Biological Potentials of Some Schiff Bases and Their Chelates: A Short Review

Abstract

In the twenty-first century, the most significant task for scientists has been the development of novel and effective therapeutic agents. Many natural chemicals have been discovered and identified as having biological functions in the body that are beneficial to maintaining a healthy lifestyle. In addition, various classes of compounds are synthesized and assessed for their potential use in biological systems. Schiff bases have the capacity to react and form complexes with metals and proteins due to their superior basic characteristics; hence, the synthesis and pharmacological application of Schiff bases has recently become one of the most popular chemical and pharmaceutical science study subjects. As a result, this review discusses some of the novel Schiff bases and chelated complexes, as well as some proven pharmacological applications.

1. Introduction

Schiff bases are known with the structural formula R₂C=NR₁. They are prepared by the condensation of $1^o$ NH₂ and C=O [1]. Hugo Schiff, a German Chemist who earned a Nobel Prize in 1864 [2], developed this group of chemicals. Schiff bases are carbonyl compounds where C=O is substituted with an azomethine or imine functionality in a reaction to generate a carbon to nitrogen double bond [3]. Figure 1 shows Schiff’s base structure.

Figure 1.

Schiff’s base structure.

Unsaturated -C=N- compounds that are easily coordinated to various metal ions are known as Schiff bases [4, 5, 6]. They have a flexible mode due to coordination (no set pattern) and a larger number of applications [7, 8, 9, 10]. Due to the ease of their synthesis by condensing carbonyl compounds with amines, Schiff bases are frequently referred to as favored ligands [11]. They can also coordinate to a variety of metal ions with varying oxidation states. R₂C=NR₁ compounds are considered as a vital class of organic compounds in the current development surge of medicinal compounds due to their vast applications in numerous disciplines [12]. This is because the azomethine groups attached to the nitrogen atom form a strong hydrogen bond [13] with different labile moieties and functional groups of various constituents of cell, interfering with or distorting vital cell metabolism and resulting in various desired effects [14]. The design of R₂C=NR₁ compounds was critical to the advancement of coordination (complex compound) chemistry, as well as inorganic biochemistry and many optical materials [15]. Metal complexes derived from chelating agents and R₂C=NR₁ compounds have been synthesized by a number of scientists [16, 17, 18, 19, 20, 21, 22, 23, 24, 25].

1.1 Antimicrobials

Due to a number of factors, such as continuous emergence of contagious ailments and the explosion of various microbial infections that are multidrug resistant in nature, the search for an effective treatment material for various forms of contagious diseases has been and continues to be one among the most important challenges of the century. Despite the existence of a significant number of natural, synthetic antibiotics and chemotherapeutic substances for battling these diverse diseases, there has been an explosion of both old and new microorganisms that have become highly resistant to antibiotics developed in recent decades. This illustrates the critical need for classes of novel antimicrobial agents to be discovered and developed through diverse research and advancements [26].

The Knoevenagel condensate of keto esters (phenyl 2-(2-hydroxybenzylidene)-3-iminobutanoate) was used to prepare a Schiff base by reacting 2-[3-(3-hydroxynaphthalen-2-yl)-phenyl-3-imino-2-methylidenebutanoate]benzoic acid, and o-aminobenzoic acid in a molar ratio of 1:1. The Schiff base (Compound 1, Figure 2) was discovered to be biocidal against Botrytis cinerea, Escherichia coli, Aspergillus niger, and Staphylococcus epidermidis, implying that it has greater therapeutic (antimicrobial) efficacy than the relevant standards (ciprofloxacin and Co-trimoxazole) [3]. From benzaldehyde and sulfathiazole, a novel schiff base, 4-[(E)-(benzylideneamino)]-N-thiazol-2-yl-benzenesulfonamide, and its nickel chelate (Compounds 2 and 3 in Figure 2) were synthesized [27]. On a gram-negative strain of Pseudomonas aeruginosa and E. coli, and gram-positive strains of Salmonella typhi and Staphylococcus aureus, the new compounds’ antibacterial activity was assessed in vitro. Both strains of bacteria demonstrated considerable antibacterial activity against the Schiff base. Overall, the metal complex demonstrated increased activity against bacterial strain, as it was discovered to be active against all bacterial strains tested [27]. Cu, Ni, Cd, Co, and Zn divalent chelates of the novel R₂C=NR₁ compound, 3-((4-phenylthiazol-2-ylimino) methyl)-2-hydroxybenzoic acid (Compounds 4 and 5 in Figure 2), have been reported [11]. The potential antibacterial activities of these new compounds were investigated. When compared to the new Schiff base ligand, the results revealed that the chelates were more antimicrobially active. The new compounds’ activities involving DNA cleavage were also evaluated, and the plasmid DNA pBR 322 was strongly cleaved. The compounds’ cytotoxicity was also assessed. The divalent Cu and Ni chelates were not cytotoxic, according to the results of the cytotoxicity tests [11].

Figure 2.

Compounds showing antimicrobial activity.

The condensation of equivalent molar ratio of 1-(4-methylaniline)acetaldehyde oxime and 4-(diethylamino)-2-hydroxybenzaldehyde yielded a novel bidentate R₂C=NR₁ compound (E)-1-(4-((E)-(4-(N,N-diethylpropan-2-amine)-2-hydroxybenzylidene)amino)phenyl)ethanone oxime [28] (Compound 6, Figure 2). Using a 1:2 molar ratio of metal to ligand, a collection of chelates of the synthesized Schiff base with divalent Co, Ni, and Cu complexes (Compound 7, Figure 2) were also synthesized. The antimicrobial (in vitro) properties of the new R₂C=NR₁ compound and its chelates were investigated using the disk diffusion method, with dimethyl sulfoxide (DMSO) serving as a negative control. The study showed that the ligand, as well as its metal complexes, had equivalent inhibitory action against Klebsiella spp., P. aeruginosa, and S. epidermidis strains. The findings also revealed a significant inhibitory effect on harmful bacterial growth. The new compounds’ inhibitory effects on the microbial fungus Candida were found to be greater at 10⁻⁴ M than at 10⁻³ M [28]. The divalent Mn, Co, Ni, Cu, and Zn complexes of the ligand (Compounds 8 and 9, Figure 2) were synthesized by the condensation of 5-chloro-2-hydroxybenzaldehyde with para-fluoro amino benzene at ambient temperature. The diffusion method using disks was applied to test the antibacterial potential of the novel R₂C=NR₁ compound and its coordination compounds against bacteria that are Gram-negative such as P. aeruginosa and E. coli as well as bacteria that are Gram-positive such as S. typhi and B. subtilis. The antibacterial assessment reports suggested that the chelates were more effective against bacteria than the uncoordinated Schiff base [29].

The condensation of tricyclo[3.3.1.13,7]decan-1-amine with three aromatic alkanals (2-hydroxybenzaldehyde, 3-ethoxy-4-hydroxybenzaldehyde, and 4-(diethylpropan-2-amine)2-hydroxybenzaldehyde) yielded a collection of novel R₂C=NR₁ compounds [30]. The divalent cadmium chelates of these R₂C=NR₁ compounds were also prepared [30]. The reaction of 4-methylaniline with 3-ethoxysalicyaldehyde yielded four Schiff bases [30] (Compound 10, Figure 2). The four Schiff base ligands that were synthesized had active antibacterial action against the tested bacterial strains, with S. aureus having the maximum activity. When compared to amikacin, the metal complexes had better antimicrobial action against P. aeruginosa, Shigella flexneri, E. coli, S. typhi, B. subtilis, and S. aureus [30]. Divalent Ni, Cu, and Co chelates of a novel R₂C=NR₁ complexing agent (Compounds 11–13, Figure 2) prepared from isatin and 1,2-cyclohexanediamine were tested for antibacterial potential against three different microbiological species such as P. aeruginosa, E. coli, and S. aureus [31]. The octahedral divalent Cu and Co chelates were shown to have significantly higher activity against microbial stains than the square planar Ni(II) complex and ligand [31].

1.2 Antidepressant

Depression is a common psychiatric condition that affects about 21% of the world’s population [32]. The physiological causes of depression are yet to be fully proven, despite repeated attempts to do so. However, some evidence suggested that depressive disorders could be caused by a lack of serotonin and noradrenaline. The majority of synthetic chemotherapeutic agents used to treat disorders like depression work by influencing the brain’s biogenic amine system, resulting in the activation of a process capable of boosting biogenic amine concentration in the brain [33]. Oxidases of monoamine are an enzyme family that catalyzes the oxidation or inactivation of biogenic amines in the central nervous system (CNS) [34]. In addition to the wide range of antidepressant formulations and chemicals presently in the market, there are considerable proportions of patients who do not react to treatment or only have a partial response to drugs, necessitating the development of new antidepressants [34].

By using a standard approach, a novel Schiff base of indole-carrying azetidinone derivatives was synthesized with high purity and higher yields [35]. The compounds’ derivatives (Compounds 14, Figure 3) showed antidepressant activity that was comparable to that of fluoxetine, a well-known antidepressant. The ortho-position of the phenyl ring system was replaced with nitrogen and chlorine, resulting in active compounds with immobility times of 66.82 and 65.61%, respectively. The results of the evaluation of molecular docking studies were in agreement with the pharmacological studies with a docking score of −2.8474 kcal/mol [35].

Figure 3.

Compounds showing antidepressant properties.

1.3 Antitubercular

Mycobacterium tuberculosis is a bacterium that causes tuberculosis infection [36]. The prevalence or dominance of tuberculosis, which has been on the rise in recent years as tuberculosis is resistant to a variety of drugs [37, 38], has created the need for a broad search for more potent therapeutic agents with lesser negative effects that could help control its spread. Tuberculosis resisting therapy and management have proven to be a difficult task in recent years, as second-line drugs have generally become ineffective against them [39]. M. tuberculosis is a bacterium that is distinguished by its thick and waxy cell wall.

The condensation cyclorization of 2-amino-5-phenyl-5H-thiazolo[4,3-b]-l,3,4-thiadiazole with various aromatic alkanals resulted in a collection of R₂C=NR₁ complexing agents [40]. The antitubercular activity (in vitro) of these R₂C=NR₁ complexing agents (Compound 15, Figure 4) was assessed using the method of Microplate Alamar Blue Assay. Streptomycin and pyrazine-2-carboxamide antitubercular drugs at varied concentrations ranging from 0.1 to 100.0 g/mL were used as standards. Two of the newly synthesized compounds (labeled 4f and 4i) had a larger molecular weight than the others. When compared to pyrazinamide and streptomycin (standards), two of the novel synthesized Schiff bases showed a comparatively higher antitubercular activity, while four other Schiff bases exhibited action that was exactly similar to that of pyrazine-2-carboxamide, but showed lower effectiveness compared to streptomycin [40]. When compared to traditional medications, molecular docking result implied that the new Schiff bases had a decent docking score. The antitubercular activity of 4-amino-5-(4-fluoro-1,1′-oxydibenzene)-4H-1,2,4-triazole-3-thiol and its synthesized R₂C=NR₁ complexing agents were tested against H37Rv and multidrug-resistant Mycobacterium tuberculosis (MDR MTB) strains at concentrations ranging from 0.2 to 32 g/mL (Compounds 16–19, Figure 4). The antitubercular activity obtained revealed that the parent compound had the most promising antitu-bercular activity, with inhibition concentrations of 50 µg/ml at a concentration of 5.5 and 11.0 g/mL. The remaining compounds (Compounds 17, 18, and 19) were exclusively active against H37Rv, indicating that they did not have good antitubercular efficacy against MDR strains up to 32 g/mL concentrations. Compounds 17 and 19 had similar antitubercular effects against MTB strains H37Rv at doses of 2 g/mL [40].

Figure 4.

Compounds with antitubercular activities.

By reacting ethyl-2-amino-4,5,6,7-tetrahydrobenzo-1-carboxylato-1H-1λ⁴-thien-1-yl and salicylaldehyde derivatives, Bootwala and coworkers [41] developed two active Schiff bases. Streptomycin, pyrazinamide, and ciprofloxacin were used as standards to test these drugs for antitubercular efficacy against Mycobacterium tuberculosis [41]. According to the findings, the new Schiff base compounds were the most active antitubercular compounds against Mycobacterium TB, whereas the metal complexes show only minor action against the bacteria, with minimum inhibitory doses ranging from 12.5 to 50.0 g/ml.

1.4 Anthelmintic

The anthelmintic activity of some substituted 1,3,4-thiadiazole Schiff bases synthesized from benzimidazole (Compound 22, Figure 5) was investigated [42]. The new compounds had a mean paralyzing time (min) of 9.10–18.23 and 13.11–22.31 min against Perionyx excavatus and Pheretima posthuma, respectively, indicating good action when compared to albendazole, which had a mean paralyzing time of 9.70 and 12.20 min. The evaluated drugs’ mean death times (min) against P. excavatus and P. posthuma varied from 13.22–28.36 to 19.00–28.32 min, which is equivalent to albendazole’s 14.80 and 20.70 min mean death time. The compound with the 4NO₂ substitution was discovered to be more effective than albendazole in killing nematodes, taking an average of 13.22 and 19.00 minutes to kill P. excavatus and P. posthuma, respectively. The anthelmintic potential of the derivatives containing bromine (Br) and OCH₃ is likewise extremely similar to that of albendazole. The results showed that derivatives having electron-drawing moieties at the ring’s o-position had a significant increase in activity, as did derivatives with hydroxyl substituents in the ring’s p-position and CH₃O substituents in the ring’s o-position. As a result of the aforesaid findings, it was deduced that the electron-withdrawing group performed a crucial role in the anthelmintic potential of the compounds [42]. Using conventional methods, a series of five fluoro- and nitro- (F- and NO₂-)substituted ethenylbenzene-2 amino-1,3-benzothiazole and its derivatives (Compound 23, Figure 5) were prepared from F⁻ and NO₂-substituted 2-aminobenzothiazole with some aromatic alkanals [43]. Compound 23 was tested for antibacterial and anthelmintic properties in vitro using albendazole as a control. Compound 23 (a and f) had a paralysis time of 12 and 10 minutes, and a death time of 14 and 13 minutes, respectively, compared to 22 and 24 minutes for ordinary albendazole [43].

Figure 5.

Compounds that showed anthelmintic activity.

1.5 Antioxidant and antitumor

The azomethine compound, 2-(2-oxoacenaphthylen-1(2H)-ylidene)-N-(prop-2-en-1-yl)hydrazinecarbothioamide, and its divalent Zn, Co, and Ni (Compounds 24–26, Figure 6) derivatives were prepared and evaluated for antioxidant and antitumor properties [44]. The results implied that the complexing agent and divalent Zn chelate have higher antioxidant potential than other chelates, with values of 88.5 and 88.6%, respectively, when compared to a standard ascorbic acid. The compound’s antitumor potential against the cell line of hepatocellular carcinoma (HepG2) revealed that both the Zn(II) complex and Schiff base ligand showed considerable activity, with 6.39 ± 0.18 and 6.45 ± 0.25 μM IC₅₀ (half-maximal inhibitory concentration) values, respectively [44].

Figure 6.

Compounds having antioxidant and antitumor properties.

1.6 Anticonvulsant

Epilepsy is a neurological condition characterized by abnormal electrical impulses in the CNS. It causes seizures that occur spontaneously and repeatedly, with loss or gain of consciousness [45]. Six Schiff bases (Compound 27, Figure 7) were synthesized from 1H-indole-2,3-dione and tricyclo[3.3.1.13,7]decane-1-carbohydrazide and were investigated for efficacy of anticonvulsants in a 6,7,8,9-tetrahydro-5H-tetrazolo[1,5-a]azepine-induced seizure paradigm using 5-benzyl-5-methylpyrimidine-2,4,6(1H,3H,5H)-trione as a positive reference standard [46]. Pentylenetetrazole (PTZ)-induced seizures were significantly reduced by these synthesized Schiff bases. The delay of recurrent convulsions was increased in all synthesized compounds, and the length of time that epilepsy lasted was reduced, as well as neurological symptoms and seizure intensity [46].

Figure 7.

Compounds having anticonvulsant properties of the SARS CoV 2 (severe acute respiratory syndrome coronavirus 2) inhibitor.

The SARS-CoV-2 virus, which produced the unique coronavirus epidemic known as Coronavirus 2019 (COVID-19), quickly expanded throughout the world, with Wuhan, China, serving as its epicenter by the end of 2019 [47, 48, 49, 50]. The virus, called coronavirus, has a diameter of 60–140 nm and resembles spike glycoproteins in the form of a crown when viewed under an electron microscope [50, 51, 52, 53]. On March 11, 2020, the World Health Organization (WHO) declared the COVID-19 epidemic to be a pandemic due to its high rate of infection, intensity, and rate of spread [54]. Currently, COVID-19 is a problem in over 225 countries, and the number of infections is still growing quickly. This coronavirus epidemic has not only put people’s health at danger but has also had a significant negative impact on the global economy [55, 56].

Vaccines, however, are being researched on children and have been found to be safe for adults [57]. Once more, virus mutations or alterations could render vaccinations useless [58]. Drugs to treat those infected with SARS-CoV-2 are still required, even though vaccination rates have decreased. Nevertheless, a number of local and international research organizations are still working to find a COVID-19 therapy medicine or vaccine that works while taking into account the risk factors related to viral infection. New chemotherapeutics have caught the interest of medicinal chemists in recent years. Isatin’s schiff base ligands have been shown to exhibit antiviral properties against the SARS, vaccinia, rhino, and Moloney leukemia viruses [59]. Considerable antiviral activity was demonstrated by Schiff bases made from 5-acyl-1,2,4-triazines containing oximes, hydrazones, semicarbazones, and thiosemicarbazones [60]. Some 1,6-hexanediamine tetra-dentate symmetrical bis-Schiff bases were predicted in silico to be potential coronavirus (SARS-CoV-2) inhibitors [61]. Some previously synthesized Schiff base ligands have been optimized using density functional theory, and their physicochemical characteristics have been studied [62, 63, 64]. In order to comprehend the interactions and binding affinities between ligands and receptor proteins, molecular docking has been used. To determine their biological position, including absorption, metabolism, and carcinogenicity, the ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) analysis was performed. It has been reported that some schiff bases have been evaluated in silico for their potency against the SARS-CoV-2 main protease (Mpro), PASS (prediction of activity spectra for substances), and ADMET studies (Compounds 28, Figure 8) [65].

Figure 8.

Proposed SARS CoV 2 inhibitors.

2. Conclusion

Schiff bases are a type of chelating agent that can be found in a variety of drugs. There has been a lot of research on Schiff bases. This study emphasized the importance of R₂C=NR₁ compounds in the advancement of novel compounds with medicinal applications. Regardless that study in this field is still in its infantile phase, there have recently been surges in reports demonstrating the impact of R₂C=NR₁ compounds on therapeutically important microorganisms. For decades, because of this bioactive core, researchers have been interested in obtaining several R₂C=NR₁ compounds and chelates of biological significance. The goal of this study was to look at all of the biological information available.