INTRODUCTION:

Aldehyde or ketone groups are combined with primary amines to generate Schiff bases, which have the general formula R1R2C=NR3 and can be alkyl, aryl, heteroaryl, or cycloalkyl for R1, R2, and R3. Schiff bases exhibit numerous biological activities. Schiff bases are employed in various fields besides biological activities, such as catalysts, intermediates, pigments and dyes, polymer stabilizers, and corrosion inhibitors¹.

Schiff bases are an essential class of ligands in coordination chemistry because they consistently form stable complexes with different transition metal ions. Isatin is an indole derivative, also known as 1H-indole-2,3-dione. Isatin can be produced using various methods, including the Gassman, Stolle, and Sandmeyer methods. These are compounds with an indole moiety developed by fusing a pyrrolidine ring to benzene to form 2,3-dihydroindole. Two carbonyl groups are present at positions 2 and 3, along with one nitrogen atom at position 1. These groups allow for the application of isatin as a building block in the making of therapeutic drugs. When various aromatic primary amines and the carbonyl group of isatin react, isatin Schiff bases are produced, and these compounds exhibit many biological activities. The antioxidant activity of the Schiff base derived from isatin has a significant application^2-4. Thus, the antioxidant activity of isatin's Schiff base derivative and its metal complexes from 2015 to 2023 was summarized in this review.

ANTIOXIDANT ACTIVITY:

Free radicals cause many diseases in the body, and antioxidants have become an essential class of medication. Drug discovery is now more crucial than ever to produce compounds with antioxidant activity. A few techniques, including DPPH, ABTS, CUPRAC, and ferric reducing ability of plasma (FRAP), can be used to assess the antioxidant activity of various substances^5-7. Ascorbic acid, Trolox, Quercetin, and Butylated hydroxytoluene (BHT) are a few examples of the standard antioxidants used to compare synthetic compounds' antioxidant activity.

Isatin acyl hydrazones with sterically hindered phenol fragments were tested for their antioxidant activity. In a model reaction with a free chromogen radical, 2,2-diphenyl-1-picrylhydrazyl(DPPH), N'-[1-(3,5-Di-tert-butyl-4-hydroxybenzyl)-2-oxo-1,2-dihydro-indol-(3E)-ylidene]-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-propionohydrazide(Figure 1) had high antioxidant activity when compared to antioxidant drug Irganox 1010⁸.

Figure 1. Structure of Isatinacylhydrazone

Novel bioactive Schiff base ligands, L1[(N, N'E, N'N'Z)-N, N'-(5-chloroindoline-2,3-diylidene) bis (5-nitrobenzol [d]thiazol-2-amine)], and L2[(N, N'E, N, N'Z) N, N'-(5-chloroindoline-2,3-diylidene)bis(5-nitrothiazol-2-amine)], derived from 2-amino-5-nitro benzothiazole and 2-amino-5-nitro thiazole with 5-chloro isatin and their metal complexes [Cu(L1)₂]Cl₂, [Zn(L1)₂(H₂O)₂]Cl₂, [Cu(L2)₂]Cl₃, and [Zn(L2)₂(H₂O)₂]Cl₄were synthesized. Elemental analysis, spectroscopic data (FT-IR, 1H-NMR,13C-NMR, Mass, and EPR), and geometry of the proposed ligands and their complexes were used to clarify their composition, stoichiometry, and structure. Using the DPPH method with standard antioxidant L-ascorbic acid, the antioxidant efficacy of free ligands and their metal complexes were investigated. When compared to L-ascorbic acid, significant antioxidant activity is displayed by Cu and Zn complexes of L1(Figure 2)⁹.

Figure 2. Structure of Cu and Zn complex of L¹

It has been reported that a wide range of heterocyclic compounds can be synthesized by reacting 2-amino-5-chlorobenzo phenone with 5-substituted isatins to create Schiff bases. The Schiff bases of isatin were created by treating spiro thiazolidine-4-ones and 5'-methyl-spiro-4-thiazolidiones with thioglycolic acid and thiolactic acid, respectively, in the presence of 1,4-dioxane and anhydrous zinc chloride. These synthesized compound structures were clarified using spectral and elemental analysis. By using the DPPH method, the antioxidant activity of these compounds was evaluated 3-(2-benzoyl-4-chlorophenyl)imino]-5-bromo-1,3-dihydro-2H-indol-2-one(Figure 3) exhibits vigorous antioxidant activity in comparison to butylated hydroxytoluene (BHT) and standard ascorbic acid¹⁰.

Figure 3. Structure of 5-substituted isatin Schiff base

The synthesis of 12-membered Schiff base macrocyclic complexes [Dichloro [5,6; 11,12-dibenzophenone-1,4,7,10-tetraazacyclododeca-1,3,7,9-tetraene-2,3,8,9-diindole] metal(II) [M = Co(II), 1; Ni(II), 2; Cu(II), 3; and Zn(II), 4] by condensation of isatin and 3,4-diamino benzophenone were reported. These synthesized complexes were characterized by FT-IR, NMR, UV-Vis, EPR, TGA/DTA, and SEM. Cu (II) complex of dichloro [5, 6; 11,12-dibenzophenone1, 4, 7, 10-tetraazacyclododeca-1, 3, 7, 9-tetraene-2, 3, 8, 9 -diindole (Figure 4) exhibits significant antioxidant properties with radical scavenging potency^[11].

Figure 4. Structure of [Cu (II)LCl₂]

Five macrocyclic compounds were analyzed, and elemental analysis, FT-IR, 1D and 2D NMR, and electron spray ionization mass spectral analysis characterized them. By using DPPH, OH, and NO assays, 1a (Figure 5) exhibits the highest inhibitory effect on the radicals [IC50 = 23.59 μM (DPPH), 26.14 μM (OH), and 28.41 μM (NO)]¹².

Figure 5. Structure of macrocyclic compound of isatin

The synthesis of isatin-azomethine compounds via the reaction of isatin with various amines was reported. Various spectroscopic techniques characterize the synthesized compounds. The antioxidant capacity of isatin-azomethines was investigated by representative spectroscopic techniques, employing radical's DPPH (2,2-diphenyl-1-picrylhydrazyl), FRAP (Ferric Reducing Antioxidant Power) and Ferrous ions chelating activity assays compared to that of ascorbic acid. Isatin-azomethines displayed a superior scavenging activity paralleled that of ascorbic acid.2-(2-oxoindolin-3-ylamino)-5-phenyl-1,3,4-thiadiazole (1), 3-(4-(ethyl benzoate) imino) indolin-2one (2) and 2-(2-oxoindolin-3-ylamino)-5-mercapto-1,3,4thiadiazole (3) had higher antioxidant capacity (Figure 6)¹³.

Figure 6. Structure of isatin-azomethines

A novel set of 21 Schiff bases of spiro-isatin were synthesized and reported for their DPPH, CUPRAC, and ABTS cation radical scavenging abilities for antioxidant activity. The results showed that all the synthesized compounds exhibited antioxidant activity in each assay. 5̍-(2,3-Dihydroxy benzylidene amino) spiro [[1,3] dioxolane-2,3̍-indoline]-2-one (IC50 = 4.49 μM for DPPH; IC50 = 0.39 μM for ABTS. +; and A0.50 = 0.42 μM for CUPRAC) demonstrated significantly higher ABTS, CUPRAC, and DPPH radical scavenging ability than quercetin (IC₅₀= 8.69 μM for DPPH; IC₅₀ = 15.49 μM for ABTS; and IC50= 18.47 μM for CUPRAC). SAR study showed that the synthesized compounds had higher ABTS activity than DPPH and CUPRAC activities. Among these compounds, (E)-5̍-(2,3-Dihydroxy benzylidene amino) spiro [[1,3] dioxolane-2,3̍-indoline]-2-one and (E)-5̍-(2,5-Dihydroxy benzylidene amino) spiro [[1, 3] dioxolane-2,3̍-indoline]-2-one (Figure 7) exhibited the highest antioxidant activities. Quantum chemical calculations were also carried out to support the SAR results¹⁴.

Figure 7. Structure of Schiff bases of spiro-isatin

A series of compounds were synthesized from isatin, carbo hydrazides, and thio carbo hydrazides under reflux in absolute ethanol. FT-IR, 1H-NMR,13C-NMR, elemental analysis, and other techniques were used to examine the structures of the synthesized compounds. It also reported on quantum chemical calculations like density of states (DOSs) and HOMO-LUMO energy eigenvalues. QTAIM analysis was carried out to find out how intramolecular interactions, digital data, and antioxidant activity relate to one another; using a DPPH radical scavenging technique, each synthesized compound's in vitro antioxidant activity was evaluated. Between 246.86 and 1916.32μM were the IC50 values of the synthesized compounds.1,5-Bis(5-chloro-2-oxoindolin-3-ylidene) thio carbo hydrazone exhibits vigorous antioxidant activity (Figure 8)¹⁵.

Figure 8. Structure of bis-isatinthiocarbohydrazone

The synthesis of four mixed ligand complexes of the type [ML1L2X2] with M = Co(II), Ni(II), Cu(II), Zn(II), and X = Cl. Modern analytical methods like elemental analysis, IR, UV-visible, conductivity measurements, magnetic moment measurements, and thermogravimetric analysis have all been used to examine all the mixed ligand complexes. For all four mixed ligand complexes, octahedral geometry is assigned. The ligands' and mixed ligand complexes' cytotoxicity and antioxidant capacities are examined¹⁶.

Figure 9. Complex structure of HL

The synthesis of a new series of novel Schiff base ligands (HL) and their metal complexes of Cu (II), Zn (II), Ni (II), and Co (II) and their antimicrobial, antioxidant, and catalytic activities were reported. The structures of these complexes were characterized by UV-Vis, IR, proton NMR, and mass spectral studies, which exposed the octahedral nature of the complexes. All the synthesized complexes have good potential as antioxidants, especially Cu (II)[CuLY]Cl and [ZnLY]Cl complexes of HL (Figure 9), which possess enhanced antioxidant activity¹⁷.

Seven new Schiff bases of isatin and its derivatives were made using isatin, thio carbohydrazide, and substituted aldehydes in the presence of ethanol under reflux. The 1,1-diphenyl-2-picrylhydrazyl free radical scavenging method assessed the compounds' in vitro antioxidant properties. In the synthesis process, monosubstituted products made with aldehyde groups and disubstituted products bound with an isatin group were evaluated separately for their antioxidant effects. The results show that1-(4-(Dimethyl amino) benzylidene)-5-(6-chloro-2-oxoindolin-3-ylidene) thio carbono hydrazone] (Figure 10) exhibited the highest antioxidant activity¹⁸.

Figure 10. Structure of Schiff base-isatin derivative

The five new Schiff bases of isatin and its derivatives from mono thio carbo hydrazides and 5-chloro isatin were created. The 1,1-diphenyl-2-picrylhydrazyl free radical scavenging method assessed the synthetic compounds' in vitro antioxidant activities. Quantum chemical calculations and supporting experimental spectroscopic data were used to examine the compounds' antioxidant abilities.1-(4-hydroxy-3-methoxybenzylidene)-5-(5-chloro-2-oxoindolin-3-ylidene) thio carbo hydrazone is the synthesized compound with the highest antioxidant activity(Figure 11), and its IC₅₀ value is comparable to that of Trolox, the reference antioxidant¹⁹.

Figure 11. Structure of β-isatin aldehyde-N, N′-thio carbo hydrazones

New isatin based Schiff bases were synthesized using hydrazine, 5-substituted isatins, and aldehydes under reflux in ethanol. Using IR, 13C-NMR,1H-NMR, and elemental analysis helped clarify the structures of the synthesized compounds. Using the 1, 1-diphenyl-2-picryl hydrazyl, the in vitro antioxidant activity of all the synthesized compounds was evaluated. Compared to standard antioxidant Trolox, (3Z)-5-chloro-3-{2-[(3-hydroxy-4-methylphenyl) methylidene] hydrazin-1-ylidene}-2,3-dihydro-1H-indol-2-one] (Figure12) had the lowest antioxidant activity against DPPH radicals and the highest antioxidant activity than other synthesized compounds²⁰.

Figure 12. Structure of 5-Substituted Isatin-Hydrazones

Four Schiff bases were synthesized from 5-substituted isatins, thio carbo hydrazides, and carbo hydrazides under reflux in absolute ethanol. The structures of the synthesized compounds were characterized by FT-IR, 1H-NMR, and 13C-NMR spectroscopy, as well as elemental analysis. In-vitro antioxidant activity of all the compounds was evaluated by the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free-radical scavenging method.1-(5-methoxy-2-oxoindolin-3-ylidene) thio carbo hydrazone and 1–(5-methoxy-2-oxoindolin-3-ylidene) carbo hydrazone (Figure 13) exhibit higher antioxidant activity than other compounds²¹.

Figure 13. Structure of isatin thio carbo hydrazone and carbo hydrazone

The synthesis of eight isatin-based Schiff base derivatives, namely β-isatin aldehyde N, N′-thio carbo hydrazone, and carbohydrate derivatives, were reported. Spectroscopic techniques were used to determine the structures of the synthesized compounds. The DPPH method was used to measure the antioxidant activity of the synthesized compounds. FMO energies, NBO, QTAIM, NCI, Fukui, and DOS analyses examined the relationship between electronic properties and antioxidant activity. IC₅₀ values of the obtained products ranged from 10.99 ± 0.03 to 77.95 ± 0.15 μM. DFT calculations showed that compounds with smaller ∆E values showed higher antioxidant properties. 1-(4-hydroxy-benzylidene)-5-(2-oxoindolin-3-ylidene) thio carbohydrazone and 1-(3-ethoxy-4-hydroxy-benzylidene)-5-(2-oxoindolin-3-ylidene) carbo hydrazone (Figure 14) showed the highest inhibition rates among other compounds, although they were low compared to standard antioxidants²².

Figure 14. Structure of isatin-based Schiff bases

The condensation reactions of isatin hydrazone with aldehydic groups were planned to produce five isatin hydrazone Schiff base-linked acetylenic scaffolds. Infrared, 1H, and 13C -NMR, elemental analysis, and X-ray crystallography were used to characterize the structure. The outcomes demonstrated that the substances had improved antioxidant activity. (3Z)-3-(benzylidene hydrazono)-1-(prop-2-yn-1-yl) indolin-2-one is the one that had the most effective antioxidant activity (Figure 15)²³.

Figure 15. Structure of isatin hydrazone Schiff base

Novel asymmetric bis-isatin derivatives with the urea and thiourea moiety were created, synthesized, characterized, and studied. The structures of the synthesized compounds were clarified using elemental analysis, FT-IR, 1H-NMR, and 13C-NMR spectroscopic methods. Antioxidant activity was examined for their capacity to scavenge CUPRAC and ABTS cation radicals. The synthesized compound's IC₅₀ values for ABTS•+ activity ranged from 18.44 μM to 27.38 μM, and their A0.50 values for CUPRAC activity were between 0.600 μM and 0.810 μM. With IC₅₀ values of 18.44 μM, (Z)-1-(5-chloro-2-oxoindolin-3-ylidene)-5-(5-methoxy-2-oxoindolin-3-ylidene) carbonohydrazide exhibited the highest ABTS activity. (Z)-1-(5-chloro-2-oxoindolin-3-ylidene)-5-(2-oxoindolin-3-ylidene)thiocarbonohydrazide(Figure 16) had the highest CUPRAC activity, with an A0.50 value of 0.600 μM. Most synthesized substances had marginally higher CUPRAC activity than the standard BHT (A0.50 = 0.634 μM)²⁴.

Figure 16. Structure of asymmetric bis-isatin derivatives

Condensation of 2-(1-aminobenzyl) benzimidazole with symmetrical bis-isatins connected via five alkyl chains (n =2–6), 15 novel bis indole-based Schiff bases were produced. These were examined for their absorption, distribution, metabolism, and excretion (ADME), physiochemical characteristics, molecular docking, and in vitro antibacterial and antioxidant studies. {3-[(1H-benzimidazol-2-yl)-phenyl methyl] imino-5-bromo-1H-indol-2-one}-1,10-(1, 6-hexane diyl) bis show that the hexyl-linked analog has the highest antioxidant activity (Figure 17)²⁵.

Figure 17. Structure of bis-Schiff base derivative

When isatin-thiocarbohydrazides and carbohydrazides are combined with various aromatic aldehydes, new Schiff bases based on isatin and thiocarbohydrazone and carbo hydrazone derivatives are created. The synthesized compounds' antioxidants were assessed using their DPPH, ABTS, and CUPRAC activities. The IC₅₀values for these substances ranged from 27.13 to 43.35 μM for DPPH, from 6.47 to 24.96 μM for ABTS, and with the A0.50 values ranging from 9.04 to 47.52 μM for CUPRAC. For each assay, N'-(2, 4-dihydroxy benzylidene)-2-((Z)-2-oxo indolin-3-ylidene) hydrazine-1-carbo thio hydrazide, which has two hydroxyl groups (Figure 18), displayed the most potent antioxidant activity (IC₅₀ = 27.13 μM for DPPH, 6.47 μM for ABTS, and A0.50= 9.04 μM for CUPRAC)²⁶.

Figure 18. Structure of isatin-thiocarbohydrazides

The ONO donor Schiff base ligand N'-(6-chloro-2-oxoindolin-3-ylidene) nicotinohydrazide, which is produced by the reaction of 6-chloro isatin and isoniazid, had been used to synthesize the series of octahedral Zn (II), Cu (II), Ni (II), and Co (II) complexes. Spectral and physicochemical methods were used to reveal the chemical structures of the compounds. Excellent antioxidant activity could be seen in the Ni (II) and Co (II) complexes. Comparing the Ni(II) and Co(II) complexes of N'-(6-chloro-2-oxoindolin-3-ylidene)iso nicotine hydrazide to the standard medication, they showed excellent antioxidant activity (Figure 19)²⁷.

Figure 19. Structure of Ni (II) and Co (II) Complexes

The reactions of organotellurium (IV) chlorides (RTeCl3 and R2TeCl2) with Schiff base (NMeIATP) derived by condensation of N-methyl isatin with 2-aminothiophenol result in the formation of new organotellurium (IV) complexes of type RTeCl2.NMeIATP and R2TeCl.NMeIATP (where R = 4-Methoxyaryl, 4-Hydroxyaryl and 3-Methy-4-hydroxyaryl; aryl = phenyl) were reported. Spectroscopic methods such as elemental analyses, molar conductance, SEM analysis, FT-IR, DFT calculations, powder X-ray diffraction, mass spectrometry, 1H-NMR, 13C-NMR, UV-Vis, and thermogravimetric analysis were used to characterize these complexes. The DPPH assay assessed the NMeIATP and organotellurium (IV) compounds' antioxidant activity. These Complexes had a higher radical scavenging activity (IC₅₀=59.08 μg/ml)²⁸.

A novel 1-{[bis(2-chloroethyl) amino] methyl}-3-(phenylimino)1,3-dihydro-2H-indole-2-one derivatives were synthesized. 1H-NMR, MASS, and IR were used for structural confirmation of the synthesized compounds. All the compounds were tested for cytotoxicity assays and antioxidant activity. All the compounds showed good cytotoxic activity. All compounds were screened for antioxidant activity, and among them, (3Z)-1-{[bis(2-chloro ethyl) amino]methyl}-3-(phenyl imino)-2,3-dihydro-1H-indol-2-one-4-fluoridewas found to be the most effective antioxidant (Figure 20)²⁹.

Figure 20. Structure of bis-isatin derivative

Twenty Schiff bases were created using isatin and its analogs as the starting ketones, along with a few different diamines, 4-amino antipyrines, and 2-amino phenols. These compounds' antioxidant potential was assessed experimentally using the DPPH method and molecular docking studies with an enzyme (PDB ID:1HD2)³⁰.

5-nitroisatin-thiocarbohydrazone containing Schiff bases were reported for their antioxidant activity. Through spectroscopy and elemental analysis, the chemical structures of the synthesized compounds have been clarified. Antibacterial, antifungal, antimicrobial, and antioxidant activities were also examined. The synthesized compounds outperformed standard antioxidant BHT in terms of total antioxidant activity and standard antioxidant Trolox³¹.

CONCLUSION:

By utilizing some antioxidant techniques, the Schiff bases created from isatin and a variety of aromatic amines demonstrate excellent antioxidant activities. When compared to standard antioxidants, N'-[1-(3,5-Di-tert-butyl-4-hydroxybenzyl)-2-oxo-1,2-dihydro-indol-(3E)-ylidene]-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-propionohydrazide (Figure 1),(2-benzoyl-4-chlorophenyl)imino]-5-bromo-1,3-dihydro-2H-indol-2-one (Figure 3),1-(4-hydroxy-3-methoxybenzylidene)-5-(5-chloro-2-oxoindolin-3-ylidene) thio carbo hydrazone (Figure 11),(Z)-1-(5-chloro-2-oxoindolin-3-ylidene)-5-(5-methoxy-2-oxoindolin-3-ylidene)carbohydrazide, and(Z)-1-(5-chloro-2-oxoindolin-3-ylidene)-5-(2-oxoindolin-3-ylidene)thiocarbohydrazide (Figure 16) exhibits the highest antioxidant activity. The activities of Schiff bases derived from isatin have been the focus of numerous studies in this field. From this, additional research on this subject will probably contribute to the pharmaceutical industry's continued expansion. In addition to being used to create antioxidants, these substances also have other functions. As a result, we can produce these antioxidants and those with additional biological functions. More research in this area will provide future researchers with a new, valuable perspective.

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Received on 05.12.2024 Revised on 24.02.2025

Accepted on 28.04.2025 Published on 10.07.2025

Available online from July 17, 2025

Asian J. Pharm. Res. 2025; 15(3):287-294.

DOI: 10.52711/2231-5691.2025.00045

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