Isatin Derivatives Research Articles

Synthesis of quinoline/oxindole appended phenylvinyl-2,5-dihydrofuran derivatives via ring-closing enyne metathesis

A sequential synthetic process was developed to synthesize quinoline/oxindole appended phenylvinyl-2,5-dihydrofuran derivatives. The synthesis involved multiple steps, starting with the base-promoted nucleophilic addition of terminal alkynes to specific carbonyl compounds (11H-indeno[1,2-b]quinolin-11-one and isatin derivatives). The resulting propargyl alcohol derivatives were then subjected to O-allylation. Subsequently, the 1,6-enyne compounds obtained underwent ring-closing enyne metathesis using Grubb's II catalyst, resulting in the desired quinoline/oxindole appended phenylvinyl-2,5-dihydrofuran derivatives. The structures and relative stereochemistry of the synthesized compounds were confirmed by spectroscopic analysis and single-crystal XRD studies.

Straightforward synthesis of quinoxaline-furan bis-heterocyclic structures via a multicomponent reaction

An efficient and straightforward synthetic strategy based on the higher-order multicomponent reactions (MCRs) is established for the synthesis of quinoxaline-furan bis-heterocyclic structures. The process includes a one-pot, pseudo-five component reaction of 3,4-diaminobenzoic acid, a 1,2-dicarbonyl compound, a dialkyl acetylenedicarboxylate, and two equivalents of an isocyanide as the readily available precursors. The noticeable features of the method are pot and atom economy, seven new bond formations, operational simplicity, high yields, and applicability on the gram-scale. Indolo[2,3-b]quinoxaline-furan tris-heterocycles were also synthesized using isatin derivatives via consecutive reactions.

One-pot multicomponent green synthesis of novel series of 4-hydroxy-2-pyridone-fused spiropyrans catalyzed by acetic acid

An efficient one-pot multicomponent reaction is reported for synthesizing a novel series 4-hydroxy-2-pyridone-fused spiropyran through the reaction of 4-hydroxy-6-methylpyridine-2-ones alkaloids, malononitrile or ethyl cyanoacetate, and ninhydrin or isatin derivatives. The optimized conditions for this reaction were obtained in ethanol solvent, acetic acid as catalyst, ambient temperature (for ninhydrin) or 70 °C (for isatin), and 8 hr reaction time. Mild and safe conditions, easy work-up and separation, high to excellent yields, and eco-compatibility are the main advantages of this synthesis for affording potentially bio-effective novel products.

Evaluation of Anti-Neuroinflammatory Activity of Isatin Derivatives in Activated Microglia.

Neuroinflammation plays a crucial role in the progression of Alzheimer's disease and other neurodegenerative disorders. Overactivated microglia cause neurotoxicity and prolong the inflammatory response in many neuropathologies. In this study, we have synthesised a series of isatin derivatives to evaluate their anti-neuroinflammatory potential using lipopolysaccharide activated microglia as a cell model. We explored four different substitutions of the isatin moiety by testing their anti-neuroinflammatory activity on BV2 microglia cells. Based on the low cytotoxicity and the activity in reducing the release of nitric oxide, pro-inflammatory interleukin 6 and tumour necrosis factor α by microglial cells, the N1-alkylated compound 10 and the chlorinated 20 showed the best results at 25 µM. Taken together, the data suggest that 10 and 20 are promising lead compounds for developing new neuroprotective agents.

Synthesis and Biological Activity of Barbituric acid- linked Isatin Derivatives

Synthesis and Biological Activity of Barbituric acid- linked Isatin Derivatives

Regio- and diastereoselective synthesis of new dispirocyclopentanebisoxindoles using a three-component strategy

An efficient and facile one-pot, multi-component reaction for the regio- and diastereoselective synthesis of novel dispirocyclopentanebisoxindoles has been reported by a reaction between phenyl-2-(triphenylphosphoranylidene)ethanone and isatin derivatives. The great advantages of this synthetic protocol are the minimal reaction steps, short reaction time, and operational simplicity. In consequence, a variety of new dispirocyclopentanebisoxindole derivatives with potential medicinal applications were synthesized through one-pot and multi-component reaction in high to excellent yields.

Synthesis, Antimicrobial, and Anticancer Activities of Novel Nitrofuran Derivatives

Keeping in view the varying therapeutic attributes of 5-nitrofuran and isatin derivatives, novel 5-nitrofuran‒isatin molecular hybrids (2, 5–7) were synthesized by standard protocols, characterized by various spectroscopic techniques, and eventually evaluated against a group of pathogenic bacteria and fungi. Greater potency against Methicillin-resistant Staphylococcus aureus (MRSA) was exhibited by hybrids 5 and 6 with minimum inhibitory concentration values of 8 and 1 μg/mL, respectively. Cytotoxicity against both human embryonic kidney cells (HEK-293) and human red blood cells (RBCs) was investigated for the hybrids in hand. All hybrids appeared to have good safety; all of them were devoid of cytotoxicity, and none displayed hemolytic activity at the highest test concentration (CC50 and HI10 > 32 μg/mL). To support the postulation that these hybrids would be analogous to drugs containing the 5-nitrofurn ring system, molecular docking was carried out to streamline the binding affinity of the investigated hybrids towards the E. coli nitroreductase (NTR). Compared to the standard drug nitrofurazone, hybrid 6 demonstrated a higher affinity and better binding interactions with the NTR binding pocket. Therefore, it could be concluded that 6 displays its antibacterial action through a mechanism similar to that of nitrofurazone. Nonetheless, further wet investigations are to be conducted to confirm this finding. Encouraged by the well-established anticancer activity of isatin derivatives, 2, 5–7 were assessed for their potential antitumor activity, and they well demonstrated potent inhibitory activity against the human colon cancer cell line HCT 116 (IC50 = 1.62–8.8 μM) with isatin hybrid 3 being the best (IC50 = 1.62 μM). Thus, it is herein reported that these 5-nitrofuran‒isatin molecular hybrids could represent an ideal starting point for future studies to develop potent antimicrobial agents.

Synthesis and Anti-Tumor Activity of New Isatin Derivatives

Synthesis and Anti-Tumor Activity of New Isatin Derivatives

Alkynylation of Isatin Derivatives Catalyzed by a Silver-Chiral Quaternary Ammonium Salt Derived from Quinine.

Asymmetric addition of terminal alkynes catalyzed by a transition metal to isatins obviously is an efficient and economic method for the synthesis of 3-alkynyl-3-hydroxy-2-oxindoles. The new dimeric chiral quaternary ammoniums derived from a natural chiral alkaloid, quinine, can be used as cationic inducers of the enantioselectivity for the Ag(I)-catalyzed alkynylation of isatin derivatives under mild conditions. The desired chiral 3-alkynyl-3-hydroxy-2-oxindoles can be obtained in good to high yields with high to excellent enantioselectivites (≤99% ee). A variety of aryl-substituted terminal alkynes and substituted isatins are tolerated in this reaction.

Spirocyclic isatin-derivative analogues: Solvation, structural, electronic, topological, reactivity properties, and anti-leukaemic biological evaluation

The present work investigates, via computational methods, three spirocyclic isatin derivatives with α-methylene-γ-butyrolactone cores, whose synthesis, experimental data and structural-activity relationships have been reported, to compare their properties and biological action. DFT (Density Functional Theory) studies, including geometry optimisation, FMO Analysis, theoretical UV spectral analysis, NBO and NLO studies, are performed using Gaussian 09 W with a standard basis set. The IEFPCM model is employed to investigate the solvent effect on the reactivity and stability of the compounds. Topological analyses are also performed, including ELF, LOL, RDG and charge transfer studies. ADME profiling is performed using SwissADME online tool. Anti-leukaemic target proteins are selected and docked with the title compounds to understand their suitability to act against leukaemic conditions.

Isatin-pyrimidine hybrid derivatives as enoyl acyl carrier protein reductase (InhA) inhibitors against Mycobacterium tuberculosis

Tuberculosis is a worldwide problem that impose a burden on the economy due to continuous development of resistant strains. The development of new antitubercular drugs is a need and can be achieved through inhibition of druggable targets. Mycobacterium tuberculosis enoyl acyl carrier protein (ACP) reductase (InhA) is an important enzyme for Mycobacterium tuberculosis survival. In this study, we report the synthesis of isatin derivatives that could treat TB through inhibition of this enzyme. Compound 4l showed IC50 value (0.6 ± 0.94 µM) similar to isoniazid but is also effective against MDR and XDR Mycobacterium tuberculosis strains (MIC of 0.48 and 3.9 µg/mL, respectively). Molecular docking studies suggest that this compound binds through the use of relatively unexplored hydrophobic pocket in the active site. Molecular dynamics was used to investigate and support the stability of 4l complex with the target enzyme. This study paves the way for the design and synthesis of novel antitubercular drugs.

Synthesis, Characterization, and Antibacterial Activity of New Isatin Derivatives.

1H-indol-2,3-dione (isatin) class of biologically active compounds have analgesic, anti-microbial, anti-inflammatory, anti-tubercular, anti-proliferative properties, and is also useful for the treatment of SARS-CoV. Schiff bases containing isatin moiety are known to have broad spectrum of biological activities like anti-viral, anti-tubercular, anti-fungal, and anti-bacterial. In this work, several Schiff base derivatives have been synthesized using two methods (synthetic and microwave) by reacting isatin with o-phenylenediamine. The synthesized compounds were structurally characterized and their in-vivo antimicrobial activity was tested against Gram-negative and Gram-positive bacteria using the inhibition zone method. Several newly synthesized isatin derivatives were found effective as antimicrobial agents and showed good potency (compounds 3c, 3d, 6a, 6b, 6d). Compound 3c displayed higher antimicrobial activity than standard drug (Amoxicillin) against Staphylococcus aureus at higher concentration (16 μg/mL) and against Escherichia coli at lower concentration (1 μg/mL).

Deep Red Emitting Heteroleptic Ir(III) Complexes that Incorporate Unsymmetrical 4‐quinoline Carboxylic Acid Derived Ligands

AbstractSix disubstituted ligands based upon 2‐(2′‐pyridinyl/pyrazinyl)quinoline‐4‐carboxylic acids have been synthesised, solvent‐free, in one step from a range of commercially available isatin derivatives. These species behave as ancillary chelating ligands for Ir(III) complexes of the form [Ir(C^N)2(N^N)]PF6 (where C^N=cyclometalating ligand; N^N=2‐(2′‐pyridinyl/pyrazinyl)quinoline‐4‐carboxylic acids). An X‐ray crystallographic study on one complex shows a distorted octahedral geometry wherein a cis‐C,C and trans‐N,N coordination mode is observed for the cyclometalating ligands. DFT calculations predicted that variations in N^N ligand from 2,2′‐bipyridine to L1–6 should localise the LUMO on to the Ln ligand and that the complexes are predicted to display MLCT/LLCT character. All complexes displayed luminescence in the deep red part of the visible region (674–679 nm) and emit from triplet states, but with little apparent tuning as a function of L1–6. Further time‐resolved transient absorption spectroscopy supports the participation of these triplet states to the excited state character.

Discovery of sulfonamide-tethered isatin derivatives as novel anticancer agents and VEGFR-2 inhibitors

In this work, new isatin-based sulphonamides (6a-i, 11a-c, 12a-c) were designed and synthesised as potential dual VEGFR-2 and carbonic anhydrase inhibitors with anticancer activities. Firstly, all target isatins were examined for in vitro antitumor action on NCI-USA panel (58 tumour cell lines). Then, the most potent derivatives were examined for the potential CA inhibitory action towards the physiologically relevant hCA isoforms I, II, and tumour-linked hCA IX isoform, in addition, the VEGFR-2 inhibitory activity was evaluated. The target sulphonamides failed to inhibit the CA isoforms that could be attributable to the steric effect of the neighbouring methoxy group, whereas they displayed potent VEGFR-2 inhibitory effect. Following that, isatins 11b and 12b were tested for their influence on the cell cycle disturbance, and towards the apoptotic potential. Finally, detailed molecular modelling analyses, including docking and molecular dynamics, were carried out to assess the binding mode and stability of target isatins.

QSAR and molecular docking studies of isatin and indole derivatives as SARS 3CLpro inhibitors

The 3C-like protease (3CLpro), known as the main protease of SARS-COV, plays a vital role in the viral replication cycle and is a critical target for the development of SARS inhibitor. Comparative sequence analysis has shown that the 3CLpro of two coronaviruses, SARS-CoV-2 and SARS-CoV, show high structural similarity, and several common features are shared among the substrates of 3CLpro in different coronaviruses. The goal of this study is the development of validated QSAR models by CORAL software and Monte Carlo optimization to predict the inhibitory activity of 81 isatin and indole-based compounds against SARS CoV 3CLpro. The models were built using a newer objective function optimization of this software, known as the index of ideality correlation (IIC), which provides favorable results. The entire set of molecules was randomly divided into four sets including: active training, passive training, calibration and validation sets. The optimal descriptors were selected from the hybrid model by combining SMILES and hydrogen suppressed graph (HSG) based on the objective function. According to the model interpretation results, eight synthesized compounds were extracted and introduced from the ChEMBL database as good SARS CoV 3CLpro inhibitor. Also, the activity of the introduced molecules further was supported by docking studies using 3CLpro of both SARS-COV-1 and SARS-COV-2. Based on the results of ADMET and OPE study, compounds CHEMBL4458417 and CHEMBL4565907 both containing an indole scaffold with the positive values of drug-likeness and the highest drug-score can be introduced as selected leads.

Design, synthesis, docking, and antidepressant activity evaluation of isatin derivatives bearing Schiff bases.

Depression is a prevalent psychiatric disorder. Treatment of depression is still a challenge due to the lack of response of some patients to a variety of available medications and side effects. Isatin is an interesting molecule with diversified biological effects. It also participates in many synthetic reactions, as a precursor molecule. In this study, a new series of N-alkyl and N-benzyl isatin derivatives bearing Schiff bases were synthesized and screened for antidepressant activities in mice. The synthesis was initiated by N-alkylation and N-benzylation of isatin by an alkylation reaction to give N-substituted isatins. 2-(Benzyloxy) benzohydrazide derivatives were synthesized by treating methyl2-hydroxybenzoate with benzyl bromide or 4-chlorobenzyl bromide which was followed by a reaction with hydrazine hydrate to provide acid hydrazide derivatives. The final compounds were obtained by condensation of N-substituted isatins with 2-(benzyloxy) benzohydrazide derivatives as Shiff-base products. Compounds were evaluated for antidepressant activities in mice by the locomotor activity, marble burying test, and forced swimming test. Monoamine oxidase-A (MAO-A) enzyme has been used for molecular docking studies. Compounds 8b and 8e in both doses, and 8 c in the lower dose, reduced immobility time during the forced swimming test relative to the control group. All preparations reduced the number of marbles buried compared with the control group. The highest docking score was -11.01 kcal/mol for compound 8e. N-Benzylated-isatin (8b, 8e) and N- acetic acid ethyl ester -isatin derivatives (8c) showed more effective antidepressant activity compared with N-phenyl acetamide isatin derivatives. Docking results relatively confirm the pharmacological results.

Synthesis and Biological Evaluation of Isatin Derivatives as Antibacterial Inhibitors

Synthesis and Biological Evaluation of Isatin Derivatives as Antibacterial Inhibitors

Synthesis, solvent polarity(polar and nonpolar), structural and electronic properties with diverse solvents and biological studies of (E)-3-((3-chloro-4-fluorophenyl) imino) indolin-2-one

Isatin compounds' intriguing biological potential has captivated chemists' interest. A synthetic (E)-3-((3-chloro-4-fluorophenyl) imino) indolin-2-one (3CF4I) containing isatin derivatives has been evaluated experimentally and computationally by DFT while being used in a solvation research investigation with a variety of solvents, polar protic (PP), aprotic (PA) and non-polar (NP). DFT has been performed using WB97XD/ 6–311++ G (d, p) basis set, most stable optimum structure has uncovered, followed by FTIR, UV and NMR investigation. NCA has been exploit to supplement vibrational allocations attributed to various vibration modes with potential energy distribution. According to the recorded frequency, predicted vibrational absorption bands correlated well. Using IEFPCM, we probedoptimal geometrical characteristics, UV–Vis spectra, band gap (ΔE) energy, and MEP analyses in PP, PA, and NP solvents. Global classifiers and chemical reactivity have been substantially altered by solvents. Electrophilic and nucleophilic areas were located on the MEP map. The molecule's stability has been scrutinized utilising NBO analysis. The transition π* (C14-C15) → π* (C12-C13) has a higher stabilization energy 223.09 kcal/mol indicating strong delocalization inside the phenyl ring. Using Multiwfn 3.7, topological investigations ELF, LOL, and RDG have been conducted to identify the bonding zones and weakest contacts in 3CF4I. Using Lipinski's behest of five, substance's drug-like properties had been proven and molecule is recommended for use in pharmaceuticals using ADMET contour. In-vitro antiproliferative activity of 3CF4I was tested against sixty human cancer cell lines. Antimicrobial tests have been performed to see how well the chemical worked against various bacterial and fungal strains. Docking of 3CF4I with 6GCM (E. coli),3FYW (Staph. aureus),6M4C (C. albicans),4YNT (Aspergillus Flaves) proteins have been done, and lowest binding energy −6.8 kcal/mol has been achieved for 4YNT protein. Utilizing molecular dynamics simulations (MDS), stability of the titular molecule has been explored.

Palladium-Catalyzed Chemoselective Oxygenation of C(sp2)–H and C(sp3)–H Bonds in Isatins

The palladium-catalyzed chemoselective C(sp2)-H and C(sp3)-H bond oxygenation of substituted isatin derivatives is reported. This mild protocol exhibits the C5 C(sp2)-H oxygenation of isatins through electrophilic intermolecular C-H palladation in concentrated solutions using PhI(OAc)2 or Selectfluor as an oxidant, whereas it exhibits-N-CH3 C(sp3)-H oxygenation in dilute solutions via carbonyl-assisted intramolecular palladation in the presence of K2S2O8. This oxygenation reaction provides a direct and unified approach for synthesizing diverse oxygenated isatins with sensitive functionalities, including biorelevant compounds.

Effect of Substituents on the Biological Activity of Isatin Hybrids – A SAR Study

Isatin (2,3-dioxindole) is a benzopyrrole derivative that belongs to a large class of heterocyclic chemicals. Isatin derivatives are essential synthetic substrates that can be utilized as starting materials to build a wide range of heterocycles with diverse applications in pharmaceutical sciences. Isatin derivatives therefore have recently gained a lot of attention. This review emphasizes on the Schiff base derivatives from isatin, isatin quinoline/flouroquinone, isatin -thiazole, isatin–azole hybrids, all possessing potential biological activity. The structure–activity relationships of these potential leads are also discussed.