink colonies on MacConkey agar confirms the presence of E. coli. A classification of various types of E. coli is shown in Fig. 1.

Fig. 1

Pathotypes classification of E. coli.

The two major types of E. coli are intestinal and extra-intestinal pathogens. Among the intestinal, enteropathogenic E. coli produces verocytotoxin which causes infantile enteritis, fever, diarrheal diseases, vomiting, nausea and non-bloody stool in children. Another type of E. coli, enterohemorrhagic also produces verocytotoxin and is found in animal and human faeces which cause mild diarrhoea, fatal hemorrhagic colitis and uremic syndrome (HUS) [5]. Enterotoxogenic type of E. coli produces heat labile toxins in children of more than 5 years. Enteroinvasive are non-motile strains which cause mild diarrhoea or dysentery. Enteroaggresive is brick like aggregates on cell surfaces and inhibits fluid absorption. Intestinal E. coli are obligate pathogens and extraintestinal, uropathogenic and meningitis-associated E. coli are facultative pathogens. Uropathogenic E. coli causes urinary tract infections, pyelonephritis and infectious complications, acute renal failure in adults and blood poisoning in new born babies [6].

The complete cure of infection caused by E. coli is difficult, but if necessary doctor may suggest the fluid replacement method and use of antibiotics such as amoxicillin (I), gentamycin, norfloxacin, ciprofloxacin (II), erythromycin, nitrofurantoin (III), tetracycline (IV), cephalosporins (V), aztreonam (VI) etc. in various types of infection caused by E. coli (Fig. 2) [7]. These treatments are generally used but not usually unless systemic infections prevails e.g. hemolytic-uraemia syndrome.

Fig. 2

Antibiotics used against the infections due to E. coli.

Coumarin, a naturally occurring compound, is a privileged scaffold in medicinal chemistry. Therefore, coumarin derived Schiff bases (a subclass of imines) are extensively used in broad range of pharmacological activities including antibacterial, antifungal, and antimalarial activities [8 –10]. Metal and their alloys are used as antibacterial agents since ancient times. For instance copper and silver vessels are used for water disinfection and food storage [11]. Copper coated surfaces are also used in kidney tray in clinics [12]. On coordination to metal ions, Coumarin derived Schiff’s bases activities are enhanced, generating a variety of complexes with different stoichiometry, chelating, magnetic, and spectroscopic characteristics [13]. In recent years, Schiff bases have been employed as versatile scaffolds to obtain physiologically significant compounds. Schiff bases complexed with metal, in particular, will have improved biological activity. As a result, one of the main medicinal chemistry techniques for obtaining optimal drug candidates is the coupling of Schiff base metal complexes with pharmacologically essential small-molecule chemical ligands like coumarins [14]. Coumarin-derived Schiff’s base metal complexes are crucial in fighting bacterial infections due to their strong antibacterial effects [15]. Their unique structure lets them interact precisely with bacteria, reducing the chance of resistance [16, 17]. These complexes work against a wide range of bacteria by disrupting their membranes, inhibiting enzymes, and causing oxidative stress [18, 19].Therefore, owing to the biological significance of various metals and coumarin derived Schiff’s bases, we have focused on their antibacterial activity against most common disease causing bacterium E. coli in this review article.

2 Bioactivity of coumarin derived Schiff’s base metal complexes against E. coli

In 2010, Patil and co-workers synthesized two Schiff’s bases SB-4 and SB-5 and their cobalt, nickel and copper complexes (Scheme 1). The SB-4 and SB-5 were synthesized by refluxing 3-methylthiosemicarbazone (1) with either 5-formyl-7-hydroxycoumarin (2) or 8-formyl-7-hydroxy-4-methylcoumarin (3) in hydrochloric acid for 4–5 hours. The resulting schiff bases were further reacted by refluxing them in an alcoholic solution containing cobalt, nickel, or copper chloride salts for 2 hours to form metal complexes [20]. The synthesized compounds were characterized by analytical, spectral, and thermal studies.

Scheme 1

Synthesis of Metal complexes from Coumarin-thiosemicarbazide.

In order to access antibacterial activity by using agar diffusion method, the synthesized Schiff’s bases SB-4, SB-5 and their metal complexes (6–11) were tested against E. coli. The agar diffusion method assesses antibacterial activity by placing a substance on an agar plate with bacterial culture. If the substance inhibits bacterial growth, it creates a zone of inhibition. The size of this zone indicates its potency. This method quickly evaluates compounds like coumarin-derived Schiff’s base metal complexes for antibacterial effectiveness [21]. The antibacterial activity was evaluated at concentration of 10, 30, 50 and 100 μg/mL in N,N-dimethylformamide. The bacterial strain was incubated for 48 h at 37deg. From results it was evaluated that SB-4 and SB-5 were moderately active against E. coli but their activity was enhanced when they were coordinated with metal. Chelating tends to make metal complexes act as more effective and powerful bactereostatic agents, which inhibits the growth of the microorganisms. The activity may be increased due to the change in structure caused by coordination [22]. It was found that copper complex 8 exhibited highest activity in terms of zone of inhibition i.e. 93 mm against E. coli (equivalent to Gentamycin), as compared to other metal complexes. Cobalt complexes 6 and 9 also showed good zone of inhibition i.e. 78 mm and 77 mm and copper complex 8 exhibited moderate activities (Table 1). The minimum inhibitory concentration of copper and nickel complexes of coumarin-thiosemicarbazide hybrids was found to be equivalent to Gentamycin (10 μg/mL).

Table 1

Antibacterial activities of coumarin-Schiff base hybrids and their metal complexes against E. coli

Compd.	L/M	Substituent	Conc. (μg/mL)	Inhibition zone	MIC (μg/mL)
SB-4			10	17	25
			30	21
			50	37
			100	53
SB-5			10	19	25
			30	27
			50	41
			100	65
6	Co		10	69	10
			30	78
			50	83
			100	94
7	Ni		10	47	10
			30	58
			50	68
			100	78
8	Cu		10	50	25
			30	53
			50	61
			100	73
9	Co		10	65	10
			30	77
			50	83
			100	93
10	Ni		10	45	10
			30	53
			50	69
			100	78
11	Cu		10	84	25
			30	93
			50	96
			100	98
SB-14		H	25	42	10
			50	45	10
			100	53
SB-15		Br	25	43	15
			50	47
			100	55
16	Co	H	25	68	10
			50	73
			100	79
17	Ni	Br	25	63	10
			50	69
			100	76
18	Cu	H	25	61	25
			50	64
			100	82
19	Co	Br	25	77	25
			50	78
			100	84
20	Ni	H	25	71	–
			50	77
			100	89
21	Cu	Br	25	68	10
			50	70
			100	70
SB-24		Cl	25	24.39	15
			50	46.13
			100	57.12
SB-25		^NO2	25	27.91	25
			50	45.06
			100	60.0
26	Co	Cl	25	11.98	10
			50	31.33
			100	60.12
27	Ni	Cl	25	22.76	25
			50	43.76
			100	68.03
28	Cu	Cl	25	34.65	10
			50	69.89
			100	81.23
29	Co	^NO2	25	39.59	10
			50	73.71
			100	86.13
30	Ni	^NO2	25	14.28	25
			50	22.87
			100	42.85
31	Cu	^NO2	25	57.14	25
			50	64.28
			100	69.04
SB-34		H	100	7	10
			200	15
			500	23
SB-35		CH₃	100	6	10
			200	14
			500	24
36	Co	H	100	8	25
			200	15
			500	24
37	Ni	CH₃	100	15	10
			200	22
			500	25
38	Cu	H	100	8	10
			200	14
			500	24
39	Co	CH₃	100	11	10
			200	16
			500	19
40	Ni	H	100	6	20
			200	17
			500	19
41	Cu	CH₃	100	9	15
			200	17
			500	24
SB-45			100	–
			200	06
SB-46			100	09
			200	10
47	Co		100	09
			200	10
48	Ni		100	10
			200	11
49	Cu		100	06
			200	08
50	Co		100	07
			200	11
51	Ni		100	09
			200	12
52	Cu		100	09
			200	13
SB-55				75
56	Co			50
57	Ni			12.5
58	Cu			25
59	Cd			12.5
60	Zn			50
61	Hg			25
SB-64		H		16	–
SB-65		Cl		17	6.25
66	Co	H		19	3.12
67	Ni	H		18	–
68	Cu	H		20	1.56
69	Zn	H		18	–
70	Co	Cl		21	3.12
71	Ni	Cl		19	–
72	Cu	Cl		24	1.56
73	Zn	Cl		19	–
SB-87		Cl	25	41.86
			50	51.16
			100	60.46
SB-88		^CH3	25	45.63
			50	59.03
			100	68.23
89	Co	Cl	25	55.81
			50	67.44
			100	86.04
90	Ni	Cl	25	62.79
			50	88.37
			100	65.34
91	Cu	Cl	25	46.51
			50	46.51
			100	87.34
92	Co	^CH3	25	58.12
			50	75.33
			100	86.02
93	Ni	^CH3	25	59.12
			50	83.25
			100	74.26
94	Cu	^CH3	25	79.06	25
			50	90.69
			100	69
SB-98			50	62	25
			25	25
			100	68
SB-99			50	61	10
			25	24
			100	82
100	Co		50	72	10
			25	46
			100	76
101	Ni		25	39	25
			50	66
			100	74
102	Cu		25	20	10
			50	30
			100	62
103	Co		100	81
			50	70
			25	44	10
104	Ni		100	74	25
			50	67
			25	33
105	Cu		100	61	10
			50	31
			25	6.97
SB-109			25	23.25	25
			50	95.34
			100	8.26
SB-110			25	25.36	10
			50	92.55
			100	27.9
111	La		25	67.44	10
			50	81.39
			100	44.66
112	Th		25	70.69	30
			50	78.34
			100	37.20
113	V		25	48.83	10
			50	76.74
			100	29.63
114	La		25	29.63	10
			50	65.32
			100	81.39
115	Th		25	43.59	50
			50	71.29
			100	79.29
116	V		25	41.26	15
			50	55.63
			100	81.32

Further, in 2011, Patil et al. reported the synthesis of coumarin-naphthol carbohydrazides (SB-14, SB-15) and their metal complexes (16–21) and characterized them by spectral (IR, UV–Visible, ¹H NMR) and thermal studies (Scheme 2). The SB-14 and SB-15 were synthesized through the reflux reaction of 2-hydroxy-1-naphthaldehyde (13) with either 2-oxo-2H-chromene-3-carbohydrazide (14) or 6-bromo-2-oxo-2H-chromene-3-carbohydrazide (15), catalyzed by a small quantity of hydrochloric acid, for 3–4 hours. Metal complexes of the Schiff’s bases were synthesized by subjecting the Schiff’s bases to reflux conditions in the presence of metal chloride salts for 4 hours. The antibacterial activity was performed by using agar diffusion method against E. coli at the concentration of 25, 50, 100 μg/ml and calculated the minimum inhibitory concentration of synthesized compounds [23]. The bacterial cultures were inoculated on Mueller Hinton agar media for 24 h at 310 K by spread plate method in dimethylsulfoxide to acquire concentration of 25 μg. It was observed that SB-14 and SB-15 were highly active but metal complexes were found to exhibit even better activity than Schiff base ligands.

Scheme 2

Antibacterial activity of metal complexes of coumarin-naphthol carbohydrazides.

Gentamycin was taken as reference drug and the results showed that particularly metal complex 19 having bromine as substituent on coumarin ring exhibited highest zone of inhibition against E. coli (78 mm at 25 μg/ml).The cobalt and copper complexes 16, 17, 20 and 21 exhibited >70% inhibition of E. coli and showed excellent value of minimum inhibitory concentration i.e. 10 μg/mL which is equivalent to Gentamycin (Table 1).

Patil et al. assessed the antibacterial efficacy of metal complexes 26–31 and coumarin-N-aryl thiosemicarbazide hybrids SB-24 and SB-25. The Schiff bases were synthesized through the condensation reaction between m-substituted thiosemicarbazide (22) and 8-acetyl-7-hydroxy-4-methylcoumarin (23) in the presence of concentrated hydrochloric acid. Subsequently, metal complexes were prepared by refluxing metal chlorides with the Schiff bases on a steam bath 3 hours. The synthesized ligand and their metal complexes were characterized by elemental, spectral, magnetic and thermal analyses (Scheme 3).

Scheme 3

Synthesis of metal complexes of coumarin and m-substituted thiosemicarbazide hybrids.

The antibacterial activity was screened by agar diffusion method at 25, 50 and 100 μg/ml concentration against E. coli. It was observed that synthesized metal complexes showed promising antibacterial potential and activity was high in comparison to corresponding Schiff base ligands SB-24 and SB-25. Biological activities of metal complexes are comparable to reference drug Gentamycin (81 mm) at 100 μg/mL concentration. The cobalt complexes 26 and 29 with chloro- and nitro-group, respectively as substituents showed moderate activities. The nickel complexes (26–31) were found to be more active than Gentamycin (Table 1) [22].

In 2012, same lab workers evaluated the antibacterial activity of coumarin-naphthalene hybrids and their metal complexes in dimethylforamide by using agar diffusion method against E. coli [23]. The SB-34 and SB-35 were synthesized by reacting ethanolic solutions of 8-formyl-7-hydroxy-4-methylcoumarin/8-acetyl-7-hydroxy-4-methylcoumarin (32) with 1,8-diaminonaphthalene (33) under reflux for 4-5 hours, with the addition of a few drops of hydrochloric acid to catalyze the reaction. Following synthesis, metal complexes of SB-34 and SB-35 were prepared by refluxing alcoholic solutions of the Schiff bases with cobalt, nickel, or copper chloride salts on a steam bath for 3 hours. The synthesized ligands SB-34, SB-35 and their cobalt, nickel and copper complexes (36–41) were characterized by analytical, IR, UV–Vis, ¹H NMR and thermal studies (Scheme 4).

Scheme 4

Synthesis of metal complexes of coumarin-naphthalene hybrids.

From antibacterial activity against E. coli it was revealed that their activity was enhanced when SB-34 and SB-35 coordinated with metal ligand, whereas the copper complexes 40 and 41 showed good inhibition zone against the bacterium. The results of the minimum inhibitory concentration indicated that chemicals were most effective in preventing the growth at concentration of 10 μg/mL (Table 1).

Patil et al. also screened the antibacterial activity of metal complexes 47–52 of Schiff bases SB-45 and SB-46 against E. coli. SB-45 and SB-46 were synthesized by refluxing a reaction mixture of o-toluidine (43) or 3-aminobenzotrifluoride (44) and 6-formyl-7,8-dihydroxy-4-methylcoumarin (42) in glacial acetic acid for 6 hours. Metal complexes of the Schiff bases were prepared by refluxing the Schiff bases with metal chlorides on a water bath for a hour [24].The synthesized compounds were characterized by spectral, magnetic, thermal, fluorescence, mass and ESI-MS studies (Scheme 5).

Scheme 5

Synthesis of metal complexes of coumarin-aniline hybrids.

For antibacterial activity of SB-45, SB-46 and their metal complexes, the disc diffusion method was used at different concentration dissolved in DMF as solvent [25]. The E. coli was sub-cultured in nutrient agar medium and was incubated at 37deg for 24 h. From the results obtained it was observed that copper complexes showed highest activity whereas the other complexes showed moderate activity against E. coli when compared to standard drug Gentamycin (Zone of inhibition = 14 mm at 100 μg/ml) (Table 1).

Halli and coworkers evaluated the antibacterial activity of coumarin-naphthofuran hybrid Schiff’s base SB-55 and its metal complexes (56–61) and the synthesized compounds were characterized by spectral (IR, ¹H NMR, UV-visible) data (Scheme 6). Schiff bases were synthesized by refluxing a mixture of naphthofuran-2-carbohydrazide (53) and 8-formyl-7-hydroxy-4-methylcoumarin (54) for 20 minutes in the presence of a few drops of concentrated hydrochloric acid on a water bath. Subsequently, these Schiff bases were refluxed with cobalt(II), nickel(II), copper(II), cadmium(II), zinc(II), and mercury(II) chlorides for 3 hours on a water bath to yield their respective metal complexes.

Scheme 6

Synthesis of metal complexes of coumarin-naphthofuran hybrids.

For antibacterial study against E. coli the synthesized compounds were filled with different concentrations and the diameter of inhibitory zones was evaluated by using agar diffusion method and minimum inhibitory concentration method [26]. It was found that all the metal complexes exhibited promising results in comparison to SB-55, and nickel (57) and cadmium (59) complexes showed excellent antibacterial activities. The zone of inhibition values of these complexes were equivalent to the reference drug Gentamycin (12.5 mm) against E. coli. The copper (57) and mercury (61) complexes showed better activities than cobalt (58) and zinc (60) complexes (Table 1).

Phaniband and co-workers evaluated the antibacterial activity of metal complexes (66–73) of coumarin-pyridine hybrid Schiff’s bases in dimethylforamide against E. coli and compared it with Norfloxacin, a reference antibacterial drug [27]. The SB-64 and SB-65 were synthesized by refluxing 8-formyl-7-hydroxy-4-methyl-coumarin (62) with 3-amino-pyridine or 3-amino-2-pyridine (63) for 2 hours in ethanol. Subsequently, the Schiff base metal complexes were synthesized by refluxing an ethanolic solution containing SB-64, SB-65, and metal chlorides of cobalt, nickel, copper, and zinc on a water bath for 4 hours. The synthesized compounds were analyzed by elemental, spectral techniques (Scheme 7).

Scheme 7

Synthesis of metal complexes of coumarin-pyridine hybrid.

For antibacterial activity the bacterial colony of test and control plates were counted for the results of activity. The minimum inhibitory concentration of active compounds with some modifications was carried out by using the method of G. W. Clause [28]. The spread plate method was used against bacteria and it was concluded that inhibitory zone of synthesized ligands SB-64 and SB-65 were enhanced when coordinated with metal salts to form complexes. The metal complexes 66–73 exhibited zone of inhibition between 16–24 mm (for 100 μg/mL concentration) which is comparable to standard drug Norfloxacin (26 mm). It was concluded that copper and cobalt complexes 66, 69 and 73 were moderately active and copper complex 72 was most active against the bacterium E. coli having 1.56 μg/ml MIC value (Table 1).

M. Manjunath et al. synthesized metal complexes 79–84 of Schiff bases SB-77, SB-78 and characterized them by elemental analyses, spectral and magnetic studies (Scheme 8) [29].The SB-77 and SB-78 were prepared by refluxing 4-aminoantipyrine (74) with either 8-formyl-7-hydroxy-4-methylcoumarin (76) or 5-formyl-6-hydroxycoumarin (75) in the presence of a few drops of concentrated hydrochloric acid. The resulting Schiff bases were then refluxed with cobalt, nickel, and copper chlorides on a water bath for 2 hours to yield the respective metal complexes.

Scheme 8

Synthesis of metal complexes of coumarin-amino antipyrine.

The synthesized compounds were examined for antibacterial study which was performed using different concentrations against E. coli by the agar diffusion method. These bacterial strains were cultured for 24 h at 37degC and compared with standard drug Gentamycin. From results, it has been observed that all metal complexes showed better antibacterial activities in comparison to SB-77 and SB-78 against pathogen E. coli. The metal complexes 81 and 84 showed promising activity (Table 1).

Kulkarni and co-workers evaluated the antibacterial activity of coumarin derived Schiff’s base’s SB-87 and SB-88 and their metal complexes (89–94) against E. coli by agar diffusion method in DMF by measuring the activities in term of their zone of inhibition (Scheme 9) [30]. The SB-87, SB-88 were synthesized by refluxing 8-formyl-7-hydroxy-4-methylcoumarin (85) and o-chloroaniline/o-toluidine (86) for 4–5 h with few drops of hydrochloric acid. The metal complexes were prepared by refluxing alcoholic SB-87, SB-88 with metal chlorides for 1 hour on water bath.

Scheme 9

Synthesis of coumarin-phenyl hybrid Schiff’s bases metal complexes.

The bacterial strain was incubated for 24 h at 37deg and activity was measured in comparison to standard reference drug Gentamycin. It was revealed that all of the screened metal complexes have effective activity against E. coli than corresponding ligands SB-66 and SB-67. Copper complex 91 showed highest inhibition (79 mm) as compared to other Schiff’s bases metal complexes. Nickel complex 90, with chlorine as substituent showed 62.79 mm inhibition, whereas cobalt complex 89 and nickel complex 93 with methyl group as substituent showed approximately 59 mm diameter of zone of inhibition (Table 1).

Kulkarni and co-workers evaluated the antibacterial activity of coumarin derived Schiff’s bases SB-98, SB-99 and their metal complexes (100–105) against E. coli using agar diffusion method [31]. The SB-98, SB-99 were synthesized by heating a mixture of 8-formyl-7-hydroxy-4-methylcoumarin (96) or 5-formyl-6-hydroxycoumarin (97) and o-aminophenol (95) under reflux conditions for 4–5 hours, with the addition of 2–3 drops of hydrochloric acid. Alcoholic solutions of SB-98 and SB-99 were then refluxed with CoCl₂.6H₂O, NiCl₂.6H₂O, or CuCl₂.2H₂O in ethanol on a water bath for an hour. Following this, sodium acetate was introduced, and reflux was continued for an additional 3 hours. The synthesized compounds were characterized by elemental analyses, spectral, magnetic, and thermal studies (Scheme 10).

Scheme 10

Synthesis of Coumarin derived Schiff’s bases metal complexes.

The prepared compounds were examined for the antibacterial activity against bacteria at 50 μg/mL concentration in DMF and compared with the standard drug Gentamycin (88 mm). The cobalt (100,103) and nickel (101, 104) complexes showed high activity against E. coli, whereas copper complexes 102 and 105 exhibited poor activity against the E. coli (Table 1).

In another work same lab worker examined the antibacterial assay against E. coli by using agar diffusion technique for the metal complexes of coumarin-diamine Schiff bases SB-109 and SB-110. The SB-109 and SB-110 were prepared by mixing hot ethanol solutions of either o-phenylenediamine (107) or ethylenediamine (108) with hot ethanol solution of 8-formyl-7-hydroxy-4-methylcoumarin (106). This mix was heated for 4–5 hours with a few drops of concentrated hydrochloric acid. Then, the Schiff bases were mixed with La(III)/Th(IV) nitrate and vanadyl sulphate in dry alcohol and the mixture was heated for another 4–5 hours to get the final products [32]. The structure of compounds has been characterized by using analytical, spectral, magnetic and thermal studies (Scheme 11).

Scheme 11

Synthesis of coumarin-diamine metal complexes.

The synthesized Schiff’s base SB-109, SB-110 and their Lanthanum/Thorium/Vanadium complexes 111–116 were screened against E. coli by dissolving 10 mg of the test compound in 10 mL of dimethylformamide. From the results, it was observed that the metal complexes showed enhanced activity than Schiff’s base against E. coli which is almost similar activity as Gentamycin (88.37 mm) (Table 1).

Kapoor et al. synthesized Schiff’s bases SB-119 and SB-120 by reacting 3-formyl-4-chlorocoumarin (117) with thiosemicarbazide or semicarbazide hydrochloride (118) in the presence of sodium acetate, followed by irradiation in a solvent for 5–6 minutes. Complexes were prepared by irradiating a mixture of LnCl₃.6H₂O and the corresponding sodium salt of the ligands in a 1 : 3 molar ratio (Scheme 12).

Scheme 12

Synthesis of metal complexes of coumarin-hydrazine carbohydrazide.

The schiff’s bases SB-119 and SB-120 and their lanthanide (III) complexes (121–126) were screened for the antibacterial activity against E. coli with the help of paper disc plate method [33]. Whatman filter paper was cut in uniform diameter of 2 cm, sterilized, and after that paper disc was soaked in the solution of 500 ppm concentration. The metal complexes solutions were poured in the petridishes containing nutrient agar media seeded with E. coli and incubated at 310 K for 24 h. The MIC was evaluated by liquid dilution method and Ciprofloxacin (17.6 mm) was taken as a reference drug having a minimum inhibitory concentration 0.016 μg/mL. From the results obtained it was concluded that the neodymium (121) and gadolinium (123) complexes exhibited highest activity. The samarium complexes 122, 125 and gadolinium complex 126 showed good activity i.e. 11.5, 11 and 11.1 mm zone of inhibition, respectively (Table 2).

Table 2

Activity of coumarin-hydrazine carbohydrazide hybrids against E. coli

Compd.	M	X	Conc. (μg/mL)	Inhibition Zone	MIC (μg/mL)
SB-119		S	500	8.4±0.03	20
			1000	9.6±0.06
SB-120		O	500	7.2±0.14	25
			1000	8.3±0.06
121	Nd	S	500	13.8±0.10	15
			1000	16.0±0.03
122	Sm	S	500	11.5±0.10	10
			1000	14.3±0.02
123	Gd	S	500	13.5±0.08	15
			1000	14.9±0.18
124	Nd	O	500	10.7±0.3	15
			1000	13.9±0.14
125	Sm	O	500	11.0±0.1	20
			1000	12.8±0.02
126	Gd	O	500	11.1±0.04	15
			1000	12.8±0.02

Hunoor and co-workers evaluated the antibacterial activity of Schiff’s base SB-129 and their copper, nickel, cobalt and zinc complexes (130–132) against E. coli. The Schiff base SB-129 was synthesized via refluxing 3-acetylcoumarin (127) with isonicotinoyl hydrazide (128) in methanol for 3 hours. Following synthesis, SB-129, dissolved in chloroform, was combined with equimolar amounts of metal (II) chlorides (Co, Ni, Cu, and Zn) in ethanolic solution. The resulting mixture was stirred at room temperature for 2 hours. The synthesized compounds were characterized by various spectroscopic techniques, elemental analysis, magnetic properties and thermogravimetric analysis, and also by the aid of molar conductivity measurements (Scheme 13).

Scheme 13

Synthesis of metal complexes of coumarin-isonicotinic carbohydrazide.

The antibacterial results were evaluated by using serial broth micro dilution method and ciprofloxacin was taken as reference drug. The results showed that all the synthesized complexes (130–132) exhibited increased activity on complexation with metal ions as the MIC values of metal complexes were reduced to half in comparison to Schiff base ligand SB-129. This increase in activity may be due to the higher lipophilicity of complexes at lower concentration. The coumarin-isonicotinic carbohydrazide complexes of nickel, copper, cobalt and zinc (130–132) showed moderate activity in comparison of the standard reference drug ciprofloxacin against E. coli (Table 3).

Table 3

Antibacterial activity of metal complexes of coumarin-isonicotinic carbohydrazide

Compd.	M	N	MIC (μg/mL)
SB-129			100
130	Co	2	50
131	Zn	0	50
132	Ni	3	50
133	Cu	3	50

Sharma and coworkers screened the antibacterial activity of Schiff’s base (SB-136) and their copper complexes (137) against E. coli by using disc diffusion assay [35]. The synthesis of SB-136, 3,4-diaminotoluene (134) was stirred with 4-methyl-7-hydroxy-8-formyl coumarin (135) in ethanol at ambient temperature. Subsequently, to a solution of SB-136 in ethanol, copper acetate monohydrate dissolved in ethanol was incrementally added dropwise over duration of 10 minutes, while maintaining continuous stirring at 80deg. The structure of compounds has been analyzed from the elemental analysis and spectroscopic techniques (Scheme 14).

Scheme 14

Synthesis of metal complexes of coumarin-toluene hybrid Schiff bases.

For the comparison of solvent effect on the bacterial growth, a control experiment was performed and it was assessed that dimethylsulfoxide had no role in the inhibition of microorganisms concentrations. Ampicillin was used as a reference drug. From the activity results it was observed that Cu complex (137) was found to be more active than ligand SB-136 and they exhibited good MIC values at different concentration ranging from 12.5–200 μg/mL. The activity of copper complex 137 against E. coli was comparable to the reference drug ampicillin (Table 4).

Table 4

Antibacterial activity of metal complexes of coumarin-toluene hybrid Schiff bases

Compd.	Zone of Inhibition(mm)					MIC (μg/mL)
	200	100	50	25	12.5
SB-136	18	16	13	–	–	200
137	32	24	19	17	13	50
Control (DMSO)	32	31	30	30	30	12.5

Raj and coworkers synthesized coumarin derived Schiff’s base metal complexes (141–144) from the Schiff’s base SB-140 and evaluated their antibacterial activity against E. coli by using Muller–Hinton agar media method [36]. SB-140 was synthesized by mixing equal amounts of 3-chloro-benzo[b]thiophene-2-carbohydrazide (138) and 8-formyl-7-hydroxy-4-methylcoumarin (139) with a few drops of glacial acetic acid as a catalyst in methanol. The mixture was refluxed on a water bath for approximately 4–5 hours. Next, a hot methanolic solution containing the respective metal chlorides was added to the hot solution of SB-140 in methanol. The reaction mixture was refluxed on the water bath for an additional 4 hours. To maintain a neutral pH, sodium acetate was introduced into the reaction mixture, followed by continued refluxing for another hour. The synthesized compounds were characterized by elemental analysis, various physico-chemical techniques, differential thermal analysis, magnetic measurements and molar conductance measurement (Scheme 15).

Scheme 15

Synthesis of metal complexes of coumarin-benzothiophene carbohydrazide.

The pure culture of the bacterial strains E. coli, sub-cultured by inoculating them in the nutrient broth was incubated at 37deg for about 18 h. The drug Gentamycin (MIC = 12.50 used as standard. All synthesized compounds were screened for antibacterial activity against E. coli and it was found that activities were better with the coordination of metal complexes [37]. The copper complex (141) showed good inhibition (MIC = 25 μg/mL) against E. coli than other metal complexes (141–144) (Table 5).

Table 5

Antibacterial activity of metal complexes of coumarin-benzothiophene carbohydrazideagainst E. coli

Compd.	M	MIC(mg/mL)
SB-140		75
141	Cu	25
142	Co	50
143	Ni	50
144	Zn	50

Sahoo et al. synthesized metal complexes of SB-147 and SB-148 and screened them for their antibacterial activity against E. coli by agar diffusion method. The structures of synthesized compounds were analyzed by various spectroscopic techniques, elemental analysis, magnetic properties and thermogravimetric analysis (Scheme 16).

Scheme 16

Synthesis of metal complexes of coumarin-diazenyl hybrids against E. coli.

The serial dilution procedure was used to generate five different doses (500–31.25 μg/mL). The various drug concentrations were kept into the wells and incubated at 37degC for 18–24 h. The MIC was obtained after the incubation period. From results it was revealed that activity was enhanced when coordinated with metal ions and complexes 149–150, 153–153 exhibited good antibacterial activity when compared to Ampicllin (MIC = 12.67 μg/mL) (Table 6) [38].

Table 6

Antibacterial activity of metal complexes of coumarin-diazenyl hybrids against E. coli

Compd.	M	R	Inhibition Zone (mm)	MIC (μg/mL)
SB-147		Cl	17.33±1.63	31.25
SB-148		^OCH3	19.17±2.56	31.25
149	Co	Cl	19.17±2.4	31.25
150	Ni	Cl	19.17±1.72	31.25
151	Cu	Cl	–	>500
152	Zn	Cl	–	>500
153	Co	^OCH3	21.17±2.17	31.25
154	Ni	^OCH3	23.17±2.7	31.25
155	Cu	^OCH3	–	>500
156	Zn	^OCH3	–	>500

Nora S. Abdel-Kader et al. synthesized the metal complexes of Schiff’s base and examined the antibacterial activity against E. coli by agar diffusion method (160–161) (Table 7). SB-159 was synthesized by heating a mixture of 8-acetyl-7-hydroxy-4-methyl coumarin (157) and 3-amino-1,2,4-triazole (158) under reflux for 8 hours at 160degC. The resulting product was dissolved in a mixture of DMF and methanol, then added to solutions of silver nitrate or copper acetate dissolved in methanol and water. For copper complexes, the mixture was refluxed with NH₄OH for 10 hours after a 15-minute condensation period. For silver complexes, the mixture was stirred with NH₄OH in darkness for a hour. The complexes were washed with hot water and ethanol, filtered, and dried over CaCl₂ for analysis (Scheme 17).

Table 7

Antibacterial activity of metal complexes of coumarin-triazole hybrid against E. coli

Compd.	M	Zone of Inhibition(mm)
SB-159		09
160	Ag	12
161	Cu	10

Scheme 17

Synthesis of metal complexes of coumarin-triazole hybrid.

The antibacterial activity was evaluated by measuring the zone of inhibition (in mm), where ampicillin (MIC = 25 μg/mL) was taken as standard drug [39]. According to results obtained it was observed that Silver and Copper complexes showed better antibacterial activity against E. coli in comparison to Schiff’s base ligand SB-159.

Budagumpi et al. examined the antibacterial activity of metal complexes of coumarin-pyridine hybrid Schiff’s base SB-164 against E. coli by cup plate method (165–170) [40]. SB-164 was synthesized by dissolving 3-acetylcoumarin (164) and 2,6-diaminopyridine (163) in dry ethanol or benzene and stirring for 15 minutes. The mixture was then refluxed on a water bath for 3 hours to yield the solid ligand after removing excess solvent under reduced pressure. The Schiff base was purified by recrystallization. Metal(II) chloride/nitrate/sulfate in ethanol was added to an ethanolic solution of the Schiff base and stirred for 15–20 minutes. The resulting mixture was refluxed on a water bath for about 2 hours, then cooled. The solid complexes were filtered, washed with ethanol, and dried under vacuum over fused calcium chloride. Finally, the complexes were washed with hot water and then with aqueous ethanol, followed by drying under vacuum over phosphorus pentoxide. The structure of synthesized compound was determined by analytical, spectral and thermal techniques (Scheme 18).

Scheme 18

Antibacterial activity of metal complexes of coumarin-diaminopyridine.

All the synthesized copper(II) complexes exhibited significant activity against E. coli. The cobalt(II) complex (169) has modest activity against E. coli when compared to Gentamycin (MIC = 23 μg/mL) (Table 8).

Table 8

Antibacterial activity of metal complexes of coumarin-diaminopyridine

Compd.	M	Zone of inhibition (mm)
SB-164		18
165	Cu	22
166	Cu	22
167	Cu	20
168	Co	20
169	Cu	22
170	Ni	18

Scheme 19

Synthesis of metal complexes of coumarin-amino aryl hybrid.

Elhusseiny et al. screened antibacterial activity of metal complexes 181–185 obtained from coumarin-phenylenediamine hybrid Schiff base SB-180 against E. coli.

SB-180 was synthesized by adding p-phenylenediamine (179) to a warm solution of 8-acetyl-7-hydroxycoumarin (178) in ethanol. The mixture was refluxed for 2–3 hours. Following this, the solution of SB-130 in ethanol was adjusted to a pH of approximately 8 using potassium hydroxide. Zinc(II) acetate, cadmium(II) acetate, copper(II) acetate, nickel(II) chloride, and bis(benzonitrile)-dichloro-palladium(II) in ethanol were then added successively. The resulting mixture was refluxed for 10 minutes, filtered, and the formed precipitate was thoroughly washed with methanol. Finally, the product was dried in a vacuum desiccators over calcium chloride. The synthesized compounds were characterized by spectroscopic, molar conductance, magnetic and thermal studies.

The paper disc diffusion method was used for antibacterial study against E. coli. The test substance was dissolved in 1% dimethyl sulfoxide at doses ranging from 0.1 to 0.40%. The filter paper discs were submerged in various compounds solution baths, dried, and then inserted onto Petri plates containing test organism seeds. The inhibition zone surrounding each disc was measured after the plates had been incubated for 24–30 h at 27±1degC. From results it was concluded that copper(II) complexes showed better whereas metal complexes has also shown good antibacterial activity against E. coli when compared to standard ampicillin (MIC = 15 μg/mL), chloromphenicol (MIC = 40 μg/mL), kanamycin (MIC = 40 μg/mL) (Table 9).

Table 9

Antibacterial activity of metal complexes of coumarin-amino aryl hybrid against E. coli

Compd.	M	Zone of inhibition (mm)
SB-180		30
181	Zn	17
182	Cd	38
183	Cu	50
184	Ni	10
185	Pd	30

3 Conclusion

In the past two decades, medicinal chemists working with inorganic and organometallic transition metals have synthesized new antimicrobial medicines that show tremendous and notable promise. Due to comprehensive biological properties of coumarin scaffold, it is widely used in drug development and has significant potential in medicinal chemistry. The fact that coumarin containing Schiff bases can form complexes with metal ions adds to their advantageous pharmacophore features, which undoubted include good biological properties. It was observed that coumarin derivatives having substitution specifically at 3, 4, 6, 7 and 8 positions, as shown in Figure 3, were found to exhibit good profile of antibacterial activity which can act as promising antibacterial agents in future, if underwent further for clinical trials.

Fig. 3

Substrate scope on different positions of Coumarin scaffold.

Footnotes

Acknowledgments

Authors thank Maharaja Agrasen University, Baddi and J.C. Bose University of Science and Technology, YMCA, Faridabad for providing us necessary facilities to carry out the research work.

References

Baquero

, Threats of antibiotic resistance: An obliged reappraisal, Int Microbiol 24 (2021), 499–506.

Ferens

W.A.

, Hovde

C.J.

, Escherichia coli O157:H7: Animal Reservoir and Sources of Human Infection, Foodborne Pathog Dis 8(4) (2011), 465–487.

Sharifi-Rad

, Cruz-Martins

, López-Jornet

E.P.-F Lopez, N. Harun, Yeskaliyeva and F. Sharopov, , Natural coumarins: Exploring the pharmacological complexity and underlying molecular mechanisms, Oxidative Med Cell Longev 2021 (2021), 6492346.

Ali

, Ishteyaque

, Mugale

M.N.

, Accelerative Wound-Healing Effect of Aqueous Anthocephalus Cadamba Leaf Extract in a Diabetic Rat Model, Int J Low Extrem Wounds 22(2) (2021), 409–417.

Nataro

J.P.

, Kaper

J.B.

, Diarrheagenic Escherichia coli, Clin Microbiol Rev 11(1) (1998), 142–201.

Yoon

J.W.

, Hovde

C.J.

, All blood, No stool: Enterohemorrhagic Escherichia coli O157:H7 infection, J Vet Sci 9(3) (2008), 219–231.

Kumar

, Aggarwal

, P Tyagi and S.P. Singh, Synthesis and antibacterial activity of some new 1-heteroaryl-5-amino-4-phenyl-3-trifluoromethylpyrazoles, Eur J Med Chem 40 (2005), 922–927.

Aggarwal

, Kumar

, Singh

S.P.

, Synthesis and antibacterial activity of some 4-(coumarin-3-yl)/aryl-2-(3,5-dimethylpyrazol-1-yl)thiazole, Indian J Heterocycl Chem 21(4) (2012), 331–336.

Aggarwal

, Kumar

, Kaushik

, Gupta

G.K.

, Synthesis and pharmacological evaluation of some novel 2-(5-hydroxy5-trifluoromethyl-4,5-dihydropyrazol-1-yl)-4-(coumarin-3-yl)thiazoles, Eur J Med Chem 62 (2013), 508–514.

10.

Kumar

, Aggarwal

, Sharma

, Synthesis of Some 2-(3-Alkyl/aryl-5-trifluoromethylpyrazol-1-yl)- 4-(coumarin-3-yl)thiazoles as Novel Antibacterial Agents, Synth Commun 45(17) (2015), 2022–2029.

11.

Annunziata, C. Pinna, S. Dallavalle, L. Tamborini and A. Pinto, An overview of coumarin as a versatile and readily accessible scaffold with broad-ranging biological activities, Int J Mol Sci 21 (2020), 4618.

12.

Ghanghas

, Choudhary

, Kumar

, Poonia

, Coordination metal complexes with Schiff bases: Useful pharmacophores with comprehensive biological applications, Inorg Chem Commun. 13 (2021), 108710.

13.

Annunziata

, Pinna

, Dallavalle

, Tamborini

, Pinto

, An Overview of Coumarin as a Versatile and Readily Accessible Scaffold with Broad-Ranging Biological Activities, J Mol Struct 21(13) (2020), 4618.

14.

Zabiszak

, Frymark

, Ogawa

, Skrobańska

, Nowak

, Jastrzab

, Kaczmarek

M.T.

, Complexes of β-lactam antibiotics and their Schiff-base derivatives as a weapon in the fight against bacterial resistance, Coord Chem Rev 493(215326) (2023), 215326.

15.

, Yue

, Li

, Zhang

, An operator-based expression toolkit for Bacillus subtilis enables fine-tuning of gene expression and biosynthetic pathway regulation, Appl Biol Sci 119(11) (2022), e2119980119.

16.

Mahurkar

N.D.

, N. D. Gawhale, M. N. Lokhande, S. J. Uke, M. M. Kodape, Benzimidazole: A versatile scaffold for drug discovery and beyond – A comprehensive review of synthetic approaches and recent advancements in medicinal chemistry, Results Chem 6 (2023), 101139.

17.

Muriel

A.A

, Y. Liscano, Y. Upegui, S.M. Robledo, M.T. Ramirez-Apan, D. Morales-Morales, In Vitro Evaluation of the Potential Pharmacological Activity and Molecular Targets of New Benzimidazole-Based Schiff Base Metal Complexes, Antibiotics 10(6) (2021), 728.

18.

Patil

S.A.

, Naik

V.H.

, Kulkarni

A.D.

, Badami

P.S.

, DNA cleavage, antimicrobial, spectroscopic and fluorescence studies of Co(II), Ni(II) and Cu(II) complexes with SNO donor coumarin Schiff bases, Spectrochim Acta A: Mol Biomol Spectrosc 75 (2010), 347–354.

19.

Thakur

, Bhalla

, Sustainable synthetic endeavors of pharmaceutically active Schiff bases and their metal complexes: A review on recent reports, Tetrahedron 153 (2024), 133836.

20.

Tiekink

E.R.T.

, Tin dithiocarbamates: Applications and structures, Appl Organomet Chem 22(9) (2008), 533–550.

21.

Patil

S.A.

, Unki

S.N.

, Kulkarni

A.D.

, Naik

V.H.

, Badami

P.S.

, Synthesis, characterization, in vitro antimicrobial and DNA cleavage studies of Co(II), Ni(II) and Cu(II) complexes with ONOO donor coumarin Schiff bases, J Mol Struct 985 (2011), 330–338.

22.

Patil

S.A.

, Unki

S.N.

, Kulkarni

A.D.

, Naik

V.H.

, Badami

P.S.

, Co(II), Ni(II) and Cu(II) complexes with coumarin-8-yl Schiff-bases: Spectroscopic, in vitro antimicrobial, DNA cleavage and fluorescence studies, Spectrochim Acta A: Mol Biomol Spectrosc 79 (2011), 1128–1136.

23.

S.A Patil, S.N. Unki and P.S. Badami, In vitro antibacterial, antifungal, and DNA cleavage studies of coumarin Schiff bases and their metal complexes: Synthesis and spectral characterization, Med Chem Res 21 (2012), 4017–4027.

24.

Patil

S.A.

, Prabhakara

C.T.

, Halasangi

B.M.

, Toragalmath

S.S.

, Badami

P.S.

, DNA cleavage, antibacterial, antifungal and anthelmintic studies of Co(II), Ni(II) and Cu(II) complexes of coumarin Schiff bases: Synthesis and spectral approach, Spectrochim Acta A: Mol Biomol Spectrosc 137 (2015), 641–651.

25.

Murukan

, Mohanan

, Synthesis, characterization and antibacterial properties of some trivalent metal complexes with [(2-hydroxy-1-naphthaldehyde)-3- isatin]-bishydrazone, J Enzyme Inhib Med Chem 22(1) (2007), 65–70.

26.

Halli

M.B.

, Sumathi

R.B.

, Kinni

, Synthesis, spectroscopic characterization and biological evaluation studies of Schiff’s base derived from naphthofuran-2-carbohydrazide with 8-formyl-7-hydroxy-4-methyl coumarin and its metal complexes, Spectrochim Acta A: Mol Biomol Spectrosc 99 (2012), 46–56.

27.

Phaniband

M.A.

, Dhumwad

S.D.

, Pattan

S.R.

, Synthesis, characterization, antimicrobial, and DNA cleavage studies of metal complexes of coumarin Schiff bases, Med Chem Res 20 (2011), 493–502.

28.

Singh

, Sohal

H.S.

, Verma

, Sharma

, Kaur

, Synthesis and bio-activity of complex azo compounds: A review on formazans and its complexes, Main Group Chem 23 (2023), 1–32.

29.

Manjunath

, A.D Kulkarni, G.B. Bagihalli, S. Malladi and S.A. Patil, Bio-important antipyrine derived Schiff bases and their transition metal complexes: Synthesis, spectroscopic characterization, antimicrobial, anthelmintic and DNA cleavage investigation, J Mol Struct 1127 (2017), 314–321.

30.

Kulkarni

A.K.

, Avaji

P.G.

, Bagihalli

G.B.

, Patil

S.A.

, Badami

P.S.

, Synthesis, spectral, electrochemical and biological studies of Co(II), Ni(II) and Cu(II) complexes with Schiff bases of 8-formyl-7-hydroxy-4-methyl coumarin, J Coord Chem 62(3) (2009), 481–492.

31.

Kulkarni

A.K.

, Avaji

P.G.

, Bagihalli

G.B.

, Patil

S.A.

, Synthesis, characterization, electrochemical and in-vitro antimicrobial studies of Co(II), Ni(II), and Cu(II) complexes with Schiff bases of formyl coumarin derivatives, J Coord Chem 62(8) (2009), 3060–3072.

32.

Kulkarni

A.K.

, Patil

S.A.

, Badami

P.S.

, Synthesis, characterization, DNA cleavage and in vitro antimicrobial studies of La(III), Th(IV) and VO(IV) complexes with Schiff bases of coumarin derivatives, Eur J Med Chem 44(7) (2009), 2904–2912.

33.

Kapoor

, Singh

R.V.

, Fahmi

, Coordination chemistry of rare earth metal complexes with coumarinbased imines: Ecofriendly synthesis, characterization, antimicrobial, DNA cleavage, pesticidal, and nematicidal activity evaluations, J Coord Chem 65(2) (2012), 262–277.

34.

Hunoor

R.S.

, Patil

B.R.

, Badiger

D.S.

, Vadavi

R.S.

, Gudasi

K.B.

, Chanderashekar

V.M.

, Muchchandi

I.S.

, Spectroscopic, magnetic and thermal studies of Co(II), Ni(II), Cu(II) and Zn(II) complexes of 3-acetylcoumarin–isonicotinoylhydrazone and their antimicrobial and anti-tubercular activity evaluation, Spectrochim Acta A: Mol Biomol Spectrosc 77 (2010), 838–844.

35.

Sharma

, Arora

E.K.

, Cardoza

, Synthesis, antioxidant, antibacterial, and DFT study on a coumarin based salen-type Schiff base and its copper complex, Chem Pap 70(11) (2017), 1493–1502.

36.

Raj

K.M.

, Mruthyunjaswamy

B.H.M.

, Synthesis, rspectroscopic characterization, electrochemistry and biological evaluation of some metal (II) complexes with ONO donor ligand containing benzo[b]thiophene and coumarin moieties, J Mol Struct 1074 (2014), 572–582.

37.

Berrones-Reyes

J.C.

, Munoz-Flores

B.M.

, Jimer-Perez

V.M.

, Schiff Bases and Multidentate Organic Compounds as Fluorescent Sensors of Al³⁺: Photophysical, Fluorescent Bioimaging and the Mechanisms, Eur J Org Chem 37 (2022), 202200588.

38.

Sahoo

, Paidesetty

S.K.

, Antimicrobial activity of novel synthesized coumarin based transitional metal complexes, J Taibah Univ Medical Sci 12 (2017), 115–124.

39.

Abdel-Kader

N.S.

, Moustafa

, El-Ansary

A.L.

, Farghaly

A.M.

, A coumarin Schiff base and its Ag(I) and Cu(II) complexes: Synthesis, characterization, DFT calculations and biological applications, New J Chem 17 (2021).

40.

Budagumpi

, Shetti

U.N.

, Kulkarni

N.V.

, Revankar

V.K.

, Ligational behavior of a bidentate coumarin derivative towards Co II, Ni II, and Cu II: Synthesis, characterization, electrochemistry, and antimicrobial studies, J Coord Chem 62(24) (2010), 3961–3968.

41.

Elhusseiny

A.F.

, Aazam

E.S.

, Al-Amri

H.M.

, Synthesis of new microbial pesticide metal complexes derived from coumarin-imine ligand, Spectrochim Acta A: Mol Biomol Spectrosc 128 (2014), 852–863.