Isatin Derivatives Research Articles

Synthesis, structure elucidation, antioxidant properties, and theoretical calculations of new Schiff bases–isatin derivatives

Isatin-derived Schiff bases are the subject of many studies, finding wide application areas in polymer technology, pharmaceutical industry, and medicine. In this study, a series of new Schiff bases were prepared from monothiocarbohydrazones based on isatins with different substituents (5-F, 5-Br, 5-I, and 5-MeO). The chemical structures of the synthesized compounds were determined using 1H NMR, 13C NMR, FTIR spectroscopic techniques, and elemental analysis. Antioxidant activity determinations of 23 compounds were performed using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical quenching method. The highest percent inhibition value at 10 µM concentration was shown by compound number 22, 5-bromoisatin Schiff base containing 3-methoxy-4-hydroxy group. Compound 17, a 5-iodoisatin Schiff base containing 3-methoxy-4-hydroxy group, showed the highest antioxidant activity with an IC50 value of 9.76 ± 0.03 µM. In addition to the theoretical analysis of the compounds, both their spectroscopic and antioxidant properties were investigated. The ground-state geometries and some chemical reactivity parameters of the compounds were calculated using the B3LYP/6-311 + + G(2d,2p) approach. Besides intramolecular interactions, substituent effects, and some QTAIM parameters, the calculations were also performed to study the electronic properties of reactive N/O–H bonds and were used to interpret the experimental results. The effects of the electronic parameters and intramolecular interactions of reactive N/O–H bonds on the antioxidant properties of the compounds were investigated. Additionally, the relationships of DPPH reactions with delocalization indices of N/O-H bonds and the pattern of SET/HAT mechanisms with electronic variables were analyzed. Examination of electron and hydrogen atom transfer mechanisms has shown the dominance of electron transfer, supported by the correlation coefficients between IC50 values and SET reaction energies.

Synthesis, Invitro Cytotoxic Activity and Optical Analysis of Substituted Schiff Base Derivatives.

Fluorescent cytotoxic compounds with readout delivery are crucial in chemotherapy. The growing demands of these treatment strategies require the novel heterocyclic molecules with better selectivity alongside fluorescence marker potential. In this context, a series of nine isatin Schiff base derivatives 4a-i were synthesized, characterized and evaluated for UV-visible, fluorescence, thermal and bioanalysis in order to explore the effect of structure on their bioprofiles. The analogue 4d exhibited maximum cytotoxic activity on Hella cells with percentage inhibition of 83% at 50 µM and 100% at 150 µM concentrations while 4c showed minimum cytotoxic activity with the value of 19% at 50 µM and 22% at 150 µM concentrations. Meanwhile, 4g was found to exhibit maximum inhibition potential towards Vero Cells with the percentage inhibition values of 83 at 50 µM concentration. The overall SAR study showed that the para-fluoro-substituted isatin moieties exhibited the appreciable percentage inhibition while the least activity was delivered by the isatin derivatives with para-bromo substitution.

One-pot Multicomponent Synthesis and Biological Activity of Oxindole- linked Isatin Schiff Bases Derivatives

The study focuses on the synthesis of isatin- oxindole compounds through a two-step process. In the first step, using mannich reaction, new derivatives of Isatin are synthesized by reacting Isatin with either oxindole, along with formaldehyde. This reaction results in the formation of Isatin- oxindole derivative. In the second step, these Isatin derivatives are further reacted with various aniline derivatives to generate new compounds containing Isatin. The synthesized compounds are characterized using spectroscopic techniques such as FTIR, 1H NMR, and 13C NMR. The study also explores the biological activity of some of the synthesized compounds against specific bacteria strains, such as Klebsiella pneumoniae and Staphylococcus aureus. These compounds are assessed for their potential antimicrobial properties.

Thiazole, Isatin and Phthalimide Derivatives Tested in vivo against Cancer Models: A Literature Review of the Last Six Years.

Cancer is a disease characterized by the abnormal multiplication of cells and is the second leading cause of death in the world. The search for new effective and safe anticancer compounds is ongoing due to factors such as low selectivity, high toxicity, and multidrug resistance. Thus, heterocyclic compounds derived from isatin, thiazole and phthalimide that have achieved promising in vitro anticancer activity have been tested in vivo and in clinical trials. This review focused on the compilation of promising data from thiazole, isatin, and phthalimide derivatives, reported in the literature between 2015 and 2022, with in vivo anticancer activity and clinical trials. A bibliographic search was carried out in the PUBMED, MEDLINE, ELSEVIER, and CAPES PERIODIC databases, selecting relevant works for each pharmacophoric group with in vivo antitumor activity in the last 6 years. In our study, 68 articles that fit the scope were selected and critically analyzed. These articles were organized considering the type of antitumor activity and their year of publication. Some compounds reported here demonstrated potent antitumor activity against several tumor types. This review allowed us to highlight works that reported promising structures for the treatment of various cancer types and also demonstrated that the privileged structures thiazole, isatin and phthalimide are important in the design of new syntheses and molecular optimization of compounds with antitumor activity.

Efficient Synthesis of Cyclohepta[b]indoles and Cyclohepta[b]indole-Indoline Conjugates via RCM, Hydrogenation, and Acid-Catalyzed Ring Expansion: A Biomimetic Approach.

Cyclohepta[b]indoles, prevalent in natural products and pharmaceuticals, are conventionally accessed via metal or Lewis acid-mediated cycloadditions with prefunctionalized substrates. Our study introduces an innovative sequential catalytic assembly for synthesizing cyclohepta[b]indoles from readily available isatin derivatives. The process involves three catalytic sequences: ring-closing metathesis, catalytic hydrogenation, and acid-catalyzed ring expansion. The RCM of 2,2-dialkene-3-oxindoles, formed by butenyl Grignard addition to 3-allyl-3-hydroxy-2-oxindoles, yields versatile spirocyclohexene-3-oxindole derivatives. These derivatives undergo further transformations, including dibromination, dihydroxylation, epoxidation, Wacker oxidation at the double bond. Hydrogenation of spirocyclohexene-3-oxindole yields spirocyclohexane-3-oxindoles. Their subsequent acid-catalyzed ring expansion/aromatization, dependent on the acid catalyst, results in either cyclohepta[b]indoles or cyclohepta[b]indole-indoline conjugates, adding a unique synthetic dimension. The utility of this methodology is exemplified through the synthesis of an A-FABP inhibitor, showcasing its potential in pharmaceutical applications.

Thermally generated bromine “Cation Pool-”mediated oxidation of indole to 2-oxindole

Unlike the electrolytic generation of bromine cation pool, thermally generated bromine cation pool was employed for regioselective oxidation of indole to 2-oxindole at room temperature. A combination of DMSO, DBE, and morpholine at 80 °C generates the bromine cation pool, which in turn was utilized for bromination followed by hydroxylation by water through a dearomatization and rearomatization pathway to afford the desired 2-oxindoles. At higher temperature the in situ generated 2-oxindoles undergo α-bromination followed by DMSO-mediated Kornblum oxidation to afford isatin derivatives. This bromine cation pool strategy was further exploited for one-pot synthesis of spirooxindole under metal-free conditions.

One Pot Synthesis and Biological Activity Studies of New Spirooxindoles.

This article reports one-pot synthesis of ten novel spirooxindoles using 5-methyl-2-thiohydantoin, isatin derivatives, and malononitrile in good to high yields (65-90 %). The structures of the synthesized compounds were deduced by 1H-NMR, 13C NMR, FT-IR, and Mass spectral data. The antibacterial activity of the compounds was evaluated against two Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) and two Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) based on the Kirby-Bauer method. According to the obtained data, the synthesized compounds show more activity against Gram-positive bacteria than Gram-negative bacteria. Also, the antioxidant activity of these compounds was measured using the DPPH radical scavenging test method, which showed good to excellent activity (59.65-94.03 %). Among them, the chlorinated derivatives (4 f-j) exhibited more antioxidant activity (84.85-94.03 %) than the other compounds (4 a-e) (56.65-74.4 %) and even ascorbic acid as a standard antioxidant compound (82.3 %).

Design, synthesis, in vitro and in silico evaluations of new isatin-triazine- aniline hybrids as potent anti- Alzheimer multi-target directed lead compounds

Multi target directed ligands (MTDLs) are one of the promising tools for treatment of complex disease like Alzheimer’s disease (AD). In this study, using rational design, we synthesized new 15 hybrids of the s-triazine, isatin and aniline derivatives as anti- AD compounds. The design was as way as that new compounds could had anti cholinesterase (ChE), antioxidant and biometal chelation ability. In vitro biological evaluation against ChE enzymes showed that these molecules were excellent inhibitors with IC50 values ranging from 0.2 nM to 734.5 nM for acetylcholinesterase (AChE), and 0.02 μM to 1.92 μM for butyrylcholinesterase (BChE). Among these compounds, 8 l with IC50 AChE = 0.7 nM, IC50 BChE = 0.09 μM and 8n with IC50 AChE = 0.2 nM, IC50 BChE = 0.03 μM were the most potent compounds. In silico studies showed that these molecules had key and effective interactions with the corresponding enzymes residues. The molecules with hydroxyl group on aniline moiety had also good antioxidant activity with EC50 values ranging from 64.2 μM to 103.6 μM. The UV–Vis spectroscopy study revealed that molecule 8n was also able to chelate biometals such as Zn2+, Cu2+and Fe2+ properly. It was concluded that these molecules could be excellent lead compounds for future studies.

Synthesis of spiro-oxindole-based chemosensor for detection of Hg2+ ions using SBA-Pr-N-IS-Bu-SO3H

Spiro-oxindoles were prepared efficiently via multicomponent reactions (MCRs) for finding the new chemosensors. Also, the use of the efficient nanocatalysts based on SBA-15 in these reactions are so important. Therefore, the functionalization of SBA-15 by different organic compounds are common to produce new efficient nanocatalysts. Herein, SBA-Pr-N-Is-Bu-SO3H as an efficient nanoporous catalyst was applied in the synthesis of (5,6,7,8-tetrahydro-chromene)-4,3′-spirocyclic oxindoles through the three-component reaction of isatin derivatives, malononitrile and dimedone under reflux conditions in high yield and short reaction time. Among all spiro-oxindole derivatives, 2-amino-7,7-dimethyl-5′-nitro-2′,5-dioxo-5,6,7,8-tetrahydro-spiro[chromen-4,3′-indoline]-3-carbonitrile was investigated in fluoresence spectroscopy. According to the obtained results it was observed that in the presence of various cations such as, K+, Ca2+, Na+, Cu2+, Zn2+, Cr3+, Fe3+, Fe2+, Mn2+, Co2+, Al3+, Pb2+, Ag+, Cd2+, Ni2+, Hg2+ and Mg2+, it can selectively detect Hg2+ ion and increase the emission intensity. Its calculated detection limit was 4.6 × 10−7 M, which can be considered a good value. Also, in order to determine the stoichiometric ration for ligand and Hg2+ ion, Job's plot test was performed and the ratio was 1:2.

Isatin Derivatives: A Frontier in Antimicrobial Agents

Abstract: Microbial infection is one of the major concerns for human health in the modern era. Condition is further worsening due to the development of resistance by the microbe against the available drugs. This problem can be overcome by synthesizing novel antimicrobial agents. Isatin is a promising moiety possessing antimicrobial activity. A number of isatin derivatives are present in the market for the treatment of microbial infection. : In this review, we have tried to summarize isatin derivatives as antimicrobials, including numerous potent isatin analogs. The reported literature related to the development and application of isatin derivatives have been collected from electronic data bases like Science Direct, Google Scholar, and PubMed by using key words like “design, synthesis and evaluation”, “isatin derivatives,” and “indoldione analogues” and related combinations. It was identified that isatin derivatives play an essential role in drug discovery and development. In recent years, isatin and its derivatives have shown promising antibacterial and antiviral properties. This review aims to provide an overview of the current research on isatin potential applications. Studies have shown that isatin derivatives can effectively fight against various types of microorganisms, such as gram-negative and gram-positive bacteria. They also exhibit lower toxicity and better efficacy than standard antimicrobial agents. Moreover, isatin-based products have the potential to address the rising issue of antimicrobial resistance. The current work attempts to review such innovations, which may lead to the creation of novel therapeutic agents. More research is required to confirm their safety and effectiveness in clinical practice.

Iodine-catalyzed Synthesis, Antibacterial, and Antioxidant Activity of Isatin Derivatives

Isatin is a unique compound with many bioactivities such as antiviral, anti-HIV, antitumor, anti-inflammatory, anticonvulsant, and antifungal. In this study, isatin derivatives were synthesized with an iodine catalyst and tested for antibacterial and antioxidant activities. Isatin derivatives were conducted through a Knoevenagel condensation reaction between isatin and malononitrile. The products were confirmed by thin-layer chromatography, melting point apparatus, FTIR, UV-vis spectroscopy, and LC-MS. The optimum reaction conditions were obtained at 10% mol of catalyst, at boiling point ethanol solvent for 30 min. The yield of the isatin derivative products was 71% (3a), 61% (3b), and 67% (3c). The antibacterial activities of the synthesized compounds were weak activity against S. aureus and E. coli. The antioxidant activity test resulted in IC50 values of 266.47, 220.43, and 654.85 ppm for compounds 3a, 3b, and 3c, respectively. The synthesis method using an iodine catalyst in this reaction offers a higher product yield compared to a catalyst-free reaction.

Evaluating the corrosion inhibition potential of two innovative N-benzyl-5-bromo isatin derivatives for carbon steel in alkaline environments: insights from DFT, SAR and toxicology

DFT-derived global reactivity indices, structure-activity relationships (SAR), and toxicity parameters have been used to correlate between the corrosion inhibition role of two N-benzyl-5-bromo isatin derivatives namely N-benzyl-5-bromo-3-[(imine aceto) urea]-2-oxo indole (ISAO) and N-benzyl-5-bromo-3-[(imine aceto) thiourea]-2-oxo indole (ISAS) against carbon steel corrosion in an alkaline environment and their electronic properties at molecular scale as well as understanding their impacts on human health. The computed global reactivity indices and SAR parameters establish a direct correlation with previously reported experimental data. Mulliken charge analysis provides helpful insights into the atoms responsible for electronic transfer. The predicted toxicological parameters suggest that the tested corrosion inhibitors pose no significant risk to human health.

Natural Isatin Derivatives Against Black Fungus: In Silico Studies.

During this coronavirus pandemic, when a lot of people are already severely afflicted with SARS-CoV-19, the dispersion of black fungus is making it worse, especially in the Indian subcontinent. Considering this situation, the idea for an in silico study to identify the potential inhibitor against black fungal infection is envisioned and computational analysis has been conducted with isatin derivatives that exhibit considerable antifungal activity. Through this in silico study, several pharmacokinetics properties like absorption, distribution, metabolism, excretion, and toxicity (ADMET) are estimated for various derivatives. Lipinski rules have been used to observe the drug likeliness property, and to study the electronic properties of the molecules, quantum mechanism was analyzed using the density functional theory (DFT). After applying molecular docking of the isatin derivatives with sterol 14-alpha demethylase enzyme of black fungus, a far higher docking affinity score has been observed for the isatin sulfonamide-34 (derivative 1) than the standard fluconazole. Lastly, molecular dynamic (MD) simulation has been performed for 100ns to examine the stability of the proposed drug complex by estimating Root Mean Square Deviation (RMSD), Radius of gyration (Rg), Solvent accessible surface area (SASA), Root Mean Square Fluctuation (RMSF), as well as hydrogen bond. Listed ligands have precisely satisfied every pharmacokinetics requirement for a qualified drug candidate and they are non-toxic, non-carcinogenic, and have high stability. This natural molecule known as isatin derivative 1 has shown the potential of being a drug for fungal treatment. However, the impact of the chemicals on living cells requires more investigation and research.

Molecular docking and synthesis of N-alkyl-isatin-3-imino aromatic amine derivatives and their antileishmanial and cytotoxic activities.

Isatin derivatives have excited attention due to their biological attractions, especially, anticancer properties. Isatin analogs such as semaxanib and sunitinib were exposed to tyrosine kinase inhibitory properties. N-substituted isatins were reported to show cytotoxic activity. On the other, the extension of impressive and cost-effective agents against leishmaniasis is necessary in third-world countries. The capability of isatin derivatives to create novel anticancer and anti-leishmanial compounds has been identified in medicinal chemistry research. The current study aimed to synthesize N-alkyl-isatin-3-imino aromatic amine compounds and evaluate their biological effects. Synthesis started with the formation of 2-chloro-N-phenylacetamide derivatives by the reaction of aniline derivatives with chloroacetyl chloride. N-alkylation of isatin was performed in the presence of K2CO3 in N, N-dimethylformamide. Final products were prepared via the condensation of N-alkyl isatin derivatives with aromatic amines. Cell viability was checked out by using the MTT assay against cancer cells. Final compounds were screened for anti-leishmanial activity. The molecules were docked in the active sites of the epidermal growth factor receptor tyrosine kinase to define the possible interactions. Compounds 5c and 4d with IC50 value of 50 μΜ showed cytotoxic activity on the MCF-7 cell line. Compound 5b presented anti-leishmanial activity against promastigote form after 48 h (IC50:59 μΜ) and 72 h (IC50: 41 μΜ) incubations. The highest docking score was -7.33 kcal/mol for compound 4d. The nature of substitution in the N1 region of isatin seems to be able to influence the cytotoxic activity. Based on the obtained results of docking and cytotoxic tests, compound 4d seems to be a good compound for further investigations.

Reusable Cu‐Poly(4‐vinylpyridine‐co‐ethylbenzene) Complex as Catalyst for Chan‐Lam C−N Cross Coupling

AbstractA novel heterogeneous polymer supported catalyst Cu‐PVPEVB has been developed by complexation of CuI in the matrix of the polymer poly(4‐vinylpyridine‐co‐ethylvinylbenzene). Characterization of the catalyst using different spectroscopic techniques revealed that the copper metal is bound through the pyridine substructure of the polymer. The versatility of the catalyst was established by utilizing it for Chan‐Lam coupling reactions in an eco‐friendly solvent methanol. High yields of C−N cross coupled products are obtained within a short time in presence of K2CO3 and 10 weight % of the catalyst having 13.6 weight % of copper. The catalyst could be recovered after carrying out the reaction by simple filtration and reused. Additionally, among a variety of N‐functionalized products synthesized during this study, an N‐phenyl isatin derivative was found to be promising candidate as a fluorescent probe for detection of the Hg2+ ion in aqueous acetonitrile solution.

Molecular structure prediction, experimental and theoretical properties, and biological activities of (E)-5-nitro-3-(phenylimino) indolin-2-one- in-vitro against 60 lethal tumour cell lines

In this study an isatin derivative (E)-5-nitro-3-(phenylimino) indolin-2-one (5NPI) has been synthesized and examined utilizing quantum chemical calculations of DFT approach for structural optimization, electronic and vibrational characteristics. Functional groups have been detected using FT-IR spectra and compared with simulated spectra. To model UV–vis absorption and identify electronic characteristics in solvents and gas phase, TD-DFT computations have been performed. The GIAO technique was used to measure chemical shifting in NMR in several different solvents. Theoretical parameters coincide perfectly with experimental data. HOMO and LUMO band gaps reflect chemical activity and have satisfactory charge exchange inside the molecule. RDG analysis, topological and NBO investigations have been used to study weak intermolecular interactions. Reactive regions of the 5NPI compound have been determined using MEP and Fukui functions. NLO behavior has been computed using hyperpolarizability parameters. The anticancer activities of the compound 5NPI were evaluated from the National Cancer Institute (NCI), USA and subjected to in-silico analysis such as drug-likeness, ADMET and molecular docking. The compound 5NPI has been docked with 3RUX, 8ADA, 3TFU and 6TOJ proteins and showed moderate binding affinity as −7.14, −6.42, −6.68 and −8.41 kcal/mol respectively. Compound 5NPI is used as a lead molecule in the treatment of TB along with various tumors.

A Mini-Review on the Synthesis of Substituted Isatins: From Early Approaches to Recent Advances with a Specific Focus on Sulfamoyl and Amino Derivatives

Abstract: As a member of heterocyclic compounds, indole possesses a diverse set of biological activities. Studies on the structure-activity relationship of 2-indolinones have shown that they are important bioactive compounds in the field of pharmaceutical chemistry. Isatin and structures bearing isatin scaffold are derivatives of indole, which have shown to be of biological and pharmacological significance. This review focuses on different ways of obtaining compounds containing isatin structure, considering both earlier and recent methods of synthesis. The syntheses given herein were grouped into three categories, syntheses using anilines as their starting substance, synthetic methods based on the oxidation of indoles, and finally, due to the extensive research going on 5-substituted isatins and their possible pharmacological efficacy, pathways for synthesizing 5-amino and 5-sulfamoylisatins were gathered to underline the importance of 2-indolinone and isatin derivatives as prospective therapeutic compounds in current and future drug discovery studies.

Application of thin-layer chromatography in the assessment of bioactivity properties of isatin derivatives

Application of thin-layer chromatography in the assessment of bioactivity properties of isatin derivatives

Selective Functionalization of Indole: Synthesis of Bioinspired 2,2′‐thiobisindoles, 3‐substituted Oxindoles, and 1‐(chloromethyl) Indoline‐2‐dione in One‐pot manner

AbstractIndolyl thioethers and indolin‐2‐one motifs are extremely common in pharmaceuticals and organic materials, therefore developing a method to create these scaffolds is considered to be a vital endeavour in the chemical sciences. Here we have reported a unified strategy developed by the fine‐tuning of catalyst‐solvent combination [SOCl2 /AlCl3 in CHCl3 and SOCl2/DMSO (1 : 1) in CHCl3 at 25 °C] towards selective functionalization of Indole to synthesize 2,2′‐thiobisindoles and 3‐chloro‐3‐alkyl substituted oxindoles selectively in one‐pot manner with good to satisfactory yield (52‐86 %; 26 Examples). In application, reactions of 3‐subsituted indole and isatin derivatives produced the 1‐(chloromethyl) indoline‐2,3‐diones by just changing the reaction condition (60 °C), which shows the synthetic utility of the developed method.

İsatinin HepG2 ve AML12 hücre hatları üzerindeki moleküler etkilerinin araştırılması

Isatin is an indole-derived organic compound. It is a natural component of the Couroupita guianensis plant. It is also the metabolic derivative of the human body hormone adrenaline. Studies have shown the anti-tumoral effects of isatin derivatives. In this study, the cytotoxic effects of isatin on HepG2, a hepatocellular cancer cell line was investigated. Additionally, its cytotoxic and protective-proliferative effects on AML12, a healthy liver cell line was investigated. This evaluation was conducted using MTT, fluorescent staining, wound healing, and real-time polymerase chain reaction analyses. The IC50 values for 48 hours of isatin application were calculated as 186.23 µM for HepG2 and 7.05 mM for AML12. The analysis of wound healing and fluorescent staining at varying doses of HepG2 application revealed suppression of proliferation and triggered apoptosis in HepG2 cells. In contrast, AML12 cells exhibited promoted proliferation under similar conditions. Moreover, the observed upregulation of oxidative stress genes CuZn/Mn-SOD and mitochondrial apoptotic pathway genes Bax, cleaveled-Cas3, APAF1, and p53 in HepG2 cells contrasted with their decreased expression in AML12 cell lines. These results suggest the potential of natural isatin as a promising anti-cancer agent for liver cancer cell lines and as a protective supplement for healthy liver cells.