The Isatin Scaffold: Exceptional Potential for the Design of Potent Bioactive Molecules

Dedicated to Prof. Klaus Jurkschat (TU Dortmund, Germany)

Abstract

Since its discovery the isatin scaffold has been recognized for its significance, but it gained particular attention after being isolated from natural sources and identified as a natural product. This discovery prompted extensive research into its synthesis, as well as its chemical and biological applications. The isatin scaffold undergoes several key chemical reactions, including oxidation, reduction, ring expansion, Friedel–Crafts reactions, and aldol condensation, resulting in the formation of biologically active compounds such as 2-oxindoles, tryptanthrin, indirubins, and others. In recent years, numerous derivatives of isatin, particularly those involving substitution at nitrogen and the C3 and C5 positions, have been synthesized and investigated for their diverse biological activities, with some even receiving FDA approval as therapeutic agents. This account provides a concise overview of the isatin scaffold, highlighting its synthesis, reactivity, and structural features of the scaffold as well as those of its main derivatives, particularly their ability to engage in various non-covalent interactions. Additionally, the selected recent biological applications of isatin derivatives are discussed, with an emphasis on contributions from our own research group. The goal is to enhance the understanding of the potential of the isatin scaffold as a platform for designing potent bioactive molecules, with an optimistic outlook on its future in drug development.

1 Introduction

2 Synthesis of the Isatin Scaffold

3 Tautomerism, Reactivity, and Functionalization Sites of the Isatin Scaffold

4 Structural Features of the Isatin Scaffold and Its Derivatives

5 Potent Bioactive Molecules from the Isatin Scaffold

5.1 N-Functionalization

5.2 C3-Functionalization

5.3 N- and C3-Functionalization

5.4 C5-, C5,N-, and C5,N,C3-Functionalization

6 Coordination Chemistry of Isatin Scaffold Derived Compounds

7 Conclusions and Outlook

Introduction

Isatin, also known as 1H-indole-2,3-dione, indoline-2,3-dione, or 2,3-dioxoindoline (Scheme [1]), is a biologically active heterocyclic compound characterized by a fused six-membered and a five-membered ring structure, with a nitrogen atom at position 1 and two carbonyl groups at positions 2 and 3.[1] This compound serves as a flexible and versatile synthetic scaffold, incorporating an indole nucleus along with two distinct carbonyl functionalities: a keto group and a lactam group. These structural features render isatin a favorable building block for Schiff base reactions, heterocyclic synthesis, and pharmacophore development.[1]

Isatin crystallizes as orange-red monoclinic prism-shaped crystals from solvents such as water, alcohol, or acetic acid, having a melting point of 200–201 °C.[2] It exhibits complete solubility in acetone, 1,4-dioxane, dimethylformamide (DMF), methanol, and dimethyl sulfoxide (DMSO), while displaying limited solubility in butanol, chloroform, ether, ethyl acetate, and propan-2-ol. Additionally, isatin is soluble in concentrated hydrochloric acid and sulfuric acid. Upon dissolution in sodium or potassium hydroxide, isatin forms the corresponding sodium or potassium salt. Heating the resulting solution induces ring opening, affording the salt of isatic acid. Acidification of the solution facilitates ring closure, causing isatin to precipitate.[2]

Isatin is an oxidized derivative of indole, first synthesized by Erdmann and Laurent in 1841 through the oxidation of indigo dye using nitric and chromic acids (Scheme [1]).[3] For nearly 140 years, it was believed to be a purely synthetic compound; however, later studies revealed its natural occurrence in various biological sources. Isatin has been identified in plants such as those in the Isatis genus,[4] Calanthe discolor,[5] and the fruits of the cannonball tree (Couroupita guianensis Aubl.),[6] as well as in the secretions of the parotid glands of Bufo frogs.[7] Additionally, substituted isatins have been isolated from plants,[8] fungi,[9] and marine mollusks.[10] In humans and other mammals, isatin is a metabolic derivative of adrenaline, synthesized in vivo from tryptophan-rich foods such as meat, dairy products, and whole grains.[11]

Initially, tryptophan is converted into indole by intestinal bacteria, absorbed, and transported to the liver, where it is oxidized to isatin via 3-hydroxyindole.[11] Isatin has also been identified as a component of coal tar,[12] further demonstrating its widespread occurrence in both biological and environmental contexts.

Synthesis of the Isatin Scaffold

A variety of methods are available for the synthesis of the isatin scaffold, typically starting from substituted anilines or aniline derivatives. Among these, the Sandmeyer, Stolle, Gassman, and Martinet procedures are the most conventional and widely used.[13] The Sandmeyer synthesis, one of the oldest methods, involves treating an aniline with chloral hydrate and hydroxylamine hydrochloride in aqueous sodium sulfate to form an intermediate, isonitrosoacetanilide 1, which is then reacted with concentrated sulfuric acid to yield an isatin (Scheme [2a]). This method is particularly effective for anilines with substituents at C2, such as 2-fluoroaniline, but suffers from low yields and the formation of inseparable mixtures when using substrates with substitution at C3 or electron-withdrawing groups.[14] The Stolle method involves reacting an N-substituted aniline with oxalyl chloride to form intermediate 2, which is then treated with anhydrous aluminum chloride to produce an isatin (Scheme [2b]).[15] In contrast, the Gassman method takes a fundamentally different approach, involving the formation of an intermediate 3-(methylthio)-2-oxindole 3, which on reaction with N-chlorosuccinimide (NCS) generates the unstable 3-chloro-3-(methylthio)-2-oxindole 4 that hydrolyzes to an isatin in the presence of red mercuric oxide and BF₃·Et₂O in aqueous THF (Scheme [2c]).[16] The Martinet procedure involves reacting aniline, a substituted aniline, or amino aromatic compound with either an oxomalonate ester or its hydrate in the presence of an acid to form a 3-hydroxy-2-oxindole-3-carboxylic acid derivative 5, which then undergoes oxidative decarboxylation to yield an isatin (Scheme [2d]).[17] This method is particularly useful for synthesizing 5,6-dimethoxyisatin and also for producing benzoisatin derivatives from naphthylamines.[17]

Apart from the traditional methods, directed ortho-metalation (DoM) of a protected aniline derivative with diethyl oxalate was employed to synthesize α-keto ester 6. This was followed by hydrolytic deprotection of the amino group and subsequent cyclization to yield an isatin (Scheme [2e]).[18] A similar approach has also been utilized for the preparation of 5-azaisatin from a protected 4-aminopyridine.[19] Another useful strategy for the isatin synthesis is the Cu-catalyzed intramolecular C–H oxidation/acylation method, using CuCl₂ and O₂. This efficiently converts N-arylformamide 7 into an isatin (Scheme [2f]).[20] A metal-free synthesis utilizing I₂-DMSO as a catalyst enables the synthesis of N-alkylated and N-arylated isatins from 2-aminoacetophenones 8 via C–H activation and internal cyclization (Scheme [2g]).[21] Additionally, environmentally friendly methods have been developed to convert α-hydroxy N-arylamides 9 and α-formyl amides 10 into isatins using hydrogen peroxide and pyridinium chlorochromate (PCC) under aerobic conditions (Scheme [2h] and 2i).[22] Efficient synthesis of the isatin scaffold is also promoted by molecular iodine from 2-aminophenylacetylenes 11, 2-aminostyrenes 12, and β-(2-aminophenyl)-β-keto esters 13 through oxidative amidation of sp, sp², and sp³ C–H bonds, respectively. This procedure involves consecutive iodination, Kornblum oxidation, and intramolecular amidation, providing a metal-free and peroxide-free synthesis of isatins (Scheme [2j, 2k], and 2l).[23]

In addition to the synthesis of isatins from substituted anilines or aniline derived compounds (Scheme [2]), several alternative methods have been developed for accessing the isatin derivatives. Notably, the synthesis of N-substituted isatin derivatives can be achieved through the oxidation of N-substituted indoles, using molecular oxygen as the oxidizing agent, facilitated by a dicyanopyrazine derivative.[22] Such approaches offer an efficient and direct route to various N-substituted isatins, as they do not require the need to synthesize the indole ring, simplifying the overall synthetic process.

Tautomerism, Reactivity, and Functionalization Sites of the Isatin Scaffold

In 1882, Baeyer first proposed that isatin scaffold exists as two tautomeric forms: the lactam and the lactim, in which proton transfer occurs between the nitrogen and oxygen atoms on the second carbon (Figure [1a]).[24] In the solid state, isatin predominantly adopts the lactam structure. The formation of O-alkyl ethers from its silver salt and alkyl halides provides evidence for the lactim form.[2] Furthermore, isatin reacts with phosphorus pentachloride in hot benzene solution to yield isatin-α-chloride.[2] The ¹H NMR spectrum of isatin in CD₃OD shows signals corresponding to both lactam and lactim forms, whereas in DMSO-d ₆, only the signal for the lactam form is observed.[25] Importantly, isatin is considered as the first recognized example of a tautomeric substance.[2]

The isatin scaffold is highly reactive at three primary sites, allowing for versatile modifications that enable the synthesis of a wide range of derivatives with diverse biological activities (Figure [1b]).[1] [2] These reactive sites include: (1) electrophilic aromatic substitution at C5; (2) nucleophilic substitution at the nitrogen atom (including alkylation, aminomethylation, arylation, acylation, and sulfonylation; (3) carbonyl chemistry at C3. While isatins having substituents attached to the aromatic ring are typically obtained from the corresponding functionalized anilines (vide supra),[13–23] they can also be synthesized through electrophilic aromatic substitution of the isatin scaffold, generally leading to substitution at the C5. Halogenated isatins at the C5 can be obtained using various electrophilic halogenating reagents.[26] [27] [28] The introduction of different substituents at this position can influence both the lipophilicity and binding affinity of the resulting compounds. If C5 is occupied, substitution typically occurs at C7.[1] [2] Similarly, substituted isatins can be further modified at the C4 and C6 of the isatin ring.[1] [2] Additionally, the nitrogen atom at position 1 of the isatin ring system provides an excellent nucleophilic site for various modifications (Figure [1b]). For example, N-alkylation or N-arylation reactions are particularly valuable for enhancing the solubility and stability of isatin derivatives, while N-acylation and N-sulfonylation reactions can improve interactions with specific biological targets, thereby fine-tuning their activity.[1] [2] Furthermore, the carbonyl group at C3 (Figure [1b]) is highly reactive in condensation reactions, enabling the formation of derivatives with enhanced biological properties, such as improved receptor affinity or bioavailability.[1] [2] If electron-withdrawing groups are present on the benzene ring or the nitrogen atom, nucleophilic attack may also occur at C2.[1] [2] This broad reactivity of the isatin scaffold has led to diverse functionalizations, resulting in pharmacologically significant derivatives, such as tryptanthrin and indirubin derivatives (Figure [1c] and 1d), which contribute to the development of compounds with varied therapeutic potentials.[29]

The isatin scaffold also serves as a versatile starting material in various synthetic transformations beyond straightforward nucleophilic substitution, nucleophilic addition, and electrophilic addition (vide supra). They have been reported to involve in multicomponent reactions (MCRs) such as the N-Mannich reaction,[30] Ugi reaction,[31] Passerini reaction,[32] and other isocyanide-based reactions.[33] Additionally, the isatin scaffold undergo reactions including 1,3-dipolar cycloaddition, the Knoevenagel reaction, and many MCRs based on these transformations.[32] [34] Furthermore, isatins are known to undergo the Morita–Baylis–Hillman (MBH) reaction[35] as well as the aza-Michael reaction (Figure [1b]).[36] However, chemoselective N-functionalization of isatins via the aza-Michael reaction has traditionally been challenging, particularly under basic conditions, due to the occurrence of unwanted side reactions. One such side reaction involves the decomposition of the isatin scaffold, while another arises from the lack of chemoselectivity between the C3 and N1 sites. These issues are usually mitigated by protecting the C3 position of the isatin. In the case of unprotected isatins, the Morita–Baylis–Hillman (MBH) reaction, which predominantly functionalizes the C3 position, is favored over the aza-Michael reaction.[36] In this context, two efficient methods for chemoselective N-functionalization of isatins are reported. The first method employs KF-Celite in 2-methyltetrahydrofuran,[36a] while the second utilizes an N-heterocyclic carbene (NHC) and 1,4-diazabicyclo[2.2.2]octane (DABCO) as catalysts.[36b] Both approaches achieve high chemoselectivity for the N-aza-Michael addition in the absence of any C3 protection.

Another important feature of isatin scaffold is its ability to undergo various ring-expansion reactions, yielding a variety of biologically significant fused heterocyclic compounds, including derivatives of quinoline, isoquinoline, quinazolinone, quinazoline, acridine, and acridone, among others (Figure [2]).[37] These transformations exploit the ring-opening characteristics of the isatin scaffold including N1–C2 cleavage, C2–C3 cleavage, and insertion of atoms between C2 and C3 carbonyl of isatin under specific conditions.[37] The simplicity of these reactions offers the added benefit of diversity-oriented synthesis.

Structural Features of the Isatin Scaffold and Its Derivatives

The structural features of molecules and their ability to interact with biological targets through non-covalent interactions are crucial determinants of biological activity. Isatin has been extensively investigated in both behavioral and metabolic assays, with proteomic analyses identifying over 90 potential protein targets.[38] The interactions with these targets are likely mediated by a range of non-covalent forces, including hydrogen bonding, π-π stacking, van der Waals forces, and electrostatic interactions. The structural characteristics of the isatin scaffold, particularly the two carbonyl groups and the NH group, facilitate these interactions, enabling isatin to function both as a hydrogen bond donor and acceptor. The isatin scaffold exhibits a distinctive structural duality, consisting of an electron-rich six-membered ring and an electron-deficient five-membered ring.[39] This duality endows the isatin scaffold with the capacity to form strong antiparallel π-π stacking interactions (Figure [3a]).[40] However, in the case of its 3-carbonyl Schiff base derivatives, these interactions are often impeded by steric effects and competing interactions.

A notable example of biological activity of isatin scaffold is its potent inhibition of monoamine oxidase B (MAO-B), an enzyme responsible for the degradation of neurotransmitters such as dopamine.[41] The carbonyl group in isatin can form hydrogen bonds with amino acid residues within the MAO-B active site, while the aromatic indole ring can engage in π-π interactions with adjacent residues, contributing to effective inhibition.[41] Beyond MAO-B, isatin has been shown to interact with a wide array of proteins involved in neurotransmitter signaling, protein folding, cell cycle regulation, and immune modulation.[42] This versatility in protein binding, facilitated by diverse non-covalent interactions, positions the isatin scaffold as a promising candidate for drug development, particularly for neurodegenerative diseases and other conditions where multiple protein targets are implicated.[42] The benefit of non-covalent interactions is their ability to selectively modulate biological processes without permanently altering the structure of target proteins, thus offering therapeutic advantages with a reduced risk of off-target effects.[43] Recent studies have highlighted the significance of carbonyl-carbonyl (CO···CO) interactions as an important non-covalent interaction, contributing to the stability of biomacromolecules.[44] In a recent work, our group demonstrated that isatin scaffold has also the potential to participate in CO···CO interactions (Figure [3b]), thereby expanding its potential involvement in various biological processes.[45]

In contrast to other isatin derivatives, such as Schiff base derivatives, isatin hydrazones exhibit pronounced antiparallel π-π stacking interactions, which are believed to be central to their broad biological activities.[46] The isatin core demonstrates partial antiaromaticity due to its 8π-electron Hückel antiaromatic system.[47] Modification at C3 with a hydrazide group introduces a resonance structure consistent with a 10π-electron Hückel aromatic system, altering the electronic properties of the isatin scaffold (Figure [3c]).[39] Furthermore, an intramolecular hydrogen bond between the C2 carbonyl oxygen and the NH group of the hydrazide enforces a planar geometry in the hydrazone derivatives, promoting π-π stacking interactions and enhancing their biological efficacy.[46]

Similarly, isatin thiosemicarbazone derivatives modify the electronic structure of the scaffold, introducing a resonance form consistent with a 10π-electron Hückel aromatic system.[47] Additionally, thiosemicarbazones exhibit resonance stability through their thioamide-thioiminol structures, which extend conjugation and further enhance their stability (Figure [3d]).[48] The cis-thioamide conformation, driven by intramolecular hydrogen bonding in thiosemicarbazones (Figure [3e]),[49] along with the potential of thiosemicarbazones to form thioamide-thioamide stacking interactions (Figure [3f]), enhances their binding affinity and broadens their interaction profile with biological targets.[50] Isatin derivatives utilizing the 3-position with a free lactam amide can engage in intermolecular hydrogen bonding, specifically of the N–H···O=C type, known as amide-amide hydrogen bonding (Figure [3g]).[51]

Overall, the structural versatility of isatin and its derivatives enables interactions with a broad range of protein targets, influencing numerous biological pathways and eliciting a diverse array of pharmacological effects.[38]

Potent Bioactive Molecules from the Isatin Scaffold

Easy access and versatile reactivity of isatin and its substituted analogues, resulting in the potential for a plethora of derivatives (vide supra), has made it an extremely attractive scaffold for designing bioactive compounds. Through targeted functionalization, it is possible to create derivatives with enhanced potency, selectivity, and efficacy for applications in neurodegenerative diseases, cancer, diabetes, and other therapeutic areas.

As a result, a wide variety of isatin derivatives have been synthesized in recent years. Several isatin-based compounds, such as sunitinib, toceranib, and nintedanib, have advanced to clinical trials and have received approval for clinical use (Figure [4]).[52] Sunitinib inhibits the catalytic activity of kinases involved in protein phosphorylation by reversibly binding to their ATP-binding sites. Toceranib, a molecule structurally similar to sunitinib, selectively targets and inhibits specific receptor tyrosine kinases, thereby inducing apoptosis in tumor cells in vivo. Nintedanib, another tyrosine kinase inhibitor, is used to treat idiopathic pulmonary fibrosis, slow the progression of chronic interstitial lung diseases, and reduce lung function decline in systemic sclerosis-associated interstitial lung disease. Other derivatives, such as semaxinib, and orantinib are currently under clinical investigation for their potential anticancer effects (Figure [4]). These promising compounds have demonstrated the ability to slow or halt tumor growth by modulating cellular processes such as growth, proliferation, survival, and migration.[52] However, some of these anticancer agents exhibit side effects, including limited efficacy, diarrhea, vomiting, hypertension, neutropenia, and hand-foot syndrome, highlighting the need for the identification of more such candidates with enhanced therapeutic profiles.[53]

A review of recent literature reveals that the most potent isatin and substituted isatin derivatives are synthesized by utilizing either the nucleophilicity of the NH group, the high reactivity of the C3 carbonyl group, or a combination of both. The synthesis of these derivatives has been a central focus of our research group, as well as many others, due to their broad spectrum of biological activities. Moreover, several studies have emphasized the importance of functionalizing the isatin aryl ring in the development of biologically active molecules. The following sections provide an overview of these efforts, highlighting the significance of functionalized derivatives by referencing selected recent studies; the figures highlight the most potent compound(s).

N-Functionalization

Diabetes is a global health crisis, leading to severe complications such as cardiovascular disease, nephropathy, and neurodegenerative disorders. One promising strategy to manage hyperglycemia is the use of α-glucosidase inhibitors, which slow carbohydrate digestion and glucose absorption, thereby helping to regulate blood sugar levels.[54] Phenoxy pendant isatins 14 (Figure [5]) were synthesized by the straightforward reaction of isatin/5-substituted isatins with 1-(2-bromoethoxy)-4-substituted benzenes and their anti-diabetic potential was evaluated by in vitro α-glucosidase inhibition assays.[45] All tested compounds exhibited potent α-glucosidase inhibition (IC₅₀ values ranging from 5.32 to 150.13 μM) when compared to the marketed α-glucosidase inhibitor, acarbose (IC₅₀ = 873.34 ± 1.67 μM). Compound 14a (X = Br, R = Cl) emerged as the most potent α-glucosidase inhibitor (IC₅₀ = 5.32 μM), followed by compound 14b (X = Cl, R = H) with strong inhibition (IC₅₀ = 7.87 μM), while compound 14c (X = Br, R = Br) exhibited significant activity (IC₅₀ = 16.17 ± 0.19 μM), ranking third (Figure [5]). A detailed analysis of the IC₅₀ values indicated that the introduction of chloro and bromo substituents at C5 of isatin significantly improved α-glucosidase inhibition. In contrast, the effect of various substituents at C4 of the phenoxy pendant on α-glucosidase inhibition was less consistent, with the observed variations in IC₅₀ values likely reflecting the overall affinities of compounds for the binding site of the enzyme.[45] Additionally, when assessed for acetylcholinesterase inhibition, the phenoxy pendant isatins 14 also exhibited significant activity, demonstrating efficacy comparable to the standard drug, donepezil.[40] It is now well-known that the active site of acetylcholinesterase contains a 20 Å long gorge, called the ‘active-site gorge’, composed of 14 aromatic residues, covering approximately 40% of the surface area.[55] Therefore, this structure is particularly conducive to interactions with planar and aromatic scaffolds, which explains the strong acetylcholinesterase inhibitory activity observed for the phenoxy pendant isatins 14, likely due to the π-π interaction potential of the isatin moiety.[40] [45] However, structure-activity relationship (SAR) studies revealed that halogen substituents at C5 of isatin or C4 of the phenoxy pendant did not significantly enhance acetylcholinesterase inhibition.[40]

With cancer cases projected to rise by 75% over the next two decades and the limitations of conventional treatments and side effects of existing drugs (vide supra), there is an urgent need to develop new antitumor agents with the potential to selectively target cancer cells.[56] Isatin-benzofuran hybrids 15 (Figure [6]) were synthesized through a nucleophilic substitution reaction between isatin or substituted isatins and benzofurans bearing a bromoalkoxy side chain.[57] These hybrids were subsequently evaluated for their VEGFR-2 inhibitory activity and in vitro anticancer potential against MCF-7, MCF-7/DOX, DU-145, and MDR DU-145 cancer cell lines using MTT assays. Most of the compounds demonstrated greater sensitivity toward DU-145 and MDR DU-145 cancer cell lines. Notably, six analogues 15a–f exhibited enhanced potency, with IC₅₀ values (μM) either comparable to or exceeding those of the positive control, sunitinib, against one or more of the tested cell lines (Figure [6]). The SAR analysis revealed that the alkyloxy chain length linking the isatin and benzofuran rings, substitution at C5 of isatin, and the different substituents on the para position of the phenyl ring at C2 of the benzofuran moiety are crucial for improving VEGFR-2 inhibitory and anticancer activity.[57]

Similarly, isatin-triazole hybrids 16 (Figure [7]) were synthesized by reacting N-propargyl-4,7-dichloroisatin with the respective azido compounds via a Cu-catalyzed click reaction.[58] Compound 16a (R = cyclohexyloxy) exhibited significant inhibition against TE-1 and MGC-803 cells, with IC₅₀ values of 14.22 and 9.78 μM, respectively, comparable to the anticancer drug 5-fluorouracil (5-FU). Most importantly, 16a was found to be relatively nontoxic to normal cells with IC₅₀ values of 40.27 μM and 35.97 μM against HL-7702 and GES-1, respectively (Figure [7]). Detailed investigations on compound 16a revealed its ability to induce apoptosis through multiple mechanisms while also inhibiting the migration of MGC-803 cells.[58]

Isatin-triazole-coumarin hybrids 17 (Figure [8]) were also synthesized via a click reaction between N-(ω-azidoalkyl)-substituted isatins and coumarins bearing a propargyl moiety, using catalytic CuSO₄·5H₂O and sodium ascorbate (as a reducing agent for CuSO₄).[59] These hybrids were then evaluated for their in vitro antimicrobial potential against E. coli, S. enterica, S. aureus, M. smegmatis, C. albicans, A. mali, Penicillium sp., and F. oxysporum using the agar gel diffusion method. Importantly, all hybrids exhibited activity against the tested bacterial strains. Among them, hybrid 17a was found to be the most active antibacterial agent against S. aureus, with an MIC of 312 μg/mL, while compound 17b demonstrated promising antifungal potency with an MIC of 30 μg/mL against Penicillium sp. (Figure [8]). SAR analysis showed that the length of the carbon chain between the triazole and isatin scaffold, as well as the electronic environment of the isatin scaffold, significantly influenced the activity of these hybrids.[59]

Isatin-ciprofloxacin hybrids 18 (Figure [9]) were synthesized by reacting N-(3-bromopropyl)isatins with ciprofloxacin.[60] Assessment of their antimycobacterial activities against MTB H37Rv and MDR-TB strains revealed that hybrid 18a demonstrated excellent antitubercular potential, with MICs of 0.20 and 0.5 mg/mL against MTB H37Rv and MDR-TB, respectively. Hybrid 18b (MIC = 0.10 mg/mL) exhibited four- and eightfold greater activity than ciprofloxacin (MIC = 0.78 mg/mL) and rifampicin (MIC = 0.39 mg/mL), respectively, against MTB H37Rv. Additionally, this compound (MIC = 0.5 mg/mL) was found to be 4 to >256 times more potent than the reference drugs ciprofloxacin (MIC = 2.0 mg/mL), rifampicin (MIC = 32 mg/mL), and isoniazid (MIC = >128 mg/mL) against MDR-TB. Hybrid 18b, with low cytotoxicity (CC₅₀: 64 mg/mL), also demonstrated acceptable metabolic stability and favorable in vivo pharmacokinetic properties (Figure [9]).[60]

Following a similar strategy, ciprofloxacin was linked to the isatin scaffold through 1,2,3-triazole moiety during the synthesis of isatin-triazole-ciprofloxacin hybrids 19 (Figure [10]).[61] Reaction of N-propargyl isatin, 5-fluoroisatin, or 5-methylisatin with azidoacetyl-ciprofloxacin intermediates via click chemistry, using a catalytic amount of Cu(OAc)₂, yielded hybrids 19. The azidoacetyl-ciprofloxacin intermediates were in turn synthesized from azidoacetic acid employing a straightforward nucleophilic substitution and nucleophilic acyl-substitution reactions. The results of in vitro anticancer activity of these hybrids against various human cancer cell lines showed that the compounds 19a, 19b, and 19c are highly potent against A549 (lung carcinoma), HepG2 (liver cancer), and SF-268 (central nervous system cancer), with efficacy comparable to or greater than the reference drugs ciprofloxacin and vorinostat in one or more cancer cell lines (Figure [10]). SAR analysis revealed that 5-fluoro substitution at the isatin ring was relatively more beneficial than no substitution or 5-methyl substitution of isatin.[61] Additionally, hybrid 19d (Figure [10]) when evaluated for its in vitro antimycobacterial activity against MTB H37Rv (MIC = 0.5 μg/mL) and MDR-MTB strains (MIC = 0.12 μg/mL), demonstrated comparable efficacy to the first-line anti-tubercular agents isoniazid (MIC = 0.12 μg/mL) and rifampicin (MIC = 0.25 μg/mL).[62] Importantly, it exhibited twofold greater activity than the parent ciprofloxacin (MIC = 1.0 μg/mL) against MTB H37Rv, and was ≥16 times more potent than ciprofloxacin (MIC = 2.0 μg/mL), isoniazid (MIC = >64 μg/mL), and rifampicin (MIC = >64 μg/mL) against MDR-MTB. However, hybrid 19d demonstrated significant cytotoxicity (CC₅₀ = 16.0 μg/mL) against VERO cells.[62]

Isatin-dihydropyrimidinone hybrids 20 (Figure [11]) were synthesized by the reaction of isatin with dihydropyrimidinone derivatives which were prepared in three steps (straightforward microwave-assisted Biginelli reaction, followed by treatment of the resultant product with ammonia and subsequently with chloroacetyl chloride).[63] Upon evaluation of these hybrids for non-nucleoside HIV-1 reverse transcriptase (RT) inhibitory activity, hybrids 20a and 20b exhibited the highest percent inhibition, with values of 95.96% (IC₅₀ = 64 nM) and 94.63% (IC₅₀ = 67 nM), respectively, compared to the reference drugs rilpivirine (94%, IC₅₀ = 68 nM) and nevirapine (88%, IC₅₀ = >100 nM) 19 (Figure [11]). The presence of electron-donating methyl groups at both R¹ and R² positions in 20a and an ethyl group at R¹ coupled with a methyl group at R² in 20b were found to favorably influence the inhibitory activity.[63]

C3-Functionalization

Isatin-3-hydrazones 21 (Figure [12]) were synthesized via the reaction of various benzoic acid hydrazides with isatin and its 5-substituted halo derivatives under microwave-assisted conditions.[64] The synthesized compounds were evaluated for their inhibitory activity against monoamine oxidase isoforms MAO-A and MAO-B. Notably, most compounds exhibited preferential inhibition of MAO-B over MAO-A. Among the tested compounds, 21a demonstrated the most potent inhibition of MAO-B, with an IC₅₀ value of 0.082 μM, followed by 21b (IC₅₀ = 0.104 μM) and 21c (IC₅₀ = 0.124 μM). Conversely, 21d exhibited the strongest inhibition of MAO-A (IC₅₀ = 1.852 μM), followed by 21e (IC₅₀ = 2.385 μM). Selectivity index (SI) analysis further confirmed 21c as the most selective MAO-B inhibitor (SI = 263.80), followed by 21a (SI = 233.85) and 21e (SI = 212.57). Kinetic studies revealed that 21a, 21b, and 21c, exhibited reversible inhibition of MAO-B, with K_i values of 0.044, 0.061, and 0.068 μM, respectively. Similarly, 21d reversibly inhibited MAO-A, with a K_i value of 1.004 μM. Evaluation of CNS permeability using the parallel artificial membrane permeability assay (PAMPA) indicated that these compounds exhibited sufficient permeability for potential central nervous system applications. Cytotoxicity and neuroprotective potential were assessed in lipopolysaccharide (LPS) challenged SH-SY5Y neuroblastoma cells. Pre-treatment with active compounds enhanced antioxidant enzyme levels (SOD, CAT, GSH, GPx) while reducing reactive oxygen species (ROS) and pro-inflammatory cytokine (IL-6, TNF-α, and NF-κB) production. SAR analysis suggested that unsubstituted benzoic acid hydrazides and isatin cores were optimal for MAO-B inhibition. Fluoro substitution either at the benzoic acid or at C5 of the isatin was unfavorable for MAO-B inhibition. The observed inhibitory trend for MAO-B was H > Cl > Br > F, whereas for MAO-A, it was Cl > Br > F > H, indicating that increasing electronegativity reduces MAO-B inhibition.[64]

Molecular docking, molecular dynamics simulations, and MM-GBSA binding energy analyses were performed to elucidate the binding interactions. Docking scores ranged from –6.55 to –10.85 kcal/mol. The potent compounds formed hydrophobic interactions with Tyr60, Pro102, Pro104, Trp119, Phe168, Leu171, Cys172, Tyr326, and Tyr435, while Gln206 participated in polar interactions. The isatin-hydrazone moiety exhibited π-π stacking with Tyr398, contributing to the stability of the IS7–MAO-B complex. Additionally, Tyr326 facilitated further π-π stacking interactions, enhancing complex stability. During molecular dynamics simulations, Cys172 maintained interactions with the ligand for 86% of the simulation time. MM-GBSA binding energy analysis confirmed that 21a strongly stabilized the MAO-B protein.[64]

Isatin-3-thiosemicarbazones 22 (Figure [13]) were synthesized from a straightforward condensation reaction of isatin with appropriate thiosemicarbazides and their anti-urease and antiglycating potential were evaluated.[65] All synthesized compounds exhibited potent urease inhibitory activity, surpassing the reference inhibitor thiourea. SAR analysis revealed that compared to compound 22a, which lacks substituents on the phenyl ring of the thiosemicarbazide moiety, all other derivatives demonstrated enhanced enzymatic inhibition, regardless of the nature, number, or position of the substituents.[65]

Among the tested compounds, 22f, featuring 3-methoxyphenyl substituent, emerged as the most potent urease inhibitor, displaying ten- and twenty-fold higher activity than compound 22a and thiourea, respectively (IC₅₀ = 1.08 μM vs. 11.23 and 22.3 μM). In contrast, 2-methoxyphenyl 22e and 4-methoxyphenyl 22g exhibited comparatively lower activity with IC₅₀ values of 1.51 and 3.11 μM, respectively (Figure [13]).

The second most potent inhibitor was 2-methylphenyl compound 22b. While slightly less active than 22f, it exhibited significantly greater inhibition than thiourea (IC₅₀ = 1.22 μM vs. 1.08 and 22.3 μM). Comparison with structurally related 3-methylphenyl 22c and 4-methylphenyl 22d indicated that methyl substitution at C2 was more favorable for urease inhibition. Compound 22c displayed moderate activity, while 22d was the least active among the methyl-substituted derivatives (IC₅₀ = 1.62 μM vs. 1.22 and 2.17 μM, respectively) (Figure [13]).

Another relatively potent inhibitor was 4-fluorophenyl compound 22j. Although slightly less effective than 22f (IC₅₀ = 1.38 μM vs. 1.08 μM), it exhibited significantly higher activity than both 22a and thiourea (IC₅₀ = 1.38 μM vs. 11.23 and 22.3 μM). In contrast, 2-fluorophenyl 22h and 4-fluorophenyl 22i demonstrated markedly lower inhibitory activity, approximately five- and twofold lower than 22j (IC₅₀ = 7.97 and 2.62 μM vs. 1.38 μM) (Figure [13]).[65]

The thiosemicarbazones 22 were further evaluated for their glycation inhibitory potential using rutin as the reference inhibitor.[65] Among the tested compounds, seven exhibited potent glycation inhibition, with IC₅₀ values ranging from 209.87 to 605.26 μM. Several compounds demonstrated superior antiglycation activity compared to rutin (IC₅₀ values of 209.87–231.70 μM vs. 294.5 μM) (Figure [13]).

A limited SAR analysis indicated that 4-methylphenyl compound 22d was the most potent antiglycating agent in the series, with an IC₅₀ value of 209.87 μM. The closely related 3-methylphenyl isomer 22c exhibited an IC₅₀ of 231.70 μM, demonstrating significantly greater activity than the corresponding 3-methoxyphenyl derivative 22f (IC₅₀ = 522.68 μM). The next most potent antiglycating agent was 4-fluorophenyl compound 22j. While slightly less active than the most potent derivative 22d, it exhibited significantly greater inhibition than rutin (IC₅₀ = 217.94 vs. 209.87 and 294.5 μM, respectively) (Figure [13]). This SAR suggests that the CH₃ and F substituents play a crucial role in enhancing glycation inhibition, probably due to higher lipophilicity.[65]

A series of isatin-3-thiosemicarbazones 23 (Figure [14]), incorporating chloro[66] and nitro[67] substitutions on the isatin scaffold, were synthesized to assess the impact of electron-withdrawing groups on urease and glycation inhibition. While most compounds exhibited strong urease inhibitory activity, they demonstrated significantly higher potency than the reference inhibitor, thiourea (IC₅₀ values ranging from 1.31 to 3.24 μM for 5-chloro-substituted isatin derivatives and 0.87 to 8.09 μM for 5-nitro-substituted isatin derivatives, compared to 22.3 μM for thiourea).[66] [67] Notably, while some variation in activity was observed, no dramatic influence of the electron-withdrawing substituents could be observed. In terms of glycation inhibition, eight out of fifteen compounds derived from 5-chloro-substituted isatin displayed potent activity, with IC₅₀ values ranging from 114.51 to 433.88 μM. Several of these compounds exhibited superior glycation inhibition compared to the reference inhibitor, rutin (IC₅₀ = 294.5 μM).[66] [67]

Docking studies of compound 22 and 23 conducted against Jack bean urease (PDB ID: 3LA4) revealed that most of the compounds bound to the same region within the active site. The results from these docking simulations corroborated the experimental findings, indicating that the inhibitors primarily target the catalytic site of the enzyme. Notably, significant hydrogen bonding interactions were observed between the oxygen and hydrogen atoms of the inhibitors and key amino acid residues, including Arg609, Asp494, Ala440, and His593. Additional stable hydrogen bonds were formed within the active pocket with residues His492, His593, and His594. Furthermore, the thiosemicarbazone moiety of the inhibitors was found to interact with Arg439 and Ala636 at the core of the active site. Weak interactions with the Ni842 ion, located within the catalytic site of the urease enzyme, were also observed for all compounds. Additionally, the benzyl substituent exhibited π-π interactions with the imidazole ring of His594, while the thiosemicarbazone group displayed π-charge interactions, further contributing to the inhibitory activity.[65] [66] [67]

Isatin 3-hydrazonothiazolines 24 (Figure [15]) with 5-trifluoromethoxy, 5-fluoro, and 5-chloro substitutions on the isatin scaffold were synthesized through cyclization of isatin-3-thiosemicarbazones with 4-chlorophenacyl bromide.[68] In a urease inhibition bioassay, all synthesized hydrazonothiazolines exhibited potent enzyme inhibition, with IC₅₀ values ranging from 3.70 to 849 μM. Several compounds surpassed the reference inhibitor thiourea (IC₅₀ = 22.3 μM).

Among the 5-(trifluoromethoxy)isatin derivatives, the N-2,5-dichlorophenyl-thiazoline derivative was the most potent inhibitor (IC₅₀ = 3.70 μM). Comparisons with structurally related dichloro derivatives revealed that the 2,5-dichloro substitution pattern was more favorable than the 2,4-, 2,6-, and 3,4-dichloro substitutions. Interestingly, the trichloro-substituted derivative exhibited higher activity (IC₅₀ = 14.1 μM) than its dichloro counterparts, suggesting that increased electron-withdrawing effects enhanced inhibitory potency. Among the N-fluorophenyl-thiazoline analogues, the 2-fluorophenyl compound was highly active (IC₅₀ = 7.27 μM), exhibiting superior inhibition compared to 3-fluoro- and 4-fluorophenyl compounds. Additionally, the N-(4-methylphenyl)thiazoline compound showed notable activity (IC₅₀ = 10.3 μM), whereas 2-methyl and 3-methyl substitutions led to significantly reduced inhibition, likely due to steric hindrance.[68]

For the 5-fluoroisatin derivatives, N-(4-fluorophenyl)- and N-(2,4-dichlorophenyl)thiazolines were the most potent (IC₅₀ = 8.20 and 8.40 μM). The N-(4-fluorophenyl)thiazoline was more favorable than 2- or 3-fluoro substitution. Similarly, N-(2,4-dichlorophenyl)thiazoline derivative exhibited stronger inhibition than the 2,5- and 2,6-dichloro derivatives. The N-(2,4,6-trichlorophenyl)thiazoline also retained considerable activity (IC₅₀ = 14.3 μM). The N-fluorophenyl-thiazoline analogues displayed varying activity, with the 2,6-difluoro derivative being significantly more potent (IC₅₀ = 11.0 μM) than the 2,4-difluoro derivative. Among the N-(methylphenyl)thiazoline derivatives, 4-methyl demonstrated the highest inhibition (IC₅₀ = 11.4 μM), followed by 3-methyl, while 2-methyl was considerably weaker due to steric effects.[68]

For the 5-chloroisatin derivatives, the N-(2-methylphenyl)thiazoline derivative emerged as the most potent inhibitor (IC₅₀ = 9.20 μM), followed by the compound with 3-methoxy substitution (IC₅₀ = 10.3 μM). Methyl substitution at C2 was more favorable than at C3 or C4. Similarly, methoxy substitution at C3 resulted in superior inhibition compared to C2 and C4. These findings suggested that the electronic properties and steric effects of substituents collectively influenced on interactions with enzyme.[68]

The most active compounds were found to bind deeply within the active pocket, interacting with key active-site residues and coordinating with the nickel ions in molecular docking simulations with Jack bean urease (PDB ID: 3LA4). The active site of urease includes His409, Ala436, Arg439, Ala440, His492, Asp494, His519, His593, His594, Arg609, Ala636, and Met637. Due to their structural size, the docked compounds occupied both the bottom and mid-gorge regions of the active site. The most potent compound in the series was positioned deep within the active site, with its 5-(trifluoromethoxy)isatin moiety oriented towards the bottom of the pocket. The 4-chlorophenyl and 2,5-dichlorophenyl groups attached to the thiazoline moiety were directed towards the entrance of the active site. Although the 5-(trifluoromethoxy)isatin core did not form direct interactions with the nickel center, its 2,5-dichlorophenyl group exhibited π-π interactions with the imidazole ring of His593. Additional non-covalent interactions were observed between the 5-(trifluoromethoxy)isatin moiety and Arg609. Moreover, hydrogen bonding was established between the imidazole ring of His492 and the carbonyl oxygen of the 5-(trifluoromethoxy)isatin scaffold.[68]

Isatin-bis Schiff bases 25 (Figure [16]) were synthesized through the reaction of 4-methyl-m-phenylenediamine with various isatins.[69] The antiproliferative activity of these compounds was evaluated against lung carcinoma (H157) cells using the SRB assay. All compounds exhibited significant anticancer activity with low cytotoxicity in Vero cells, a normal epithelial cell line from African green monkeys, which served as controls for assessing the safety profile. The structural diversity of the compounds, particularly the nature of functional groups at C5 of the isatin scaffold, influenced their activity. The halo-substituted derivatives 25b–d demonstrated superior inhibitory effects against H157 cells, with IC₅₀ values ranging from 2.32 to 2.99 μM, outperforming the reference anticancer drug vincristine (IC₅₀ = 1.03 μM). Among these, 5-bromoisatin 25b exhibited the highest potency (IC₅₀ = 2.32 μM), likely due to enhanced hydrophobicity, which facilitated membrane permeability and receptor binding. The second most potent compound, 5-chloroisatin 25d displayed an IC₅₀ value of 2.56 μM. Other derivatives, including 25a, 25c, and 25e–g, showed comparatively lower antiproliferative activity, with IC₅₀ values ranging from 2.99 to 3.88 μM (Figure [16]).[69]

Additionally, all the Schiff base compounds 25a–g exhibited potent inhibitory activity against Jack bean urease in vitro, with IC₅₀ values ranging from 0.04 to 25.2 μM as compared to the standard inhibitor thiourea (IC₅₀ = 22.3 μM) (Figure [16]).[69] Among these, 5-bromoisatin 25b exhibited the highest potency (IC₅₀ = 0.04 μM), whereas 5-sulfonic acid substituted isatin 25f displayed the weakest inhibition (IC₅₀ = 25.2 μM). Notably, compound 25b, with its inductively electron-withdrawing bromo group, demonstrated significantly enhanced inhibitory activity compared to the reference compound 25a (IC₅₀ = 1.15 μM). Similarly, 5-chloroisatin 25d and 5-methylisatin 25e exhibited increased inhibition with IC₅₀ values of 0.11 and 0.34 μM. Conversely, compounds 25c, 25f, and 25g, containing fluoro, sulfonic acid, and nitro groups, respectively, showed reduced activity (IC₅₀ = 1.65, 25.2, and 5.86 μM). The variations in urease inhibition suggest that the electronic effects of substituents at C5 of the isatin scaffold significantly influence enzyme interactions, either enhancing or diminishing inhibitory potential. Given their minimal cytotoxicity, these compounds hold potential as orally effective therapeutic agents for the treatment of urease-related infections, including those caused by Helicobacter pylori.[69]

Isatin-bis Schiff bases were then docked to the crystallographic structure of Jack bean urease (PDB ID: 4H9M, resolution 1.5 Å) to analyze their binding interactions. The Schiff base benzene ring was located near the flap region formed by the Ala440 methyl group. The isatin benzene ring, bearing a bromo substituent, was flanked by His593, Leu589, Arg609, His492, and Met637 on one side, while interacting with Ile411 and Gln635 on the other. Additionally, the central portion of the molecule was oriented toward Arg439, engaging in π-π interactions via the benzene ring, stabilizing the binding mode.[69]

In 2025, a series of isatin-aminoquinoline-based molecular hybrids 26 (Figure [17]) linked via an aliphatic spacer were synthesized, starting from commercially available 4,7-dichloroquinoline.[70] The synthesis involved the reaction of 4,7-dichloroquinoline with ethylenediamine under heating conditions to obtain the linker intermediate, N-(7-chloroquinoline-4-yl)ethane-1,2-diamine, which was subsequently reacted with substituted isatins to afford the desired molecular hybrids. The antibacterial activity of the synthesized hybrids was evaluated in vitro against a panel of bacterial strains, including E. coli, E. faecalis, B. subtilis, S. aureus, P. aeruginosa, and Salmonella typhi. Many of the tested compounds exhibited significant antibacterial activity, with inhibition rates ranging from 90% to 100% at a concentration of 200 μg/mL against most of the bacterial strains. Antibacterial assessments, including disk diffusion and bacterial growth curve assays, corroborated the growth-inhibitory potential of these hybrids. Compounds with R = 7-Me, R = 5-Cl, and R = 6-Cl demonstrated activity against at least four bacterial isolates but were ineffective against S. typhi at the tested concentration. In contrast, compounds with R = 5-Br, R = 6-F, and R = 6-OMe displayed inhibitory effects against S. typhi, with zone diameters of 11 mm, 7 mm, and 10 mm, respectively. Additionally, the compound with R = 6-OMe exhibited notable inhibition against E. coli, with a zone diameter of 16 mm. However, the compounds with R = 5-Me and R = 7-Cl did not exhibit inhibitory activity against any of the tested strains. These results clearly indicate the importance of different substitutions on isatin aryl ring.[70]

N- and C3-Functionalization

N-(2-Phenoxyethyl)isatin-3-hydrazones 27 (Figure [18]) were synthesized through the condensation reaction of N-(2-phenoxyethyl)isatins 14 with various acid hydrazides.[71] Upon evaluation for α-glucosidase enzyme inhibition, all the synthesized compounds exhibited significant inhibitory activity, with IC₅₀ values ranging from 3.64 to 94.89 μM when compared to the standard α-glucosidase inhibitor, acarbose (IC₅₀ = 873.34 μM). Among the series, hydrazone 27a demonstrated the highest potency, with an IC₅₀ value of 3.64 μM. A detailed analysis of the IC₅₀ values suggested that halogen substituents, particularly a chloro group at C4 of the N-phenoxyethyl group or a bromo group at C4 of the phenyl ring in the hydrazide moiety, generally enhanced α-glucosidase inhibitory activity, thereby improving the biological efficacy of these compounds. Notably, while the hydrazones 27 exhibited a modest increase in activity compared to the N-(2-phenoxyethyl)isatins 14, the improvement was still noticeable. Molecular docking studies revealed a binding energy of –9.7 kcal/mol for 27a, which slightly surpassed that of acarbose (–9.4 kcal/mol). Unlike acarbose, which predominantly forms hydrogen bonds, the binding interactions of 27a were largely driven by π-interactions (vide supra). Additionally, ADMET profiling indicated favorable pharmacokinetic properties for these compounds, including good oral bioavailability, optimal hydrophilicity, and minimal predicted toxicity.[71]

Similarly, N-ester-substituted isatin-3-hydrazones 28 (Figure [19]) were synthesized and evaluated for their inhibitory activity against α-amylase and α-glucosidase.[72] Of the ten compounds tested, three 28a, 28b, and 28c demonstrated potent α-amylase inhibition, with IC₅₀ values of 19.6 μM, 12.1 μM, and 18.3 μM, respectively, surpassing the efficacy of acarbose (IC₅₀ = 36.2 μM). SAR analysis revealed that compounds 4-chlorophenyl 28b and 3-chlorophenyl 28c, containing electron-withdrawing chloro substituents, were the most potent α-amylase inhibitors in the series; in contrast, C2 chloro substitution resulted in less than 50% α-amylase inhibition (39.34%) and was considered inactive. Notably, 4-bromophenyl compound 28a displayed significant activity, though slightly less potent than 28b and 28c. These results indicate that the nature and position of substituents on the phenyl ring of the hydrazide moiety significantly influence the α-amylase inhibition potential of these compounds.[72]

Regarding α-glucosidase inhibition, five out of the ten compounds tested, 28d, 28e, 28f, 28g, and 28h showed potent activity, with IC₅₀ values ranging from 14.8 to 25.6 μM, outperforming acarbose (IC₅₀ = 34.5 μM). SAR studies for α-glucosidase inhibition revealed that the nature of the aryl ring, along with the position and type of substituents on the phenyl ring, played a crucial role in modulating bioactivity. For example, 2-chlorophenyl 28f and 4-chlorophenyl 28g exhibited excellent α-glucosidase inhibitory activity. In contrast, 3-chlorophenyl 28c was found to be inactive, displaying only 45.8% inhibition of α-glucosidase. Interestingly, 28c was one of the three compounds that exhibited nearly twofold better α-amylase inhibition than acarbose. These findings highlight the importance of electron-withdrawing substituents, especially chloro and bromo groups at C4 of the phenyl group, in enhancing both α-amylase and α-glucosidase inhibitory activities. Furthermore, this study demonstrated that selective inhibitors for α-amylase or α-glucosidase can be obtained by strategically modifying the position of substituents on the phenyl ring. Notably, compound 2-chlorophenyl 28f and 3-chlorophenyl 28c were found to be selective inhibitors for α-glucosidase and α-amylase, respectively.[72]

Owing to the exceptional potential of hydrazones for π-π interactions (vide supra), hydrophobic interactions (including π-sigma, π-π, π-anion, and π-alkyl interactions) played a dominant role in the binding of hydrazones 28 to their target proteins, with no significant hydrogen bonding observed. These hydrophobic interactions are attributed to the perfect fit of the isatin-hydrazone moiety within the hydrophobic pocket of the enzyme active site. Among the compounds tested, 3-chlorophenyl compound 28c exhibited the highest binding affinity with α-amylase. This binding is largely attributed to π-π interactions between the isatin ring and the imidazole of histidine (A:201) as well as the phenyl ring of tyrosine (A:62). Additionally, the isatin ring forms a π-alkyl interaction with lysine (A:200). The 3-chloro substitution further enhances binding by introducing an additional π-alkyl interaction between the chlorine atom and leucine (A:165). Other interactions, including van der Waals forces, also contribute to the overall binding affinity. In the case of α-glucosidase, 2-chlorophenyl compound 28f adopts a stacking orientation such that, in addition to the isatin ring, the phenyl ring also participates in a π-π interaction with the phenylalanine ring (A:536). This arrangement further strengthens the binding of compound 28f to α-glucosidase.[72]

Isatins-3-hydrazones having 5-amino-1,3,4-thiadiazole pendant 29 (Figure [20]) showed polypharmacological potential when evaluated in a cell-painting assay.[73] The synthetic strategy involved the independent preparation of 5-amino-1,3,4-thiadiazole-2-thiol and 1-(2-bromoethyl)isatin intermediates from thiosemicarbazide and isatin, respectively. These intermediates on coupling together yielded the 5-amino-1,3,4-thiadiazole-appended isatin, which was subsequently condensed with various benzoic acid hydrazides to afford 29. In the cell-painting assay, most of the compounds demonstrated a high hit rate, ranging from 55% to 80% at varying concentrations. Among the 11 compounds that demonstrated activity at 10 μM with an induction value exceeding 5%, eight exhibited the highest biosimilarity to the antifungal agent itraconazole (ITZ), with calculated biosimilarity values ranging from 76.7% to 84.3%. It is important to note that none of the eight compounds exhibited a chemical similarity exceeding 20% to ITZ, suggesting that the hydrazones 29 represent a novel chemotype with potential antifungal activity. Among the four most potent compounds 29a–d, compound 29d, which exhibited the highest induction value at 50 μM, demonstrated 83% biosimilarity but only 18% structural similarity to BI-6901, a chemokine receptor CCR10 inhibitor currently under investigation for various therapeutic applications. Evaluation of anticancer activity of 29 via MTT assays against human breast cancer (MDA-MB-231) and colorectal carcinoma (HCT116) cell lines revealed that 29d displayed the highest antiproliferative activity, inhibiting MDA-MB-231 and HCT116 by 79% and 85%, respectively.[73]

During molecular docking studies, the top four compounds, 29a–d exhibited binding energies between –8.6 and –9.7 kcal/mol, compared to –12.1 kcal/mol for ITZ. The ranking order was 29a > 29b > 29d > 29c. ITZ formed diverse π-cation and π-alkyl interactions with key residues such as GLY 65, MET 508, ALA 61, and TYR 118, contributing to its strong binding affinity. 4-Chlorophenyl compound 29b (–9.7 kcal/mol) engaged in hydrogen bonding (HIS 468, PHE 463) and π-sulfur interactions (CYS 470), enhancing specificity and stability. Similarly, 4-methylphenyl compound 29a (–9.6 kcal/mol) interacted with GLY 303, GLY 308, and several alkyl residues, while 2-methoxyphenyl compound 29d (–8.8 kcal/mol) formed strong hydrogen bonds (HIS 468, GLY 472) and π-sulfur interactions with CYS 470.[73]

In the chemokine receptor complex, 29d demonstrated a binding energy of –9.2 kcal/mol, which is comparable to that of BI-6901 (–9.4 kcal/mol). BI-6901 formed π-sulfur, π-π stacking, and alkyl interactions with residues such as TYR 89, TRP 86, and LYS 26. In contrast, 29d displayed strong hydrogen bonding (THR 105, SER 179) and π-alkyl interactions with key residues, suggesting stable and effective binding. SAR analysis highlighted the critical role of substituents on the thiadiazole–isatin scaffold in modulating bioactivity. Notably, the 2-methoxyphenyl ring in 29d contributed to its high binding affinity and hydrophobic interactions, mirroring the behavior of BI-6901.[73]

Leishmaniasis, one of the six major tropical diseases affecting approximately millions of people annually. Coumarin-incorporated isatin hydrazones 30 (Figure [21]) were synthesized as potent and safe antileishmanial agents.[74] The synthesis involved the reaction of 4-(oxiran-2-ylmethoxy)-2H-chromen-2-one with isatin to form an intermediate, which was then condensed with various acid hydrazides to produce 30. Molecular docking studies were initially performed to explore the binding conformations of the lead compounds within the active site of the target protein, Leishmanolysin gp63, from Leishmania tropica. Among the docked compounds, 30a, 30b, and 30c exhibited the highest binding affinities, attributed to strong conventional hydrogen bonds and hydrophobic π-interactions. Molecular dynamics simulations over a 50 ns timescale revealed stable binding patterns and structural integrity for the top compound, 30c, in complex with the protein, confirming the high stability of the system. Of the ten compounds evaluated for antileishmanial activity against Leishmania tropica promastigotes and amastigotes, three demonstrated significant activity at micromolar concentrations (IC₅₀ range 0.1–4.13 μmol/L) when compared to tartaric acid (TA) and amphotericin B (AmB). Furthermore, these compounds were found to exhibit high biocompatibility, as assessed by their low toxicity in human erythrocytes.[74]

DNA binding is a critical factor in the development of novel anticancer agents, as it plays a central role in the mechanism of action for many chemotherapeutic drugs.[75] s-Triazine-isatin hydrazones 31 (Figure [22]) were synthesized by reacting an N-(4-bromophenyl)acetamide pendant isatin with a series of diphenoxy-linked hydrazinyl s-triazines.[76] Their binding interactions with salmon sperm DNA (SS-DNA) were explored at physiological conditions (pH 7.4) using UV-Vis absorption spectroscopy. The results confirmed that hydrazones 31 exhibit strong DNA-binding activity, as evidenced by absorption and intensity shifts that suggest groove-binding interactions with SS-DNA. The binding constants (K _b) of the synthesized hydrazones, calculated from the Benesi–Hildebrand plot, ranged from 10⁴ to 10⁵ M^–1. Among them, hydrazone 31a exhibited the highest binding constant (9.51 × 10⁵ M^–1) at 298 K, exceeding that of the reference compound cabozantinib. The Gibbs free energy change (ΔG) for the binding interaction of 31a was calculated to be –34.1 kJ/mol, indicating a thermodynamically spontaneous process. Molecular docking studies demonstrated notable binding affinities of all compounds toward double-helical DNA, with docking scores ranging from –8.5 to –10.3 kcal/mol. These docking results were consistent with experimental findings, with compound 31a showing the highest docking score of –10.3 kcal/mol. The docking studies further highlighted hydrophobic interactions, including π-π interactions and hydrogen bonding within the AT-rich region of the DNA grooves.[76]

The N-substituted isatin derivatives 32 (Figure [23]) were synthesized via a one-pot, multicomponent reaction involving isatins, 2-(piperazin-1-yl)quinoxaline, formaldehyde, and metformin in the presence of a nanocatalyst.[77] The resulting compounds were evaluated for anticancer activity against human ovarian (SKOV3) and colon-derived (HCT116) tumor cell lines using the MTT colorimetric assay. While most of the compounds exhibited excellent antiproliferative activity and high selectivity index (SI) values, compounds 32a and 32b emerged as the most potent antiproliferative agents. These compounds, containing halogen-substitution on isatin, demonstrated the lowest IC₅₀ values: 0.39 and 0.45 μM in HCT116 cells, and 0.44 and 0.48 μM in SCOV3 cells, respectively. Molecular docking and dynamic simulation studies indicated that these hybrid compounds can be efficiently accommodated in the catalytic cavity of the c-Kit tyrosine kinase receptor and the binding pocket of P-glycoprotein, with high binding scores.[77]

A series of mono- and bis-thiosemicarbazones 33 and 34 (Figure [24]) derived from two distinct types of isatin-triazole hybrids, incorporating either a one- or two-carbon chain linker between isatin and triazole, were synthesized via copper-catalyzed azide-alkyne cycloaddition (CuAAC), followed by condensation with various thiosemicarbazides.[78] Theoretical global reactivity analyses indicated that among the synthesized compounds, 33a, 33b, and 34a, all having nitro substituents, were the most soft, with compound 34a displaying the greatest electronegativity and electrophilicity index values, suggesting a strong binding affinity for biomolecules. Molecular docking studies against the active site of phosphoinositide 3-kinase (PI3K), a key anticancer target, demonstrated strong binding interactions. Compound 34a exhibited the highest binding energy (–10.3 kcal/mol), followed by compound 33b (–8.9 kcal/mol) and compound 33a (–8.6 kcal/mol). The binding interactions included hydrophobic interactions, hydrogen bonding, donor-acceptor atom interactions, and π-π stacking. Specifically, compound 34a formed hydrogen bonds with His 670(A), Met 811(A), Ile 633(A), Leu 632(A), and Cys 838(A) via the nitrogen of the thiosemicarbazone NH group and the oxygen of the nitro substituent. Additionally, Gly 837(A) formed C–H bonds, while Glu 172(A) and Glu 821(A) exhibited π-sulfur and π-anion interactions. Phe 666(A) engaged in π-alkyl and π-π stacking interactions with the benzene ring.[78]

Similarly, the mono-thiosemicarbazone derivative 33b, which displayed the second-highest binding score, formed hydrogen bonds via the carbonyl oxygen of isatin, the nitrogen of the 1,2,3-triazole ring, and the NH of the thiosemicarbazone moiety with Lys 548(A), Asn 575(A), and Tyr 361(A), respectively. Additionally, compound 33b exhibited C–H bonding, π-alkyl interactions, and salt bridge interactions with PI3K active site residues. Interestingly, isatin-triazole intermediates lacking the thiosemicarbazone scaffold were significantly less effective than their thiosemicarbazone derivatives. These findings highlight the critical role of thiosemicarbazones and the influence of aryl ring substitutions in enhancing target binding interactions (vide supra). Notably, compound 34a emerges as a promising anticancer scaffold, potentially exerting its activity through PI3K signaling pathway inhibition.[78]

C5-, C5,N-, and C5,N,C3-Functionalization

Isatin was among the first reversible inhibitors for which the X-ray crystal structure in complex with human monoamine oxidase B (MAO-B) was determined.[41a] It exhibited inhibitory activity with IC₅₀ values of 15 μM for MAO-A and 3 μM for MAO-B (Figure [25]). Similarly, 5-hydroxyisatin was reported to inhibit human MAO-A with an IC₅₀ value of 8.4 μM, while its inhibition of MAO-B was weak (IC₅₀ >100 μM) (Figure [25]).[79] Several isatin derivatives have demonstrated potent MAO inhibition. For instance, 5-(benzyloxy)isatin exhibited IC₅₀ values of 4.62 μM for MAO-A and 0.103 μM for MAO-B, whereas 6-(benzyloxy)isatin inhibited MAO-A and MAO-B with IC₅₀ values of 72.4 μM and 0.138 μM, respectively (Figure [25]).[80] More recently, a variety of isatin derivatives with different substituents at various positions on the aryl ring of isatin were evaluated as in vitro inhibitors of human MAO-A and MAO-B, revealing that five compounds exhibited IC₅₀ values below 1 μM.[41b] Among them, 4-chloroisatin and 5-bromoisatin were identified as the most potent inhibitors, with IC₅₀ values of 0.812 μM and 0.125 μM for MAO-A and MAO-B, respectively (Figure [25]). These compounds were also found to act as competitive inhibitors of MAO-A and MAO-B, with K_i values of 0.311 μM and 0.033 μM, respectively. SAR analysis indicated that substitution at the C5 position significantly enhanced MAO-B inhibition.[41b]

A series of N-alkylated isatin-5-sulfonamides 35 (Figure [26]) were synthesized through sulfochlorination of isatin, followed by treatment of the intermediates with ammonia to yield isatin-5-sulfonamides. Alkylation of these sulfonamides then produced a library of N-alkylated derivatives 35.[81] The synthesized compounds were evaluated for their inhibitory activity against carbonic anhydrase (CA) isoforms I, II, IX, and XII. The compounds displayed varying degrees of inhibition, with the most potent inhibitors of CA I and II isoforms being those containing hydrophobic substituents, such as phenyl groups (35a, K_i = 80.4 and 4.2 nM, respectively) and fluorinated benzyl derivatives (35b, K_i = 39.5 and 3.5 nM, respectively) as compared to acetazolamide (AAZ) (K_i = 250 and 12.1 nM, respectively). In contrast, CA IX was potently inhibited by perfluorinated derivative 35c (K_i = 194.9 nM), showing enhanced activity compared to the unsubstituted benzyl derivative 35a (K_i = 1529 nM). Chlorine-substituted derivatives, such as 35d (K_i = 162.5 nM) also demonstrated good activity against CA IX as compared to AZZ (K_i = 25.7 nM) (Figure [26]).[81]

The N-alkylated isatin-5-sulfonamides 35 were also evaluated for their antiproliferative activity against a panel of MCF7, K-562, and K-562/4 cell lines. Overall, these compounds demonstrated greater efficacy in inhibiting the growth of MCF7 cells compared to K-562 and K-562/4 cells. Notably, 9 out of 22 compounds exhibited growth inhibition of MCF7 cells at concentrations below 10 μM, while retaining activity against resistant cell lines and under hypoxic conditions. Molecular docking studies revealed that the compounds bind to the active sites of carbonic anhydrase II (CA II) and carbonic anhydrase IX (CA IX) via coordination of the sulfonamidate anions with zinc cations, accompanied by additional hydrophobic interactions, which contribute to their inhibitory potency.[81]

The 3C-like protease (3CLpro) of SARS-CoV-2 is a critical enzyme in the viral replication cycle and is considered a primary target for therapeutic intervention against COVID-19. The N-substituted isatin derivative 36 (Figure [27]) demonstrated potent inhibition of SARS-CoV-2 3CLpro. However, 36 exhibited poor antiviral activity in cellular assays and displayed high cytotoxicity.[82] Resultantly, isatin derivatives 37 (Figure [27]) were synthesized from isatin-5-carboxamide by reacting it with 3-bromopropyne to introduce a propargyl group at the N-position. The resulting derivatives were then subjected to a click chemistry with various hydrazides, yielding a set of isatin derivatives that exhibited potent inhibitory activity against SARS-CoV-2 3CLpro, as assessed by a fluorescence resonance energy transfer (FRET)-based enzymatic assay.[83]

Compounds 37a (IC₅₀ = 0.44 μM) and 37b (IC₅₀ = 0.53 μM) exhibited excellent inhibitory potency, comparable to that of 36 (IC₅₀ = 0.30 μM). Notably, both 37a and 37b demonstrated significantly reduced cytotoxicity (CC₅₀ > 20 μM) compared to 36. Despite these promising inhibitory activities, the compounds did not show significant anti-SARS-CoV-2 activity at concentrations up to 20 μM, similar to 36. Molecular dynamics (MD) simulations highlighted the balance between hydrogen-bonding and hydrophobic interactions. Additionally, a DTT-dependent assay indicated that these isatin derivatives are likely to be specific inhibitors of the 3CLpro protease, although their activity was slightly influenced by interactions with dl-dithiothreitol (DTT).[83]

A series of N-alkylated isatin-5-functionalized derivatives 38 and 39 (Figure [28]) with promising antitumor activity were synthesized.[84] N-Alkylation of 5-bromoisatin was achieved by reacting it with 1-(chloromethyl)-4-methoxybenzene. The C7 of 5-bromoisatin was nitrated using Calvary’s method, followed by a similar alkylation to produce the 7-nitro derivative. These intermediates underwent Suzuki coupling with various substituted phenylboronic acids, resulting in 5- and 7-substituted isatin derivatives 38 and 39. Evaluation of these compounds against multiple cell lines identified compound 38 as the most promising candidate, exhibiting significant inhibitory activity against colorectal cancer (CRC). Compound 39a, the nitro derivative, also showed good activity; however, its amino analogue, 39b, demonstrated poor activity (Figure [28]). The cytotoxicity profile of the synthesized isatin derivatives revealed that 38 exhibited lower IC₅₀ values in HUVEC and HK2 cells compared to the positive control sunitinib, indicating reduced cytotoxicity in normal cells. In CRC cell line HCT-116, 38 demonstrated the most potent inhibitory effect, with an IC₅₀ value of 0.33 μM, highlighting its selective and effective action against cancer cells. The anticancer effects of 38 were primarily attributed to its ability to inhibit tubulin expression, induce apoptosis, and cause G2/M cell cycle arrest. Based on these promising results, a peptide-drug conjugate, A6-38, was developed by coupling the CD44 ligand peptide A6 to 38. The A6 peptide facilitates the selective targeting of CRC cells through its affinity for the CD44 receptor, enhancing the specificity and therapeutic potential of the drug. Both in vitro and in vivo studies demonstrated that A6-38 significantly inhibited tumor growth and metastasis in CRC cells, further confirming 38 as the payload and A6 as the targeting moiety for selective drug delivery.[84]

Mechanistically, treatment with 38 resulted in a significant inhibition of β-tubulin expression, as evidenced by Western blot analysis, leading to microtubule destabilization. This disruption of microtubule dynamics interferes with essential cellular processes, ultimately triggering apoptosis through the activation of caspase-3 and PARP cleavage. Furthermore, 38 induced a shift in the Bcl-2/Bax ratio, activating the intrinsic apoptotic pathway. Treatment with 38 also resulted in changes in cell cycle regulation, including a decrease in CDK1 expression and an increase in cyclin B1, suggesting the blockade of the G2/M checkpoint. Notably, P53-mediated signaling was activated, as demonstrated by increased levels of P21 and P53, further contributing to the regulation of cell cycle progression and enhancing the anticancer effects.[84]

Coordination Chemistry of Isatin Scaffold Derived Compounds

The complexation of organic ligands with metal ions is a fundamental strategy for modifying physicochemical properties, stabilizing molecular conformation, and regulating biomolecular interactions.[53] Ligands with coordination sites facilitate metal uptake by cells and organelles, potentially influencing biological activity. Structural modifications, particularly the incorporation of additional coordination sites, can enhance ligand performance. The rational design of bi-, tri-, or polydentate ligands, tailored to specific metal ions and biological targets, is essential for developing more efficient and selective metallodrugs and biomimetic complexes. In this context, a significant number of metal complexes incorporating isatin-based ligands, particularly Schiff bases, hydrazones, and thiosemicarbazones, have been reported. These complexes, predominantly formed with transition metals such as manganese(II), cobalt(II), nickel(II), and copper(II), exhibit diverse coordination geometries and reactivities.[53] Therefore, the isatin scaffold and its derivatives possess considerable potential for coordination with metal ions, further expanding their applicability in metallopharmaceutical and bioinorganic chemistry.

For example, the copper complexes of isatin bis-Schiff bases 25 (Figure [29]) were synthesized via a stoichiometric reaction of copper chloride with the ligands in a 1:2 molar ratio.[69] These air-stable, colored crystalline solids decompose above 300 °C without melting and exhibit solubility in DMSO and DMF while remaining insoluble in common organic solvents. Their solubility behavior and analytical data suggested a monomeric nature. Molar conductance values (6.01–38.7 Ω^–1 cm² mol^–1) in DMSO (1 × 10^–3 M, 23 °C) established their non-electrolytic character. Elemental analysis also confirmed the proposed formula [Cu(L)₂Cl₂].[69]

The synthesized Cu(II) complexes 25·Cu were evaluated for their antiproliferative activity against lung carcinoma (H157) cells, demonstrating enhanced cytotoxicity compared to their parent Schiff base ligands. Coordination with the metal ion significantly improved activity,[85] with IC₅₀ values ranging from 1.29 to 2.87 μM, as opposed to 2.32 to 3.88 μM for the free ligands. Notably, 5-chloroisatin complex 25d·Cu exhibited the highest potency (IC₅₀ = 1.29 μM), despite being less lipophilic than 25b·Cu (IC₅₀ = 1.54 μM). This discrepancy was attributed to differences in enzyme interaction and apoptosis induction mechanisms. Compounds 25a·Cu and 25c·Cu also showed strong inhibition (IC₅₀ = 1.93 and 1.47 μM, respectively), while 25e–g·Cu retained moderate potency (IC₅₀ = 2.32–2.87 μM), still outperforming their parent ligands. The improved cytotoxicity of the complexes is likely due to their increased lipophilicity, facilitating membrane permeability and receptor binding.[69]

Additionally, the urease inhibitory activity of these complexes was assessed against Jack bean urease, revealing a general decline in enzymatic inhibition upon metal coordination when compared to the parent ligands (Figure [29]). Complexes 25b–d·Cu, 25f·Cu, and 25g·Cu exhibited significantly reduced activity (<50%), whereas their corresponding ligands displayed high potency (IC₅₀ = 0.04–5.86 μM). Similarly, complexation of ligand 25a with Cu(II) resulted in a notable loss of activity (IC₅₀ = 1.15 → 26.1 μM). In contrast, complex 25e·Cu showed an increase in inhibitory activity (IC₅₀ = 0.34 → 0.03 μM), suggesting a unique structural influence on enzyme binding.[69]

Conclusions and Outlook

In conclusion, we have provided a concise overview of the isatin scaffold, emphasizing its synthetic versatility, reactivity, and structural significance. A variety of well-established methods enable the synthesis of both simple and functionalized isatin derivatives, typically starting from aniline and their functionalized analogs. Furthermore, the intrinsic reactivity of the isatin scaffold allows for extensive structural modifications at the N-position, C3 position, and aryl ring. The N-position undergoes diverse transformations, including alkylation, aminomethylation, arylation, acylation, sulfonylation, carbamoylation, aza-Michael, and Mannich reactions, enabling the development of a broad range of derivatives. The C3 position participates in nucleophilic addition and condensation reactions such as the Morita­–Baylis–Hillman reaction, various multicomponent reactions (Ugi, Passerini, and other isocyanide-based reactions), 1,3-dipolar cycloaddition, aldol reaction, Knoevenagel condensation, and Wittig reaction, leading to the formation of hydrazones, thiosemicarbazones, Schiff bases, spiro compounds, and a variety of other compounds. Additionally, the aryl ring of isatin undergoes electrophilic and cross-coupling reactions, including nitration, halogenation, sulfonation, Friedel–Crafts alkylation, Suzuki coupling, and Heck coupling, further expanding its chemical space. Most importantly, a key feature of the isatin scaffold, i.e., its ability to undergo ring opening under specific conditions, facilitates ring expansion reactions, leading to the formation of various biologically significant heterocycles.

Beyond its easy accessibility, synthetic versatility, and reactivity, the isatin scaffold exhibits distinct structural features that enhance its biological potential. It functions as both a hydrogen bond donor and acceptor and has the ability to engage in strong π–π interactions as well as C=O···C=O interactions. Moreover, key isatin derivatives, such as hydrazones and thiosemicarbazones, not only contribute to structural stability but also introduce additional functionalities that strengthen interactions with biological targets. Notably, these derivatives can act as mono-, bi-, and tridentate ligands, forming metal complexes of immense biological importance.

Ongoing research is focusing on exploring the potential of this natural scaffold by leveraging the development of innovative chemical reactions, the discovery of various multicomponent reactions, and advancements in bioorthogonal chemistry. These approaches facilitate the creation of more effective drug candidates through the hybridization of this scaffold with a range of biologically significant heterocycles or pharmacophores, particularly for the design of multitarget-directed ligands (MTDLs). MTDLs offer a comprehensive strategy for addressing the complex and multifactorial nature of various modern diseases. Unlike conventional therapies that target single pathways, MTDLs possess the unique ability to simultaneously modulate multiple disease targets. Moreover, advancements in computational modeling and machine learning are significantly enhancing our understanding of how isatin derivatives interact with biological targets, thereby improving structure-activity relationship studies and enabling the design of more precise and effective drug candidates. Additionally, the coordination of isatin derivatives with different metals presents further opportunities for exploration in drug development. As advancements in chemistry, biology, and technology continue, isatin remains a key scaffold for future therapeutic innovations, driving the development of more effective and targeted treatments.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

M.M.N. acknowledge the contributions made by all our co-workers in the field. The names of the co-workers can be found in the respective citations.

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Corresponding Author

Publication History

Received: 28 February 2025

Accepted after revision: 28 April 2025

Accepted Manuscript online:
28 April 2025

Article published online:
03 July 2025

© 2025. Thieme. All rights reserved

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