1. Introduction

2. Bioactivity of imine-iron complexes

2.1. Imine-iron complexes as anticancer agents

Cancer is a well-known global threat to mankind, and there has been an upsurge of research geared toward discovering and modifying metal complexes with superior anticancer activity. Iron-imine complexes and other organometallic complexes have been found to have potent anticancer activity [20].

El-Lateef et al. synthesized two tetradentate dibasic chelating imine-iron complexes (3 and 4, Scheme 1) from the reaction of 1 and 2 with Fe³⁺ salt. The free ligand (1 and 2) and its synthesized complexes (3 and 4) were investigated for their in vitro cytotoxic effect against MCF-7, HepG-2, and HCT-116 cancer cell lines at different concentrations. These tested compounds had activity on breast carcinoma cells, with the cytotoxicity of the complexes being higher than their free ligands. Compound 4 showed the highest cytotoxicity activity against MCF-7, HepG-2, and HCT-116 (5.14, 6.75, and 4.45 µM respectively) comparable to the standard drug doxorubicin, which had the activity of 4.10, 5.15, 4.35 µM respectively and could be used as a tumor drug candidate (Table 1). The cytotoxicity of metal complexes is assumed to be due to their ability to bind DNA, hence disrupting its structure, causing replication and transcription processes to be inhibited, and eventually damaging the cancer cells (Table 1) [21].

Nguyen et al. synthesized unsymmetrical tetradentate imine-Fe(III) complexes (5 – 9, Scheme 2) by coordinating the imine ligands with FeCl₃·6H₂O and tested them on KB and Hep-G2 human cancer cell lines. The iron-imine complexes showed excellent cytotoxicity for KB and Hep-G2 (IC₅₀ < 20 µM). The presence of substituted groups in the salicyl rings affects the electrical properties and bulk of the complexes. Complex 5, which did not have the substituted group in the second salicyl ring, exhibited the best cytotoxic activity for KB and Hep-G2 (0.68, 0.83 µM respectively), even better than the standard compound ellipticine, which showed activity of 1.14 and 2.11 µM respectively (Table 1) [22].

Nine iron(III) complexes (10 – 18, Figure 1) were synthesized by Kalındemirtaş et al. The in vitro cytotoxicity activity of the iron complexes was investigated on P3HR1, K562, JURKAT, HUVEC, and 3T3 cell lines. The complexes 11, 14, 16, and 17 showed a better cytotoxicity effect (in the range of 4.81 – 14.05 μM) on the K562 cell line than the standard imatinib, which had an activity of 9.67 µM. Five complexes had significantly lower IC50 values than the positive control (imatinib) for P3HR1 cells (Table 1). Complexes 12, 15, and 18, which had a 3,5-dichloro substituent, could not compete with imatinib. All the synthesized complexes were ineffective against the JURKAT cell line in the studied concentrations. Different cells may die in different ways, and cancer cells of different types might respond very differently to the same treatment. P3HR1 and JURKAT are lymphoid cells with T- and B-lymphocytes of origin, respectively, whereas K562 is myeloid. T-cell lineage-derived leukemia includes a diverse range of neoplasms. They are typically more aggressive than their B-cell counterpart, differing in clinicopathological characteristics and biological function, and are marked by resistance to conventional chemotherapy and a bad prognosis for the patients [23]. Studies have also shown miRNAs to be critical regulators in tumorigenesis [24,25]. When exposed to chemotherapeutic drugs that are commonly used in T-cell leukemia/lymphoma treatment, like cisplatin, cytarabine, doxorubicin, and cyclophosphamide, JURKAT cells' expression of miR181a increased along with AKT activation [26]. The different results obtained in the JURKAT cells may be due to these differences [27].

Wongsuwan et al. synthesized a series of Fe(II) complexes (19–22, Scheme 3) and Fe(III) complexes (23–26, Scheme 3) by coordinating imine derived from 8-aminoquinoline and salicylaldehyde with Fe(II)/(III) chloride (Scheme 3). Imine complexes were screened against the A549 human lung adenocarcinoma cell line. The imine ligand showed no anticancer activity, but the complexes showed moderate to high anticancer activity against A549 cells with IC₅₀ values ranging from 10 to 34 µM. Complex 22 showed the highest antiproliferative activity of 10 µM, which is higher than that of two well-known commercial drugs, etoposide (19 µM) and cisplatin (16 µM) (Table 1). DNA is very critical in anticancer studies. DNA replication and transcription, which are important processes in cell proliferation, can be inhibited when an anticancer agent interacts with DNA [51,52,53]. Transition metal complexes can bind to DNA through both covalent and non-covalent interactions. Complex 6 showed very high DNA affinity and induced high levels of ROS (hydroxyl and peroxyl radicals) in A549 cancer cells. These two factors together contributed to the antiproliferative activity of complex 6. Therefore, DNA-binding and intracellular ROS that cause macromolecular or DNA damage and cell death are potential mechanisms by which the complexes enter A549 cells [28]

Iron(III) complex (30, Scheme 4) of novel imine ligand (29) was synthesized by Ismail et al., and its cytotoxicity activity against the Hep-G2 cell line was evaluated. The Fe(III) complex (30, Scheme 4) showed an enhanced antitumor activity (7.31 μg/ml) than the solo Schiff base (IC₅₀ = 27 μg/ml). Still, compared to the standard drug vinblastine, which showed a value of 2.93 μg/ml, its antitumor activity was moderate (Table 1) [29].

The ligand (33) and its metal complex (34, Scheme 5) were synthesized by Kavitha et al. and studied over three cancer cell lines: human pancreatic carcinoma (MiaPaCa-2), human cervical adenocarcinoma (HeLa), and murine melanoma cancer cells (B16F10), and one normal cell N1H/3T3 (fibroblast cells). The IC₅₀ value for the complex, 106.26 μg/ml, was beyond 100 µg/mL, signifying very low anticancer activity against the selected cancer cell lines (Table 1). DNA binding studies showed that the complex had a low binding affinity for the DNA, which could have been responsible for its low antitumor potency [30].

Abdelrahman et al. synthesized new nano Fe(III) complexes (38 - 40) of pyridazinone-acid hydrazone ligand 37, and new mixed-ligand complexes using 8-hydroxyquinoline or 1, 10-phenanthroline (Scheme 5) as an auxiliary ligand. The complexes and the imine ligand were tested against hepatocellular carcinoma cell lines (HepG-2 cells) for their antitumor activity in vitro. The imine ligand showed strong antitumor activity against the HepG-2 cells, but the activity of the synthesized iron complexes (38 - 40) was insignificant (Table 1). 37 showed an antitumor activity of 3.80 μg/mL against HepG-2, whilst the standard drug, Cisplatin, showed an activity of 3.27 μg/mL. (Table 1) [31].

Scheme 6. Synthesis of iron complexes 38 – 40.

Scheme 6. Synthesis of iron complexes 38 – 40.

Farhan et al. synthesized two heterocyclic imine ligands (43 and 46) and prepared complexes (44 and 47, scheme 6) from the fusion of the imine ligands with Fe(III), resulting in an octahedral geometry and paramagnetic complex (44 and 47). The ligands and imine complexes were investigated for their anticancer potency against the L20B cell line at a 4000 μg /mL concentration. The iron complex 44 demonstrated high anticancer activity of 8.7 μg /mL against the (L₂₀B) cell line. The anticancer activity of 47 was comparatively low, 22.9μg /mL (Table 1). The results were not compared with a standard anticancer agent [32].

Scheme 7. Synthesis of complexes 44 and 47.

Scheme 7. Synthesis of complexes 44 and 47.

Table 1. Product, synthesis conditions, and in vitro anticancer activity (IC₅₀ in µM) of selected iron-imine complexes compared to the respective positive controls.

Table 1. Product, synthesis conditions, and in vitro anticancer activity (IC₅₀ in µM) of selected iron-imine complexes compared to the respective positive controls.

Entry No.	Complex No.	Structures	Synthesis condition	Complex & Positive control	Cancer cell lines			Ref.
1.	3, 4		EtOH Reflux, 2 h Stirring	3	MCF-7 21.35±0.12	HepG-2 27.70±0.11	HCT-116 15.75± .07	[21]
				4	5.14± 0.05	6.75 ± 0.12	4.45±0.14
				Doxorubicin	4.10 ± 0.13	5.15 ± 0.07	4.35±0.15
2.	5 - 9		EtOH Reflux, 3 h		KB	HepG-2		[22]
				5 6 7 8 9	0.68± 0.05 3.25 ± 0.16 1.84 ± 0.10 2.76 ± 0.17 1.95 ± 0.13	0.83 ± 0.05 7.05 ± 0.25 6.07 ± 0.22 19.78 ± 1.07 2.38 ± 0.17
				Ellipticine	1.14 ± 0.06	2.11 ± 0.12
3.	10 - 18		Stirring, 30 min		K562	P3HR1	JURKAT	[27]
				10	>25	>25	>25
				11 12 13	9.25 ± 0.42 22.24± 0.06 >25	5.61 ± 0.19 8.09 ± 0.62 >25	>25 >25 >25
				14 15 16	4.81 ± 0.15 >25 14.05± 0.31	11.98± 0.69 22.4 ± 0.47 5.72 ± 0.28	22.79±0.54 >25 >25
				17 18	5.04 ± 0.18 >25	11.47± 0.42 21.03± 0.39	22.0 ± 0.39 >25
				Imatinib	9.67 ± 0.49	23.74± 1.02	3.73 ± 0.21
4.	19 - 26		0°C, 7 days	19 20 21 22 23 24 25 26	A549 30 ± 1.1 30 ± 7.7 28 ± 2.0 28 ± 2.0 28 ± 2.0 10 ± 2.1 34 ± 4.7 32 ± 1.5			[28]
				Etoposide	19 ± 1.3
				Cisplatin	16 ± 1.9
5.	30		Reflux, 3 h Stirring, 2 h		Hep-G2			[29]
				30	7.31
				Vinblastine	2.93
6.	34		Reflux, 8-9 h		Hela	MiaPaCa-2	B16F10	[30]
				34	106.26 ± 0.5	112.13± 0.6	104.15± 1.2
7.	38 - 40		Stir, 2 h Reflux, 12 – 15 h	37 38 39 40 Cisplatin	Hep-G2			[31]
					3.8058.00 R R 3.27
8.	44 45 46 47		Reflux, 3 – 4 h	44 45 46 47	L20B			[32]
					8.70 13.20 18.4 22.9

^†IC₅₀ values written as these have been reported in the literature.

2.2. Imine-iron complexes as antimicrobial agents

Antimicrobial agents are compounds that can inhibit (stop or reduce) the growth of microorganisms such as bacteria, fungi, protozoa, etc. Microbial resistance to antibiotics and other antimicrobial drugs has become one of the major health concerns globally. Due to their distinct characteristics and action methods, research has focused on imine-iron complexes as promising agents [33]. In recent years, metal complex-based antibiotic compounds have become a promising avenue in drug development. According to research, 21% of the metal compounds examined exhibited antibacterial action against typical strains of Candida and Cryptococcus [34]. Therefore, there is an urgent need to develop next-generation antimicrobial agents, and imine-iron complexes can be the right avenue to move forward because these complexes are known for their antimicrobial activity. The observed microbial activity of such complexes is traced to several reasons, including (i) the concept of cell permeability and chelation process which reduces the polarity of a metal ion; (ii) the chelation process which increases electron delocalization on the chelate ring and enhances lipophilicity of complex granting it easy penetration through microbial cells; (iii) the toxicity of metal ions [35]; (iv) introduction of azomethine linkage improves the hydrophobicity and liposolubility of the molecules; and additional factors that contribute to the improved biological activity are the solubility, conductivity, and dipole moment of the metal ion [36,37,38].

The antimicrobial activities of Schiff bases and their metal complexes have been studied against different bacterial and fungal strains [39].

Rahmatabadi et al. synthesized the iron metal complex (51, Scheme 8) of imine ligand (50), prepared by condensing 48 with 49. Imine iron complex (51) was tested for its in vitro antibacterial potency against gram-negative Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa) bacteria, and gram-positive bacteria Bacillus cereus (B. cereus) and Staphylococcus aureus (S. aureus) with tetracycline, gentamicin, chloramphenicol, and cephradine as standard control. 51 showed enhanced activity compared to the free ligand (50). It had the highest antibacterial activity against B. cereus (29 mm) and S. aureus (14 mm), which was higher than the activity of the standard drug tetracycline against B. cereus (11 mm) and S. aureus (9 mm), but it showed moderate activity against E. coli (14 mm), and P. aeruginosa (14 mm), which was for both bacteria (Table 2). These recorded activities of the complexes are due to the more pronounced lipophilic nature of the metal centers in the complexes [40,41].

Shukla et al. synthesized imine-ligand 54 by condensing 52 with 53 in a 1:2 molar ratio. 54, 1,10-phenanthroline, and FeCl₃ were combined to form a mixed-ligand iron complex (55, Scheme 9) and analyzed for their antibacterial activity against gram-negative bacteria E. coli in comparison to amoxicillin and chloramphenicol standard drugs. 55 exhibited enhanced activity against E. coli (29 mm) compared to 54 (23 mm). Still, it showed moderate antibacterial activity compared with standards chloramphenicol and amoxicillin, which showed inhibition zones of 39 mm and 41 mm, respectively. (Table 2). The action of metal ions on the normal cell membrane may cause the metal complex's increased activity. Either the microbes' cells' impermeability or variations in the ribosomes of microbial cells determine the complex's ability to combat E. coli. The outcome could be explained by considering the chelation theory, which suggests that chelation could facilitate a complex's capacity to pass across a cell membrane [42,43].

El-Lateef et al. explored 3 and 4 (Scheme 1) for their antibacterial potency against three selected bacteria strains: S. marcescence, E. coli, and M. Luteus. Both complexes showed high antibacterial activity against the selected bacteria, with 4 showing the highest antibacterial activity against M. luteus (2.50 μg/mL) (Table 2). The values of the activity of standard drugs were not provided. The activity of the complexes was high compared to that of the free ligands (1 and 2) due to the chelation theory. The polarity of the metal ion is greatly reduced during chelation due to electron delocalization throughout the entire chelate ring system and partial sharing of its positive charge with the hetero donor atoms of the ligand [44,45]. The different activities displayed by the complexes against the various microbes are due to the differences in the chemical makeup of the microorganisms' cell walls [21].

The iron complex (59, Scheme 10) was synthesized by Karem et al., and its antibacterial potency was evaluated against P. aeruginosa, E. coli, S. aureus, and B. subtilis. The iron complex showed no activity for all the bacteria strains except for E. coli, against which it showed activity of 25 μg/mL. This value was higher than that of the free ligand, which showed inhibition of 2.5 μg/mL (Table 2). The observed increase in activity against E. coli can be explained by Tweedy’s theory [46]. The results obtained were not compared to a standard drug [47].

The imine ligand 62 synthesized by the condensation of 60 and 61 (Scheme 11) was complexed with Fe(III) by Shukla et al. to form two imine-iron complexes 63 and 64. The complexes were tested against gram-positive bacteria, B. subtilis, and Gram-negative bacteria, E. coli, with amoxicillin as a standard. The complex 64 (14 mm and 18 mm respectively) showed enhanced activity than the free ligand (11 mm and 15 mm respectively) against B. subtilis E. coli, and this activity of 64 was similar to that of the standard amoxicillin (16 mm and 20 mm respectively) against the same microbes. The antimicrobial activity of complex 63 is similar to that of ligand 62 against the selected microbes (Table 2). The result shows that chelation makes it easier for these complexes to traverse the cell membrane, which is consistent with Tweedy's chelation theory. Due to the partial sharing of the metal ion's positive charge with donor groups during chelation, the metal ion's polarity will be lowered, and the delocalization of π-electrons over the entire chelate ring will be increased. This improves the complex's lipophilicity, favoring its passage through the lipid membrane, and interferes with the metal-binding sites in the microbes' enzymes [48].

The imine ligand 66, prepared by the condensation of 65 with 1,2-diaminobenzene and its iron complex (67, Scheme 12) was synthesized by Anacona et al. and analyzed for its antibacterial activity against pathogenic bacteria gram-positive Enterococcus faecalis (E. faecalis) ATCC 29212, S. aureus ATCC 25923, and clinical isolates of Streptococcus viridans (S. viridans), Enterococcus sp. and methicillin-resistant S. aureus (MRSA). The iron complex (67) showed enhanced activity against all the selected microbes compared to the ligand 66. It exhibited very good antibacterial activity against Methicillin-resistant S. aureus, (15 mm), whereas the standard drug and free ligand showed no activity at all. The complex under study [49] showed moderate activity against the other bacteria strains. (Table 2). The moderate to high activity of the complex is attributed to not only the chelation theory but also other factors like the nature of the metal ion, the type, and quantity of donor atoms, stereochemistry, chelate stability, and pharmacokinetic factors. [50].

Pahontu et al. synthesized Fe(III) complex (68, Figure 1) and tested its antimicrobial activity against Gram-positive bacteria, S. aureus, B. cereus, and E. faecalis, Gram-negative bacteria E. coli, A. baumannii as well as fungal strains Candida albicans (C. albicans), Candida krusei (C. krusei), and Cryptococcus neoformans (C. neoformans). The MIC values of the iron Schiff base complex obtained correlated with very low antibacterial activity against all the bacteria strains selected compared to the standards used (furacilin, ciprofloxacin, and amikacin). The complex showed improved antifungal activity against C. albicans and C. neoformans, with values 0,0156 and0.0078μg/mL, respectively than the standard drugs nystatin (C. albicans = 0.032 μg/mL, C. neoformans = 0.032 μg/mL) and miconazole (C. albicans = 0.016 μg/mL, C. neoformans = 0.0162 μg/mL) used in studies. (Table 2) [6]. The lack of activity of the synthesized complex against the bacterial strain is unclear. Still, its impressive antifungal activity against C. albicans can be attributed to the metal ion’s ability to reduce binding energy while increasing the binding affinity of the microbe protein, hence interrupting its biological processes [10].

Mumtaz et al. complexed iron (II) with an imine ligand to form the iron(II) metal complex (69, Figure 1), which was investigated for its antimicrobial activity against E. coli, Enterobacter aerogenes (E. aerogenes), S. aureus, B. pumilus, K. oxytoca, and C. butyrium. The iron complex’s zone of inhibition of the various bacteria strains was quite small, demonstrating low antibacterial activity towards the bacteria. Still, these values were higher than that of the free imine ligand. Complex 69 showed an activity of 12, 10, and 9 (mm) against E. coli, E. aerogenes, and C. barium, respectively, and the ligand showed an activity of 14, 12, and 12 (mm), respectively (Table 2). The complex's enhanced activity compared to the ligand can be explained by chelation therapy [46],[51].

Al-Wasidi et al. synthesized an iron Schiff base complex by complexing imine ligand (72) with Fe(III) to form an octahedral iron complex (73, Scheme 13) which was investigated for its antibacterial and antifungal activity against gram-positive B. subtilis, S. pneumonia, S. aureus, gram-negative E. coli Sp., Pseudomonas Sp., and fungal strain Aspergillus niger (A. niger) and Penicillium Sp. The iron-imine complex 73 showed enhanced antibacterial activity relative to the free ligand 72 with a great zone of inhibition against S. pneumonia (7-10mm) and S. aureus (7-10 mm), respectively. It demonstrated low inhibition against the selected fungal strains (Table 2). The results obtained were not compared to any standard drug. [52].

El-Sonbati et al. synthesized imine-iron complex (76) with ligand (75, Scheme 14) and evaluated its antimicrobial activity against Gram-positive bacteria, B. subtilis, and S. aureus; Gram-negative bacteria such as Salmonella sp, P. aeruginosa, and E. coli and fungal strains A. fumigatus and C. albicans. For all the bacteria strains selected, complex 76 showed similar antibacterial activity as the free imine ligand and low antibacterial when compared with the selected standard drugs ampicillin and gentamycin (Table 2). Against the fungal strains C. albicans and A. fumigatus, the complex showed improved inhibition of 16 mm and 18 mm, respectively, than the free imine ligand (13 mm and 15 mm, respectively). This inhibition was low compared to the standard antifungal drug amphotericin, which had an activity of 25 mm and 23 mm zone of inhibition, respectively. The improved antifungal activity of complex 76 in relation to the free ligand (75) can be explained by the chelation theory, where chelation of the ligand causes an increase in lipophilicity properties of the metal chelate enhancing its ability to permeate the lipoid layers of microbe membrane blocking the metal binding site [4] [46].

Kumar et al. synthesized the imine-iron complex (79, Scheme 15) of imine ligand (78) and evaluated its antibacterial activity against gram-positive P. aeruginosa and gram-negative S. aureus bacteria. The complex (79) showed an improved antibacterial activity compared to the free ligand (78) against S. aureus and P. aeruginosa with a zone of inhibition of 14 mm and 11 mm, respectively, whereas the ligand showed inhibition of 8mm and 6mm, respectively. 79 had a comparable zone of inhibition to that of the standard drugs ampicillin against S. aureus (14 mm) and chloramphenicol against P. aeruginosa (8 mm) (Table 2) and can be further investigated as an antibacterial drug candidate. The improved antibacterial activity of complex can be attributed to the chelation theory [46],[53].

Fe(II) complex (82, Scheme 16) of compound 81 was synthesized by Shinde et al. and upon investigating its antimicrobial activity against gram-positive bacteria S. aureus (ATCC 29737), gram-negative bacteria E. coli (ATCC 25922), and fungi strain C. albicans (MTCC 277) and A. niger (MCIM 545), it was found to possess high activity against E. coli (ATCC25922) and S. aureus with MIC value of 10 μg/mL against both bacteria. This value is the same for the standard drug gentamicin, which also showed an activity of 10 μg/mL. 82 also showed improved activity against both fungal strains C. albicans (MTCC 277) and A. niger (MCIM 545) with MIC value of when compared with standard drug fluconazole which showed activity of 20 μg/mL against both strains (Table 2) [2]. The reason for the exceptional antimicrobial potency of the synthesized complex (82) was not stated, but it could be due to chelation theory [46] and the good binding interaction of 82 with the proteins of the selected strains.

Mukhtar et al. synthesized an imine-iron metal complex (83, Figure 1) and its antimicrobial activity was investigated against five bacterial isolates E. coli, S. aureus, P. aureginosa, K. Pneumoniae and S. aureus and three fungal species F. solani, A. fumigate and C. albicans. The results of these studies revealed that the complex showed the highest antibacterial activity against E. coli (14mm) at a concentration of 1000 μg/mL but moderate activity against the other bacterial isolates (Table 2). Its antifungal activity was quite low. It inhibited the growth of C. albicans and F. solani by 7mm at a concentration of 2000 μg/mL and 12 mm at a concentration of 4000 μg/mL, respectively. It showed no antifungal activity against A. fumigate at the studied concentrations. The ligand showed no zone of inhibition against E. coli and P. aeruginosa at the given concentrations. It, however, showed similar activity as the complex against S. aureus (12 mm) at a concentration of 1000 μg/mL. It also showed no activity against all the selected fungi strains (Table 2). The results obtained in this study were not compared to any standard drug [54]. The reason for the improved antimicrobial activity of the synthesized complex can be attributed to the chelation theory [46].

The synthesis of chromone imine nano complexes of Fe(III) (87, Scheme 17) was synthesized by Shebl et al., and its antimicrobial activity was tested against microorganisms such as E. coli, P. vulgaris, K. pneumonia, S. aureus, and C. albicans. The results showed that the iron complex (87) has moderate activity against fungi species C. albicans (8 μg/mL) when compared to free ligand 86 (4 μg/mL) and standard (2 μg/mL) it; however, exhibited very low activity (>50µg/ml) toward all the selected bacterial stain in comparison to the standard drug doximycin which showed activity in the range of 2 – 4 μg/mL (Table 2) [3].

Knittl et al. synthesized two different iron-imine complexes (88 and 89, Figure 1) and evaluated them for their antimicrobial activity against gram-positive bacteria S. aureus (ATCC25923), gram-negative P. phaseolicol (S97), and fungal species F. oxysporium using cephalothin, chloramphenicol, and cycloheximide, respectively, as standard antibiotics. The results indicate that 88 exhibits higher antibacterial and antifungal activity against the selected microbes, S. aureus (37 mm), P. phaseolicol (26 mm), and F. oxysporium (31 mm), in comparison to 89, which showed inhibition of 32 mm, 23 mm and 30 mm against S. aureus, P. phaseolicol, and F. oxysporium respectively. These values suggest moderate antibacterial and antifungal activities of the complexes compared to the standard antibiotic and antifungal drugs Cephalothin Chloramphenicol and Cycloheximide. Both synthesized complexes showed improved antimicrobial activity against the selected microbes compared to the free ligand (Table 2). Chelation tends to increase the ligand's effectiveness as a potent antibacterial agent. From the results obtained, there is evidence for the relationship between the structure of the complexes and their activity. Antimicrobial activity is enhanced by binuclear complexes rather than acyclic complexes, revealing that these complexes are biologically more efficient and, therefore, can be useful as new drugs. It is also discussed that the chemical geometry of compounds is important in explaining the biological activity of the complexes [55]. Alosaimi et al. synthesized two symmetrical imine ligands (94 and 95) and reacted each with FeCl₃·6H₂O to form mononuclear octahedral Fe(III) complexes 96 and 97 (Scheme 18). The complexes were screened for their antibacterial activity against Gram-positive bacterial strains S. epidermidis, S. aureus, and E. faecalis and Gram-negative bacterial strains P. aeruginosa, E. coli, and P. mirabilis. Antifungal activity was also determined against the common pathogenic fungal strain C. albicans. The tested Schiff base ligands (94 and 95) exhibited negligible antibacterial action against Gram-positive bacterial species with growth-limiting diameters of 15 mm. It also showed no antifungal activity against C. albicans. Iron complex 96 showed higher antibacterial activity against the Gram-positive bacteria strain, S. epidermidis (14 mm), than iron complex 97 (with a zone of inhibition of 12 mm). The Gram-negative bacteria strain, P. mirabilis was slightly inhibited by both iron complexes, 96 (8 mm) and 97 (22 mm), but all the other strains were resistant to both complexes. The complexes exhibited low antibacterial activity compared to the standard antibiotic agent, amoxicillin. The antibiotic agent inhibited S. epidermidis and P. mirabilis with zones of inhibition of 28 mm and 44 mm, respectively. The fungus C. albicans was resistant to both iron complexes and showed no significant antifungal activity (Table 2). Overtone’s permeability concept and Tweedy's chelation theory can both be used to explain why coordination compounds have more activity than their parent ligands [46,56]. The complexes become more permeable when a metal ion is present because they dissolve in lipids and enter the cell more readily, causing negative changes in the cell environment and its enzymes, further hindering the microbe's growth. Additionally, the metal complexes impede the production of proteins by impeding the cell's respiration process, further inhibiting the organism's growth. Additionally, the probability of hydrogen bonds forming between the azomethine linkage, and the cell components will negatively impact the cell's normal functions [57,58].

Iron(III) was complexed with two imine ligands (98 and 99, Scheme 19) by Naureen et al. to form iron complexes 100 and 101. The ligands and their complexes were evaluated for their antibacterial activity against Gram-positive P. aeruginosa and Gram-negative E. coli and S. aureus using tetracycline as the standard drug. Their antifungal activity was also evaluated against C. albicans and C. glabrata with nystatin as the standard drug. The antimicrobial activity of the synthesized complexes was enhanced when compared to their free Schiff ligands. Both complexes showed similar inhibition against all the bacterial strains used in this research, but 101 showed better activity against S. aureus (20 mm) and C. albicans (24 mm) compared to 100, which showed a zone of inhibition of 16 mm and 20 mm, respectively. The complexes showed low antibacterial activity when compared with the standard drug tetracycline. Both complexes showed higher antifungal activity against C. albicans than the standard drug nystatin (19 mm) and could be investigated as promising antifungal drug candidates (Table 2) [59]. The chelation theory can explain the improved activity of the complexes to their free Schiff ligand [46].

Singh et al. synthesized an imine ligand by condensation of compounds 102 and 103, respectively, in the molar ratio of 2:1. The synthesized ligand (104) was complexed with iron to form an octahedral 105 (Scheme 20) and tested against S. epidermidis, E. coli, A. flavus, A. niger, and C. lunata to validate its antibacterial and antifungal potentials. The complex showed better antibacterial activity against the selected bacteria and fungi strains than the Schiff base ligand. The complex showed the highest activity against A. niger (16 mm) and low activity against E. coli fungal strains (15 mm) (Table 2) [60]. The improved activity of the complexes in relation to their ligands can be explained based on Overtone’s concept and Tweedy’s chelation theory [46,56].

Kavitha et al. evaluated 34 (Scheme 5) for its antibacterial and antifungal activity against gram-positive Staphylococcus sp. and Bacillus sp. as well as gram-negative E. coli, and Pseudomonas bacterial and fungal strains Macrophamina phaseolina (M. phaseolina) and Sclerotium rolfsii (S. rolfsii). The iron complex 34 showed enhanced biological activity against the bacterial and fungal strains, B. subtilis (4 mm), E. coli (4 mm), and M. phaseolina (14 mm) compared to the ligand (33), which showed activity of 1, 1, and 8 mm respectively. However, these activities of the complex are low when compared to the standard antibiotic streptomycin and standard antifungal agent mancozeb (Table 2). The concept of overtone explains the increased activity of complexes [51].

Borase et al. synthesized a pyridine imine transition metal complex of Fe (III) (109, Scheme 21) by reacting metal salts (FeCl₃) with compound 108. The complex was evaluated for its antibacterial and antifungal potency against gram-positive bacteria S. aureus, Gram-negative bacteria E. coli, as well as three fungal strains C. albicans A. niger and F. moniliforme. The iron complex (109) showed potent antifungal activity against A. niger (15.80 mm) when compared to the standard amphotericin-B (15.78 mm), respectively. 109 showed low antifungal and antibacterial activity against C. albicans (7.44 mm) and S. aureus (3.02 mm), respectively. The complex was resisted by E. coli and F. moniliforme (Table 2). The antimicrobial activities of the ligand were not provided in this study, so a comparison could not be made [61].

Deshmukh et al. reported an imine ligand and used it to synthesize a Fe(III) complex 110 (Figure 1) and analyzed for its antimicrobial activity against gram-positive S. aureus, and S. pyrogenes and gram-negative E. coli and S. typhi pathogens. The complex showed the highest activity against S. aureus (22 mm) and the least activity against E. coli (16 mm) (Table 2). Results of antibacterial activity was not compared with ligand or standard drugs and hence comparison could not be made [62].

Savcı et al. synthesized a Schiff base ligand (112) and complexed it with FeCl₂⋅4H₂O to form a transition metal imine-iron complex 113 (Scheme 22). Compounds 111, 112, and 113 were evaluated for their antimicrobial activity against gram-positive B. subtilis, S. aureus, B. megaterium gram-negative E. aerogenes, E. coli, P. aeroginosa, K. pneumonia bacterial strains and fungal strains C. albicans, Y. lipolytica, and S. cerevisiae. The results indicate that both 111 and 112 show better antibacterial activity against B. subtilis ATCC 6633 (zone of inhibition of 40 mm and 30 mm, respectively) than the synthesized iron complex 113 (21 mm) at a concentration of 0.2 mg/ml. The complex showed antibacterial activity against E. aerogenes (30 mm) and P. aeruginosa (36 mm) only at an elevated concentration of 1 mg/mL but did not show significant antifungal activity against the selected fungal strains (Table 2). Only 111 showed activities against K. pneumonia (36) at a 0.2 mg/ml concentration. Compounds 111, 112, and 113 were resisted by all the fungal strains at the tested concentrations (data was not included in Table 2 due to this). The 111 and 112 were found to have superior antibacterial activity compared to all the standard antibiotic drugs against B. subtilis, B. megaterium, E. aerogenes, and P. aeruginosa. The sizes and load distributions of the metal ions, the shape of the metal chelate, the potential for redox, as well as the increased lipophobicity of the molecules, may all affect the impact of the metal complexes on microbes [63]. However, it does not appear to be possible to simply attribute the bactericidal activity to the metal complex structure [64,65].

Kumar et al. synthesized synthesized imine ligand and complexed it with FeCl₃·6H₂O, Fe(NO₃)₃·9H₂O, and Fe(OAc)₃·2H₂O to form iron complexes 120, 121, and 122 (Scheme 23), respectively. The synthesized complexes were screened for their antimicrobial activity against S. aureus, B. subtilis (as Gram-positive bacteria) and P. aeruginosa, E. coli, Salmonella typhi (as Gram-negative bacteria), and fungi Rizoctonia sp., Aspergillus sp., and Penicillium sp. The complex 122 demonstrated the highest antibacterial activity against S. aureus (62 mm) and P. aeruginosa (65 mm). Complex 120 showed the highest activity against E. coli (41 mm) and S. typhi (42 mm). The antibacterial activity of complexes 121 and 122 was higher against the gram-positive bacteria than the gram-negative bacteria (Table 2), and this is due to the difference in the structure of the cell walls. Gram-negative cells have more complex cell walls than gram-positive ones (Table 2). The results for antifungal screening show that 122 has high antifungal potency against Aspergillus sp (80 mm) and Penicillium sp. (66 mm), even better than that of the standard drug miconazole with %inhibition of 57 mm and 65 mm, respectively at a concentration of 1.0 mg/ml. Complexes 120 and 121 showed moderate antifungal activity toward the selected strains (Table 2). Generally, the ligand demonstrated moderate, and the complexes displayed moderate to high activity toward all the organisms compared to standard drugs. This could be due to the presence of the -NH group, which is believed to impart the biological system's transformation reaction and plays a significant role in biological activity. Chelation theory also explains the enhanced activity of the complexes to the ligand [46][66].

Mohamed et al. synthesized a novel octahedral iron-imine complex 123 (Figure 1) and evaluated its antimicrobial potential on the bacterial strains Clavibacter michiganensis, Xanthomonas campestris and Bacillus megaterium and fungal strains Monilinia fructicola, Penicillium digitatum and Colletotrichum acutatum. The free Schiff base ligand showed better antibacterial activity against all the selected bacterial strains than its iron complex. The ligand exhibited higher antibacterial activity against C. michiganensis (32 mm) than the standard drug tetracycline (30 mm). It also showed similar activity as tetracycline against B. megaterium and X. campestris (Table 2). Also, complex 123 (Figure 1) showed enhanced antifungal activity against M. fructicola, (62.5 mm) and P. digitatum (62.5 mm) compared to both the free Schiff base ligand (36.0 and 28.0 mm, respectively) and the standard antifungal agent azoxystrobin (45.3 and 58.1 mm respectively) and can be considered as an antifungal drug candidate. It, however, was inactive against C. acutatum (not shown in the table). The microbicide impact of the investigated compounds may result from the chemical structure of the free ligand as well as the toxicity of the investigated metal ions [67,68]. The increased antimicrobial activity of freshly synthesized metal chelates was explained by the principle of cell permeability of the microbes [35].

An imine-iron complex 124 (Figure 1) was synthesized by Elshafie et al., and its biological activity was evaluated against both human and phytopathogens. Antimicrobial analysis was conducted on pathogenic bacterial strains E. coli, B. cereus, Pseudomonas fluorescens, and P. aeruginosa and phytopathogenic fungi, Monilinia fructicola, Aspergillus flavus, Penicillium italicum, and Botrytis cinerea. The antibacterial activity of 124 was dose-dependent. It showed the highest antibacterial activity against B. cereus with a measured zone of inhibition of 14 mm at a concentration of 100 µg/ml, higher than that of both the ligand (12 mm) and tetracycline (12 mm). Complex 124 inhibited the growth of P. aeruginosa (8 mm) and P. fluorescens (12 mm) only at a higher concentration of 200 µg/ml. Generally, the free imine showed better antibacterial activity than the metal complex 124. 124 exhibited no antifungal activity against M. fructicola. Still, it showed enhanced activity against B. cinerea (6.7 mm) at a concentration of 400 µg/ml, whereas at the same concentration, it was resisted by the free ligand. The activity of both the Schiff base ligand and the complex was low when compared to the standard natural antifungal drug cycloheximide (Table 2). The acquired antimicrobial test findings demonstrated that the tested ligands and their metal complexes have the capacity to suppress the growth of all strains under study in a dose-dependent manner. Particularly, the chemical structure of the free ligand itself and the toxicity of the metal ions under study could both contribute to the fungicidal effects of the compounds under study [63,64]. Chelation theory can also explain the enhanced activity of the complex. Also, the investigated gemifloxacin ligand and its metal complexes' capacity to block the DNA gyrase and DNA topoisomerase IV enzymes may potentially be related to their antifungal and antibacterial action [69,70].

Ismail et al. synthesized an imine-iron complex (30, Scheme 4) and evaluated it for its in vitro antibacterial activity against gram-positive bacteria S. aureus and B. subtilis, gram-negative bacteria P. vulgaris and E. coli, and fungi A. flavus and C. albicans. The imine ligand exhibited better antibacterial and antifungal activity against all the microbial strains studied than 30. Both the ligand and 30 were inactive against P. vulgaris (value not shown in Table 2). Complex 30 showed lower antibacterial and antifungal activity against S. aureus, E. coli, and C. albicans with a zone of inhibition of 17, 19, and 15 mm, respectively, than the selected antibacterial standard drugs gentamycin (S. aureus = 24 mm and E. coli = 30 mm) and ketoconazole (C. albicans = 20 mm). The ligand had high action against C. albicans, displaying antimicrobial activity (25 mm) superior to the ketoconazole standard (20 mm). Additionally, the ligand's inhibition zone value against B. subtilis is 25 mm, which is comparable to the standard gentamycin (26 mm) (Table 2). The reason for the reduced antimicrobial efficiency of the complex was not stated [29].

Abdelrahman et al. evaluated complexes 38, 39, and 40 (Scheme 6) for their antimicrobial activity against gram-positive bacteria S. aureus, B. subtilis, Gram-negative S. typhimurium, E. coli bacteria, and unicellular C. albicans and multicellular A. fumigatus fungi. The free ligand was ineffective against all the studied microbes except for C. albicans, which had an inhibition zone of 8 mm. The results obtained show that complex 39 was moderately active against S. typhimurium (15 mm), but inactive against the remaining bacterial strains (results not shown in Table 2). Iron complexes 38 and 40 showed no activity against the selected bacteria strains. Complexes 38 and 39 showed moderate antifungal activity against C. albicans with an inhibition zone of 14 mm and 22 mm, respectively; these values were high when compared to the free ligand, which showed inhibition of 8 mm. All three complexes (38 - 40) showed no activity against A. fumigatus at the tested concentrations (results not shown in Table 2). The lipophilicity of compounds significantly influences antimicrobial activity. The enhanced antimicrobial activity of the complexes in relation to the ligand is due to chelation theory. Chelation results in an increase in the lipophilicity of the metal complexes, causing the concentration of complexes in the lipid membrane to increase and reducing microorganism multiplicity. It is hypothesized that the complexes' antifungal effects result from either killing the bacteria or preventing their growth by obstructing their active sites. [71][31].

Ahmed et al. synthesized an imine-iron complex 125 (Figure 1) in a 1:1 ratio with the ligand. The synthesized compounds were tested for their antimicrobial activity against the gram-positive bacteria S. aureus and gram-negative bacteria E. coli, as well as fungal strains C. albicans and A. flavus. All the selected microbes resisted the ligand except E. coli, against which it showed an inhibition zone of 9 mm, a value higher than that of the antibacterial drug amikacin (6 mm). 125 showed the same zone of inhibition (10 mm) as the standard drug amikacin against S. aureus. and enhanced activity against E. coli (10 mm) compared to the same standard drug. Both fungal strains resisted 125 and showed no activity against them (results not shown in Table 2). Several factors could be responsible for the remarkable antibacterial activity of the complex, including interference with the creation of the cell wall, harm because of which the permeability of the cell may be changed, or disorganization of the lipoprotein, resulting in cell death. Also, different cellular enzymes, essential in the metabolic pathways of microbes, could be deactivated. Another factor can be forming a hydrogen bond between the azomethine group and the active center of the cell's components, which interferes with proper cell function [72].

A mononuclear chelate of iron (III) was synthesized by Mohamed et al. by condensing a new tridentate Schiff base ligand (128) with iron chloride (FeCl₃‧H₂O) in a 1:1 ratio. The complex formed (129) had an octahedral geometry. The in vitro antimicrobial potency of the synthesized complex (129) was evaluated against gram-negative bacteria E. coli and gram-positive bacteria S. aureus and fungal strains C. albicans and A. flavus. Complex 129 showed a broad zone of inhibition (14 mm/mg sample) against A. flavus, whereas the free Schiff base ligand demonstrated zero activity. This activity was much higher than that of ketoconazole (8 mm/mg sample), the selected standard antifungal agent. The enhanced microbial activity of the complex can be attributed to the increased lipophilicity of the metal complex upon coordination with the free ligand. This ensures easy movement of the metal chelate into the fungal cell membrane, inhibiting microbial growth or distorting its active site [73,74]. For the other microbial strains, the Schiff base ligand showed activity similar to its free ligand (Table 2). The reason for the reduced activity of Schiff base against E. coli, S. aureus, and C. albicans was not stated [75].

Scheme 24. Synthesis of complex 129.

Scheme 24. Synthesis of complex 129.

Hidayati et al. synthesized an N-(2-hydroxybenzylidene) chitosan Schiff base and its iron (II) complex and evaluated them for their antibacterial potency. Chitosan (poly-β-(1→4)-glucosamine) is a very abundant, non-toxic natural biopolymer, and its metal complexes are known to exhibit very good biological activities. Hidayati et al. evaluated chitosan, the synthesized chitosan Schiff base ligand, and its imine complex for their ability to inhibit the growth of E. coli and S. aureus and found - at a concentration of 1000 ppm - the complex being most active against both bacterial strain (9.86 mm and 10.16 mm respectively), followed by the chitosan Schiff base (9.50 mm and 9.33 mm respectively) and lastly the chitosan itself (8.75 mm and 9.25 mm respectively). The observed improvement in antibacterial activity of the chitosan Schiff base iron complex can be explained by chelation, which enhanced the lipophilicity nature of the complex, ensuring its faster diffusion across bacterial cell membranes [9][76].

Table 2. Product, synthesis conditions, and in vitro antimicrobial activity of imine-iron complexes compared to the respective positive controls^†.

Table 2. Product, synthesis conditions, and in vitro antimicrobial activity of imine-iron complexes compared to the respective positive controls^†.

No.	Complex No.	Structures of synthesized complexes	Reaction conditions		Biological activity Antimicrobial																																																								Ref.
1.	51		Stirring, 30 min Reflux, 7 h		Zone of inhibition, mm																																																								[40]
							S. aureus															E. coli															P. aeruginosa													B. cereus
					50		11															10															11													12
					51		14															14															14													29
					Tetracycline		9															10															12													11
2.	55		Stirring, 1-2 h Reflux, 2-11 h		Zone of inhibition, mm																																																								[42]
																								E. coli
					54																			23
					55																			29
					Amoxicillin																			41
					Chloramphenicol																			39
3.	3 4		Reflux, 2 h		Minimum Inhibitory Concentration (MIC)/µg/mL																																																								[21]
					Bacteria																																													Fungi
							S. marcescence				E. coli													M. luteus																							G. candidum			A. flavus									F. oxysporum
					1 2 3		7.25 5.50 3.75				7.25 6.25 4.25													6.25 4.75 3.00																							6.75 5.25 4.00			8.00 6.75 4.50									7.50 6.25 4.25
					4		3.25				3.50													2.50																							3.00			3.75									3.50
4.	59		Stirring Reflux, 1 h		Minimum Inhibitory Concentration (MIC)/µg/mL																																																								[47]
							E. coli											Pseudomonas																													S. aureus						Bacillus
					58 59		2.5 25											8 R																													15 R						17 **R
5.	63 64		Stirring, 1 h Reflux, 9 h		Zone of inhibition, mm																																																								[48]
																								Bacillus subtilis																													E. coli
					62																			11																													15
					63																			12																													11
					64																			14																													18
					Amoxicillin																			16																													20
6.	67		Reflux, 5 h		Zone of inhibition, mm																																																								[65]
							S. v								E. sp																			S. a																E. f			MRSA
					65		15								24																			16																17			R**
					67 Standard		20 19								30 36																			25 45																22 36			15 R
7.	68		Reflux, 4 h		Minimum Inhibitory Concentration (MIC)/µg/mL																																																								[10]
								C. albicans																C. neoformans																				S. aureus						B. cereus						E. coli
					68			0.0156																0.0078																				0.0625						0.0312						0.0625
					Nystatin			0.032																0.032
					Miconazole Furacillinum Ciprofloxacin Amikacin			0.016																0.0162																				0.0046 0.001						0.0046 0.0003						0.0046 0.008
8..	69		Reflux, 2 h		Zone of inhibition, mm																																																								[51]
													E. coli																						E. aerogenes																			C. butyrium
					Ligand								14																						12																			12
					69 Standard								12 11																						10 7																			9 9
9.	73		Stir and reflux, 1 h		Zone of inhibition, mm																																																								[52]
									S. pneumonia																																								S. aureus
					72				7-10																																								1-3
					73				7-10																																								7-10
10.	76		Stir and reflux, 2 h		Zone of inhibition, mm																																																								[4]
									S. aureus																	E. coli															P. aeruginosa									C. albicans									A. fumigatus
					75				15																	14															16									13									15
					76				16																	14															15									16									18
					Ampicillin Gentamycin Amphotericin				23																	19															16									25									23
11.	79		Reflux, 4 h		Zone of inhibition, mm																																																								[53]
																												S. aureus																						P. aeruginosa
					78																							8																						6
					79																							14																						11
					Ampicillin Choloramphenicol																							14																						8
12.	82		Stir (overnight)		Minimum Inhibitory Concentration (MIC)/µg/mL																																																								[2]
							E. coli																	S. aureus																						C. albicans										A. niger
					82		10																	10																						10										10
					Gentamicin Fluconazole		10																	10																						20										20
13.	83		Reflux and stirring, 3 h		Zone of inhibition, mm																																																								[54]
							E. coli							P. aeruginosa																		S. aureus																	C. albicans								F. solani
					Ligand		R							R																		12																	**R								**R
					83		14							8																		12																	7								12
14.	87		Stirring, 6 h		Minimum Inhibitory Concentration (MIC)/µg/mL																																																								[3]
							E. coli													C. albicans																				P. vulgaris										K. pneumonia									S. aureus
					86		12.5													4																				>50										1									>50
					87		˃50													8																				>50										>50									>50
					Doxymycin Fluconazole		2													2																				2										4									4
15.	88 89		Stir, 30 min Reflux, 6 h		Zone of inhibition, mm																																																								[55]
																S. aureus																								P. phaseolicol														F. oxysporium
					Ligand											22 ± 0.2																								13 ± 0.1														17 ± 0.2
					88											37 ± 0.4																								26 ± 0.1														31 ± 0.2
					89											32 ± 0.2																								23 ± 0.1														30 ± 0.2
					Cephalothin Chloramphenicol Cycloheximide											42																								36														40
16.	96 97		Reflux and stirring, 4-5 h		Zone of inhibition, mm																																																								[57]
							S. epidermidis																	E. faecalis																		S. aureus								P. mirabilis									C. albicans
					94		5																	9																		7								**R									**R
					95		6																	8																		9								**R									**R
					96		14																	15																		12								8									**R
					97		12																	8																		7								22									**R
					Amoxicillin		28																	26																		27								44
17.	100 101		Reflux and stirring 50 min		Zone of inhibition, mm																																																								[59]
							E. coli												P. aeruginosa																	C. albicans														S. aureus									C. glabrata
					98		11												15																	15														19									11
					99		12												12																	12														18									12
					100		22												19																	20														16									<10
					101		20												16																	13														20									12
					Tetracycline Nystatin		25												20																	19														23									16
18.	105		Reflux, 15 h		Zone of inhibition, mm																																																								[60]
							E. coli			S. epidermidis																						A. niger																	A. flavus								C. lunata
					104		**R			6																						11																	9								10
					105		15			15																						16																	14								15
19.	34		Reflux, 8-9 h		Zone of inhibition, mm																																																								[30]
							Bacillus																		Staphylococcus																	E. coli								S. rolfsii							M. phaseolina
					33		1																		1																	1								2							8
					34		4																		3																	4								6							14
					Streptomycin Mancozeb		9																		11																	5								18							24
20.	109		Reflux, 4-5 h		Zone of inhibition, mm																																																								[61]
												S. aureus																	E. coli																A. niger					C. albicans									F. moniliforme
					109							3.02																	**R																15.80					7.44									**R
					Chloramphenicol Amphotericin							15.11																	25.44																15.78					23.23									12.58
21.	110		Reflux, 15-16 h		Zone of inhibition, mm																																																								[62]
							S. pyrogenes																							E. coli																				S. typhi
					110		25																							16																				19
22.	113		Reflux, 6 h		Zone of inhibition, mm(concentration,mg/ml)																																																								[64]
							B. subtilis													B. megaterium																			P. aeroginosa											K. pneumonia									E. aerogenes
					111		40±0.47(0.2)													34±0.81(0.2)																			42±1.24(1)											36±0.47(0.2)									45 ± 0.00
					112		30 ± 0.81(0.2)													22±0.81(0.5)																			33±0.81(0.2)											**R									28 ± 0.00
					113		21 ± 0.00(0.2)													**R																			36±1.24(1)											**R									**R
					Erythromycin		20 ± 0.00													25±0.47																			19±0.47											19±0.00									27 ± 1.24
23.	120 121 122		Reflux, 8 h		Zone of inhibition, mm																																																								[66]
							S. aureus										P. aureginosa																E. coli													S. typhii						Aspergillus sp.							P. sp.
					119		36										08																10													10						48							29
					120		30										36																41													42						68							61
					121		24										25																22													28						51							54
					122		62										65																33													35						80							66
					Imipenem Miconazole		100										100																100													100						57							65
24.	123		Reflux, 3 h		Zone of inhibition, mm																																																								[35]
							X. campestris														B. megaterium																			C. michiganensis										M. fructicola									P. digitatum
					Ligand		30														28																			32										36.0 ± 3.1									28.0±3.5
					123		26														19																			20										62.5 ± 6.2									62.5 ± 8.2
					Tetracycline Azoxystrobin		34														28																			30										45.3 ± 2.1									58.1 ± 1.2
25.	124		Reflux, 3 h		Zone of inhibition, mm (concentraton, µg/ml)																																																								[69]
																							E. coli								B. cereus												P. fluorescens								B. cinerea							A. flavus
						Ligand																	20								12												11								0.0 ± 0.0							0.00 ±0.0
						124																	12								12												18								6.7 ± 2.3							6.7±2.6
						Tetracycline Cycloheximide																	14								10												8								42.2±2.6							9.7±3.0
26.	30			Stir and reflux, 4 h		Zone of inhibition, mm																																																						[29]
																							S. aureus															B. subtilis										E. coli							C. albicans
						Ligand																	19															25										24							25
						30																	17															16										19							15
						Gentamycin Ketoconazole																	24															26										30							20
27.	125			Stirring, Reflux, 1 h		Zone of inhibition, mm																																																						[72]
																											S. aureus																					E. coli
						Ligand																					0.00																					9
						125																					10																					10
						Amikacin																					10																					6
28.	38 39 40			Stirring, 2 h Reflux, 12 – 15 h		Zone of inhibition, mm																																																						[31]
																															S. typhimurium																						C. albicans
						Ligand																									**R																						8
						38																									**R																						14
						39																									15																						22
						40																									**R																						R
						Cephalothin																									36
						Cycloheximide																																															35
29.	129			Stirring and reflux 1 h																			Zone of inhibition, mm/mg																																					[75]
																							E. coli								S. aureus																	C. albicans							A. flavus
						128																	14								12																	10							0
						129																	13								11																	12							14
						Amikacin																	6								10																	-							-
						Ketoconazole																	-								-																	9							8
30.

^†Values written as these have been reported in the literature. **R = 0 = Resistant.

2.3. Imine-iron complexes as antioxidants

Oxidative metabolism is one of the crucial factors for cell survival. Free radicals and other reactive oxygen species (ROS) are produced because of this reliance, which leads to oxidative alterations. When too many free radicals are produced, the ROS concentration becomes above average, which can overwhelm protective enzymes and have detrimental and fatal effects on cells by oxidizing membrane lipids, cellular proteins, DNA, and enzymes, which stops cellular respiration [18]. The way to counter the reaction of these free radicals is to introduce an antioxidant that can be experimentally carried out using essays such as DPPH. [77].

Turan et al. synthesized an imine ligand and its octahedral imine-iron (II) complex 126 (Figure 1) and evaluated their in vitro antioxidant activity using the 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) radical scavenging, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) cation radical scavenging, and the ferric reducing ability of plasma (FRAP). In the ABTS assay, a compound's antioxidant ability is measured based on the reduction of ABTS•+ cation radicals [78]. Complex 126 (0.6) demonstrated weak ABTS•+ radical scavenging activity, while the parent ligand exhibited no discernible ABTS•+ radical scavenging activity. The molecule's structure and single electron transfer potential influence the results. The complex showed a more enhanced DPPH radical scavenging ability (1.25) than the ligand (1.35) itself, but this activity was moderate when compared with the standard drugs (0.10 – 0.31). The FRAP method measures a compound’s ability to cause the reduction of ferric ions (Fe³⁺) to ferrous ions (Fe²⁺). The ligand (0.5) showed an antioxidant ability similar to 126 (0.4) in this assay (Table 3). The antioxidant potency of a series of compounds has been studied for their potential that they can be influenced by the aromatic ring and the number of hydroxyl groups present in a compound [79,80].

El-Lateef et al. explored imine-iron complexes 3 and 4 (Scheme 1) for their antioxidant activity using the DPPH method. The results revealed that the free ligand and its metal complexes have better antioxidant activity than the standard antioxidant agent Vitamin C(55 μg/ml). The complexes showed enhanced activity than the free ligands (1 = 45µg/ml, 2 = 32 µg/ml), with 3 possessing the highest DPPH free radical scavenging ability with an IC₅₀ value of 22μg/ml (Table 3). The results indicate that the complexes had greater antioxidant effects against the DPPH free radical than standard Vitamin C and can be considered antioxidant drug candidates. This study did not state the reason for the exception activities of the ligands and complexes [21].

Naureen et al. explored the antioxidant activity of 100 and 101 (Scheme 19) using the DPPH assay. The free imine ligands 98 and 99 demonstrated better antioxidant activity (1.23, 1.02 μg/ml, respectively) than their iron complexes, 100 (1.70 μg/ml) and 101 (1.41 μg/ml). The free ligand 99 showed better antioxidant activity (1.02 μg/ml) than the standard Vitamin C (1.14 μg/ml). Generally, both the free ligand and iron complexes exhibited good free radical scavenging abilities (Table 3). The mode of action of the ligands and their complexes were not outlined [59].

The tetradentate Schiff base 129 was synthesized along with its Fe complex 130 (Scheme 24) by Said et al. An in vitro antioxidant activity was determined using DPPH radical scavenging, ferric thiocyanate (FTC), hydroxyl radical scavenging activity (HRSA), and hydrogen peroxide scavenging activity methods. Complex 129 demonstrated better free radical scavenging ability than the synthesized complex 130 in the DPPH radical scavenging, FTC, and HRSA methods with IC₅₀ values of 53.55, 48.81, and 63.43, respectively, whereas that of 130 was 44.65, 9.47, and 30.29. The complex showed moderate activity compared to the standard Trolox and BHA in the DPPH radical scavenging, FTC, and HRSA methods (Table 3). It, however, demonstrated a better ability (93.74 μg/ml) to remove H₂O₂ from the reaction mixture than 129 (92.52 μg/ml) and standards Trolox (91.80 μg/ml) and BHA (92.97 μg/ml) when the hydrogen peroxide scavenging activity method was employed (Table 3). Due to the presence of the hydroxyl group on the ligand, its antioxidant activity was expected to be higher than that observed in this study, and this may be due to the steric hindrance or the presence of bulky donating groups (or both), making it challenging for the ligand to supply the hydrogen atom (H) to the DPPHꞏ radical [81].

Hayder et al. synthesized a new imine ligand 135 and its octahedral imine-iron complex 136 (Scheme 25). The antioxidant activity of 135 and 136 was evaluated using the DPPH radical scavenging activity method. The iron complex showed an enhanced ability to scavenge DPPHꞏ radical (49% scavenging) than the free ligand (24% scavenging). Compared to the standard ascorbic acid (82% scavenging), the complex showed a moderate ability to scavenge the free radicals in the reaction mixture (Table 3) [16].

Elshafie et al. evaluated complex 124 (Figure 1) for its in vitro antioxidant activity. The free imine ligand and complex 124 both showed high antioxidant activity (164.6%), with the iron complex being slightly higher than the ligand (169.7%). Complex 124 can donate hydrogen to scavenge the free radical, hence reducing the oxidation process (Table 3) [69].

Borase et al. conducted an antioxidant assay on the metal complex 109 (Scheme 21) to determine its free radical scavenging ability, and it proved to have moderate antioxidant activity (1615.22 μg/ml). (Table 3). Results of the antioxidant activity of ligands were not given, and subsequent comparisons could not be made [61].

Savcı et al. investigated 111, imine ligand (112), and its imine-iron complex 113 (Scheme 22) for their antioxidant activity using the DPPH radical scavenging, total antioxidant activity, FRAP, and CUPRAC activity. The results obtained revealed that the iron complex 113 (0.7) had a high ability to remove DPPH from the reaction mixture when compared to 111 (1.9), 112 (0.8), and standard BHT (1.1). For the total antioxidant activity assay, both 112 (0.62)) and 113 (0.61) showed a similar potential as the standard BHA (0.60) in eliminating lipid peroxide from the reaction mixture and an enhanced potential than standard BHT (0.40). In the FRAP assay, 111 (0.06) showed the lowest reduction capacity in reducing the Fe³⁺ ions, followed by standard BHT (0.08), complex (0.11), BHA (0.2), and the ligand 112 (0.38) showed the highest activity. Finally, the CUPRAC method confirmed the results of the other assays, with 111 indicating the lowest antioxidant activity (Table 3). Most of the inhibitor's antioxidant effect comes from its ability to donate one electron or hydrogen to the radical centers formed in biological systems, thus neutralizing them. The inhibitor's structure and characteristics are critical factors in demonstrating activity [49]. Potential sites for biochemically active substances connected to the balance of molecular proton transfer and hydrogen bonds can be found in the Schiff bases. The biological activity of the Schiff base [82] is typically increased by complexes formed with transition metals. Hence, the good antioxidant activity of both ligand and complex was achieved in this study [83].

Table 3. Products, synthesis conditions, and antioxidant activity of selected imine-iron complexes using DPPH, H₂O₂SA (hydrogen peroxide scavenging activity assay), %RSA (radical scavenging activity), and total antioxidant assay (TAC) ^†.

Table 3. Products, synthesis conditions, and antioxidant activity of selected imine-iron complexes using DPPH, H₂O₂SA (hydrogen peroxide scavenging activity assay), %RSA (radical scavenging activity), and total antioxidant assay (TAC) ^†.

Entry No.	Complex No.	Structures	Reaction Condition	Antioxidant activity (IC50/µg/mL)						Ref.
1.	3 4		Reflux (2 h)	DPPH						[21]
				1	45
				3	22
				2	53
				4	32
				Vit C	55
					DPPH					[59]
2.	100 101		Reflux and stirring (50 min)	98	1.23
				100	1.70
				99	1.02
				101	1.41
				Vit C	1.14
3.	126		Reflux (10 min). Stirring (24 h)		ABTS (734 nm)	DPPH (517 nm)		FRAP (700 nm)		[80]
				Ligand	1.90	1.35		0.50
				126	0.60	1.25		0.40
				Ascorbic acid	0.00	0.10		2.10
				BHA	0.00	0.18		2.90
				BHT	0.00	0.31		2.30
4.	130		Reflux and stir (overnight)		DPPH	H2O2 SA	FTC		HRSA	[81]
				129	53.55 ± 2.95	92.52± 0.07	48.81±5.04		63.43±5.66
				130	44.65 ± 1.10	93.74 ± 0.43	9.47±2.191		30.29±0.81
				Trolox	85.42 ± 0.04	91.80 ± 1.77	90.45±6.70		57.72±1.62
				BHA	75.69 ± 0.11	92.97 ± 0.98	50.57±5.42		10.00±3.64
5.	136		Reflux (3 h)	135 136 Ascorbic acid	DPPH (% scavenging) 24 49 82					[16]
6.	124		Reflux (3 h)	Ligand 124	%RSA					[69]
					169.7 164.6
7.	109		Reflux (4-5 h)	109	DPPH					[61]
					1615.22
8.	113		Reflux (6 h)	111 112 113 BHT BHA	DPPH 1.9 0.8 0.70 0.60 1.20	Total Anti Oxidant 0.64 0.62 0.61 0.60 0.44	FRAP 0.06 0.38 0.11 0.08 0.20		CUPRAC 0.30 3.50 1.20 3.20 3.10	[64]

^†Values are written as reported in the literature.

DPPH: 2,2-diphenylpicrylhydrazyl, FTC: Ferric thiocyanate, FRAP: Ferric Reducing Antioxidant Power, CUPRAC: CUPric Reducing Antioxidant Capacity, BHA: beta hydroxy acid, BHT: butylated hydroxytoluene, HRSA: Hydroxyl radical scavenging activity.

2.4. Other pharmacological activities of the imine-iron complexes

Apart from the above, Kumar et al. screened imine-iron complexes 120, 121, and 122 (Scheme 23) for their in vivo anti-inflammatory activity using albino rats. All the complexes showed anti-inflammatory activity higher than the standard drug phenyl butazone (18.20), with 122 (31.1) exhibiting the highest activity at the same concentration of 25 mg/kg. 121, showed the least anti-inflammatory activity (27.20). Compared to the complexes, the ligand (9.00) showed very low anti-inflammatory activity (Table 4). Complex 122 can be explored further as an anti-inflammatory drug candidate. The increased anti-inflammatory activity of the complex in relation to the ligand can be explained by the chelation theory, which describes the increase in polarity and lipophilicity nature of the complex due to chelation and how that causes it to efficiently cross the lipid layer, affecting the desired anti-inflammatory action [66].

Imine-iron complexes have shown a few other medicinal activities. Ahmed et al. screened complex 125 (Figure 1) on coronavirus (SARS-CoV-2) using molecular docking. The molecular docking studies investigate the interaction that exists between the complex and the crystal structure of the virus (SARS-CoV-2) main protease with an unliganded active site (2019-nCoV, coronavirus disease 2019, or COVID-19) (PDB ID: 6Y84) proteins. The imine-iron complex 125, (Figure 1) had low energy, (-8.5kcal/mol), which means it has a strong binding affinity and can inhibit the biochemical processes of the proteins inhibiting its viral capability (Table 4) [72].

Elkanzi et al. synthesized imine-iron complex 139 (Scheme 26) and screened for its in vitro anti-inflammatory activity using the anti-denaturation method of egg albumin. Heat applied to the egg denatures the egg albumin, and the denatured protein produces certain antigens. These antigens are linked to type-III hypersensitivity reactions, which cause several diseases. The anti-inflammatory assay analyses test an agent’s ability to limit the denaturation process. The result obtained from this study showed that 139 exhibited a moderate percentage of inhibition (0.70) as compared to the ligand (0.13) and standard anti-inflammatory drug ibuprofen (2.9) at a concentration of 100 µg/ml (Table 4). The inverse relationship between the dipole moment of the complex and its activity explains the reduced activity of the complex. The dipole moment of the complex (10.11) is higher than the ligand (5.91), and this increases the polarity and decreases the lipophilic nature of the complex, lowering its efficiency to passing through the lipid layer hence making it less efficient as an anti-inflammatory agent [82,83].

Table 4. Products, synthesis conditions, and biological activities of selected imine-iron complexes^†.

Table 4. Products, synthesis conditions, and biological activities of selected imine-iron complexes^†.

Entry No.	Complex No.	Structures	Reaction conditions	Biological activities		Ref
1.	120 121 122		Reflux, 8 h		Anti-inflammatory activity	[66]
				119	9.00
				120	28.50
				121	27.20
				122	31.10
				Phenyl butazone	18.20
2.	125		Stirring, Reflux, 1 h		Binding energy (kcal/mol)	[72]
				Ligand	−2.1
				125	-8.5
3.	139		Reflux, 12 h	138	%Inhibition of heat-induced denaturation of proteins 0.13	[83]
				139	0.70
				Ibuprofen	2.9

^†Values are written as reported in the literature

3. Conclusions

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