Isatin Derivatives Research Articles

Ligand‐Free and Reusable Palladium Nanoparticles‐Catalyzed Alkylation of 2‐Alkylazaarenes with Activated Ketones under Neutral Conditions

AbstractA mild, efficient, and stable binaphthyl‐stabilized palladium nanoparticles (Pd−BNP) catalyzed (sp3)C−H reaction of 2‐alkylazaarenes with activated carbonyl compounds was developed. Various activated carbonyl compounds such as α‐keto amide, isatin, 1,2‐diketone, α‐keto ester, trifluoromethyl ketone, and phenylglyoxal derivatives were examined and most of the compounds underwent the reaction smoothly to provide the corresponding products in moderate to excellent yields. Moreover, chemoselective reactions of α‐keto amides in the presence of simple ketones were achieved. Also, the model reaction was extended to a gram‐scale synthesis and some of the products were utilized for derivatization to form the corresponding N‐oxides, acryl amides and 1,2‐diol, respectively. The major advantages of the protocol are neutral reaction conditions, no additional requirement of external ligand, and successful reusability of the Pd−BNP catalyst up to five cycles without losing its activity and yield. Hg‐poisoning and hot filtration tests confirmed the heterogeneity of the Pd−BNP catalyst.magnified image

Monocarbonyl Curcumin-Based Molecular Hybrids as Potent Antibacterial Agents.

Keeping in view various pharmacological attributes of curcumin, coumarin, and isatin derivatives, triazole-tethered monocarbonyl curcumin–coumarin and curcumin–isatin molecular hybrids have been synthesized and evaluated for their antibacterial potential against Gram-positive (Enterococcus faecalis and Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa and Escherichia coli) human pathogenic bacterial strains. Among all hybrid molecules, A-4 and B-38 showed the most potent antibacterial activity with inhibition zones of 29 and 31 mm along with MIC values of 12.50 and 6.25 μg/mL, respectively. Structure–activity relationship that emerged from biological data revealed that the two-carbon alkyl chain between triazole and coumarin/isatin moiety is well tolerable for the activity. Bromo substitution at the fifth position of isatin, para-cholo substitution in the case of curcumin–isatin, and para-methoxy in the case of curcumin–coumarin hybrids on ring A of curcumin are most suitable groups for the antibacterial activity. Various types of binding interactions of A-4 and B-38 within the active site of dihydrofolate reductase (DHFR) of S. aureus are also streamlined by molecular modeling studies, suggesting their capability in completely blocking DHFR.

Syntheses and Pharmacological Activities of Isatin Derivatives

Twenty derivatives of isatin (1H-indole-2, 3-Dione) were synthesized by the schematic route as per as scheme. These were further characterized by spectroscopic analysis. All the novel synthesized derivatives of isatin were screened for their antimicrobial activity against Gram-positive bacteria: Staphylococcus aureus, Bacillus subtilis, Streptococcus pneumonia; Gram-negative bacteria: Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and fungal strains: Candida albicans, Aspergillus niger, Penicillium chrysogenum, Rhizopus oryzae by cup-plate method. Results of antimicrobial screening showed that compound ID5, ID9, ID15 and ID18 possess potent antibacterial activity. Whereas ID1, ID3, ID4, ID7 and ID20 possess antifungal activity comparable to standard drugs. Keywords: Isatin; Antimicrobial; Antibacterial; Antifungal.

Tunable amphiphilic π-systems based on isatin derivatives containing a quaternary ammonium moiety: The role of alkyl chain length in biological activity

This work deals with polyfunctional biocompatible amphiphilic isatin derivatives. Isatin-3-acylhydrazones containing a quaternary ammonium moiety (Is-Q-n) with varying hydrophobicity (R = CnH2n+1, where n = 10, 12, 14, 16, 18, 20) were synthesized. Tunable self-assembly behavior, morphology of nanostructures, and their biological activity were modulated by hydrophilic-lipophilic balance of π-amphiphiles and solvent polarity.Self-assembly of Is-Q-n was investigated by tensiometry, conductometry, IR and UV–Vis spectroscopy, fluorimetry and dynamic light scattering.The unexpected values of the physicochemical parameters at long alkyl chain length have been interpreted. The CAC of Is-Q-16 is lower than CMC of classical surfactant CTAB. Solvent-induced self-assembly for Is-Q-16 was observed. The hydrophobic dye Orange OT was solubilized in Is-Q-10 solutions twice better than in CTAB solutions. Is-Q-n self-assembled structures with size 50 nm and 100 nm in a concentration range from 0.01 mM (below CAC) to 10 mM were found. Is-Q-10 forms small associates with size 3 nm. Selective antimicrobial activity of low toxic ammonium salts against Gram-positive bacteria (S. aureus 209p and B. cereus 8035) and fungus Candida albiсans 855–653 was shown. Newly synthesized 1-dodecylisatin derivatives containing a quaternary ammonium moiety may be recommended as antimicrobial agents and for drug solubilization, in particular for drugs capable for π-π stacking interactions.

Azomethine ylide cycloaddition: a versatile tool for preparing novel pyrrolizidino-spiro-oxindolo hybrids of the doubly conjugated alkamide piperine.

A facile, multicomponent (MCR) atom-economic synthesis of novel spiro-oxindolo pyrrolizidine adducts of piperine has been achieved via an intermolecular 1,3-dipolar azomethine ylide cycloaddition reaction. Either of the two conjugated double bonds in piperine takes part in the reaction to produce two regioisomeric adducts in racemic form. Acenaphthoquinone, ninhydrin and different isatin derivatives were reacted with proline and piperine to afford a never before reported library of 22 compounds. The structures of the products were determined by 1D/2D NMR, mass spectral analysis and confirmed by X-ray crystallography of selected products. Chiral HPLC separation was performed to measure the specific rotation and CD spectra of the enantiomers for two racemic compounds.

Synthesis of Substituted Isatins from the MBH Adduct of 1,5,6-Trisubstituted Isatins Using (2,4-Dinitrophenyl)hydrazine and K-10 Clay Explored as Protection-Deprotection Chemistry.

An interesting synthetic transformation of protection–deprotection chemistry in an isatin molecule is achieved. Morita–Baylis–Hillman (MBH) adduct formation used as protection of the C-3 position in the isatin molecule is reported. C–C bond cleavage in the MBH adduct of isatin with the help of phenylhydrazine and C=N bond cleavage in the phenylhydrazone derivative of isatin with the help of K10 clay are studied systematically and reported as deprotection.

Synthesis and application of new reactive disperse dyes based on isatin derivatives and their Antibacterial activity

A new two reactive disperse dyes based on a hybrid structure of isatin and benzanthrone or anthraquinone via 1, 3, 5 triazine spacer were prepared. The prepared compounds were characterized by 1H-NMR, mass spectrometry and elemental analysis. The UV/vis absorption spectra and emission spectra were measured in N, N-dimethylformamide (DMF) solution at room temperature, the effects of substituent's on the emission spectra of these compounds were interpreted. The dyeing application of the prepared dyes on wool and polyamide-6 fabrics at various concentrations of dye and different pH were investigated as well as the exhaustion and dye fixation were studied. The antibacterial activity of the prepared reactive disperse dyes were studied against different kind of bacteria such as Staphylococcus aureus (Gram-positive bacteria) and Escherichia coli (Gram-negative bacteria). The antibacterial affinity of the prepared dyes was exhibit a significant effect compared with selected antibiotics as reference standard. The fastness properties of the dyed fabrics were studied which showing excellent wash fastness, rubbing and perspiration fastness as well as high stability to light.

Systematic Review on Cytotoxic and Anticancer Potential of N-Substituted Isatins as Novel Class of Compounds Useful in Multidrug-Resistant Cancer Therapy: In Silico and In Vitro Analysis.

As the emergence of resistance to clinical cancer treatments poses a significant problem in cancer management, there is a constant need to explore novel anticancer agents which have the ability to overcome multidrug resistance (MDR) mechanisms. The search for the development of novel isatin-based antitumor agents accelerated after the approval by the Food and Drug Administration (FDA) of sunitinib malate, a C-3 isatin derivative, as a multitargeted receptor tyrosine kinase inhibitor. However, it is interesting to note that, over the last decade, various N-substituted analogs of isatin with intact carbonyl functionalities have been found to show more promising anticancer potential than its C-3 derivatives. Microtubule-targeting agents are a class of anticancer drugs which affect mitosis by targeting microtubules and suppressing their dynamic behavior. This review presents a systematic compilation of the invitro cytotoxic and anticancer properties of various N-substituted isatins and illustrates their mechanism of action to overcome MDR by acting as microtubule-destabilizing agents. Predictions of the biological activities and cytotoxic effects of potential N-substituted isatins against various cancer cell lines have also been performed using the PASS computer-aided drug discovery program. Findings from such invitro and insilico studies will act as a guide for the development of structure-activity relationship and will facilitate the design and exploration of more potent analogs of isatin with high potency and lower side effects for treatment of drug-resistant cancer. Mechanism of action of N-substituted isatin as microtubule-destabilizing agent on tumor cells. N-Substituted isatins bind to colchicine binding site on β-tubulin, which inhibits microtubule polymerization and thereby destabilizes microtubule dynamics, resulting in mitotic arrest leading to tumor cell growth suppression.

Synthesis and evaluation of new isatin-aminorhodanine hybrids as PIM1 and CLK1 kinase inhibitors

A series of new hybrid isatin-aminorhodanine molecules was prepared by microwave activation under mild conditions. Unexpected condensation of isatin derivatives at C-5 position of aminorhodanine was highlighted and confirmed by NMR and X-ray analyses. The inhibitory activity of these compounds was evaluated towards eight protein kinases, CDK's-2,-5,-9; PIM-1, CLK-1, Haspin, GSK3β and DYRK1A, whose signaling pathway dysregulation is associated to multifactorial diseases such as cancer, inflammatory, cardiovascular, and neurodegenerative diseases. Compound 3l bearing a bromo substituent has shown a potent and selective Pim1 kinase inhibitor activity.

1-Butyl-2-methylpipyridinium iodide ([BMPPY]I): novel ionic liquid for the synthesis of 6-hydroxy-6-(1H-indol-3-yl)indolo[2,1-b]quinazolin-12(6H)-ones under green solvent-free conditions

In this article we reported preparation of 1-butyl-2-methylpipyridinium iodide ([BMPPY]I), as a novel ionic liquid (IL) through simple procedure. This newly prepared IL has been characterized by FT-IR, FESEM, EDX, TGA/DTG, 1H NMR, 13C NMR, and Gc-mass techniques. The FESEM images revealed nano scale for the IL with the average diameter of 150–185 nm. Its efficacy examined for the synthesis of 6-hydroxy-6-(1H-indol-3-yl)indolo[2,1-b]quinazolin-12(6H)-ones via domino three-component reaction of isatin derivatives, isatoic anhydride, and indoles under solvent-free conditions at 100 °C. The results affirmed that ([BMPPY]I) possessed a dual catalytic/solvent role to promote this condensation. Non-flammability, thermal stability, non-toxicity and low cost of the IL that led to obtain pharmaceutically-active heterocycles though easy work-up procedure and short reaction times, are some highlighted features of this green protocol.

Synthesis, anti-proliferative activity, theoretical and 1H NMR experimental studies of Morita-Baylis-Hillman adducts from isatin derivatives.

Quaternary or spirocyclic 3-substituted-3-hydroxy-2-oxindole is considered a privileged scaffold. In other words, it is a molecular core present on several compounds with a wide spectrum of biological activities. Among its precursors, activated ketones (isatin nucleus) can be used as interesting starting points to Morita-Baylis-Hillman adducts derivatives, a class of compounds with good cytotoxic potential. In this paper, we present the synthesis, anti-proliferative activity against lung cancer cell line and a theoretical conformational study of 21 of Morita-Baylis-Hillman adducts from isatin derivatives, by DFT quantum chemical calculations, followed by a SAR and QSAR analysis. Besides, an efficient synthetic protocol and good biological activity profile were highlighted interesting observations about 1H NMR experimental spectra, molecular modeling results and crystallographic data available.

Synthesis of some new isatin derivatives of expected biological activities

Synthesis of some new isatin derivatives of expected biological activities

Synthesis and characterization of MgO nanoparticles supported on ionic liquid‐based periodic mesoporous organosilica (MgO@PMO‐IL) as a highly efficient and reusable nanocatalyst for the synthesis of novel spirooxindole‐furan derivatives

The synthesis and catalytic application of a novel MgO containing periodic mesoporous organosilica with ionic liquid framework (MgO@PMO‐IL) is described. The prepared MgO@PMO‐IL was characterized by Fourier transform‐infrared spectroscopy, N2 adsorption/desorption, transmission electron microscopy, field emission‐scanning electron microscopy, thermogravimetric and inductively coupled plasma analyses. This nanocatalyst was successfully applied as a highly efficient and recoverable catalyst for the synthesis of novel spirooxindole‐furan derivatives via the three‐component reaction of 1,3‐dicarbonyl compounds, N‐phenacyl pyridinium salts and isatin derivatives. The products were achieved in high to excellent yields with a simple work‐up procedure and short reaction times, and the catalyst could be recovered through a simple filtration process and successfully reused seven times without any significant decrease in its efficiency.

A simple and environmentally benign synthesis of novel spiro[indoline-3,5′-pyrano[2,3-d]pyrimidine] derivatives in water

A green, convenient, and efficient one-pot synthesis of a new class of spiro[indolinepyranopyrimidine] derivatives was achieved in good yields by the multi-component reaction of N-alkyl-1-(methylthio)-2-nitroethenamine derived from the addition of various amines to nitroketene dithioacetal with isatin and barbituric acid derivatives in water at reflux conditions. Notably, the present method offers desirable advantages including good yields, use of water as green solvent, absence of catalyst, simple workup procedure, and easy purification process with no chromatographic technique.

Synthesis of Some New Isatin Derivatives and Identification of Their Structures

Indole, which has an important role in heterocyclic ring systems, exhibits significant biological effects. Isatin (1H-indole-2,3-dione) has been used as a reagent in a large number of synthesis due to its biological properties. In addition, it is a heterocyclic ring system used for obtaining and other reactions of indole and quinoline derivatives. In this study, two new Schiff base compounds were synthesized by the reaction of 2-aminoantracene with an isatin/5-nitro-isatin. The structure of the synthesized compounds, were elucidated by spectroscopic methods using IR, 1H-NMR, 13C-NMR spectra and Mass analysis.

Microwave-Promoted Facile and Rapid Access to Novel Spirooxindole-furo[2,3-c]pyrazole Derivatives Using Pyridinium Ylide-Assisted Domino Reaction

Novel spirooxindole-furo[2,3-c]pyrazole derivatives containing both biologically active pyrazole and spirooxindole-furan templates are synthesized via single-pot two-step four-component reaction involving hydrazine, β-keto ester, isatin derivatives and pyridinium ylide catalyzed by triethylamine in EtOH under microwave irradiation (MWI). In this domino protocol, five bonds (2C–C, C – O, C–N, C = N) and two new rings are efficiently formed via initial Knoevenagel, subsequent Micheal and final heterocyclization reactions. High yields, short reaction time (10–15 min), operational simplicity, absence of any tedious workup or purification and avoidance of hazardous or toxic reagents/solvents are the salient features of this eco-friendly methodology.

Auto‐Oxidation‐Induced Construction of Isatins from Glycine Derivatives

AbstractAn oxygenation approach to isatins via an auto‐oxidation/intramolecular annulation tandem reaction of glycine derivatives is described. This transformation provides a metal‐free protocol for the preparation of isatin derivatives, which are important structural motifs widely found in organic molecules with various functions and privileged units for the synthesis of complex heterocycles. The reaction proceeds smoothly under mild reaction conditions and requires only Brønsted acid and oxygen.

Evaluation of a class of isatinoids identified from a high-throughput screen of human kinase inhibitors as anti-Sleeping Sickness agents.

New treatments are needed for neglected tropical diseases (NTDs) such as Human African trypanosomiasis (HAT), Chagas disease, and schistosomiasis. Through a whole organism high-throughput screening campaign, we previously identified 797 human kinase inhibitors that grouped into 59 structural clusters and showed activity against T. brucei, the causative agent of HAT. We herein report the results of further investigation of one of these clusters consisting of substituted isatin derivatives, focusing on establishing structure-activity and -property relationship scope. We also describe their in vitro absorption, distribution, metabolism, and excretion (ADME) properties. For one isatin, NEU-4391, which offered the best activity-property profile, pharmacokinetic parameters were measured in mice.

Enantioselective Alkynylation of Isatin Derivatives Using a Chiral Phase-Transfer/Transition-Metal Hybrid Catalyst System

An enantioselective alkynylation of isatin derivatives can be realized by using a hybrid catalyst system consisting of chiral phase-transfer catalyst and transition-metal catalyst. The chiral alkynylation products can be used as versatile intermediates for further synthetic transformations.

Synthesis, Characterization, and Antileishmanial Activity of Certain Quinoline-4-carboxylic Acids

Leishmaniasis is a fatal neglected parasitic disease caused by protozoa of the genusLeishmaniaand transmitted to humans by different species ofphlebotominesandflies. The disease incidence continues to increase due to lack of vaccines and prophylactic drugs. Drugs commonly used for the treatment are frequently toxic and highly expensive. The problem of these drugs is further complicated by the development of resistance. Thus, there is an urgent need to develop new antileishmanial drug candidates. The aim of this study was to synthesize certain quinoline-4-carboxylic acids, confirm their chemical structures, and evaluate their antileishmanial activity. Pfitzinger reaction was employed to synthesize fifteen quinoline-4-carboxylic acids (Q1-Q15) by reacting equimolar mixtures of isatin derivatives and appropriateα-methyl ketone. The products were purified, and their respective chemical structures were deduced using various spectral tools (IR, MS,1H NMR, and13C NMR). Then, they were investigated againstL. donovanipromastigote (clinical isolate) in different concentration levels (200 μg/mL to 1.56 μg/mL) against sodium stibogluconate and amphotericin B as positive controls. The IC50for each compound was determined and manipulated statistically. Among these compounds,Q1(2-methylquinoline-4-carboxylic acid) was found to be the most active in terms of IC50.