Isatin Ring Research Articles

(Z)-4-(3-Fluorophenyl)-1-(5-nitro-2-oxoindolin-3-ylidene)thiosemicarbazide

In the title compound, C15H10FN5O3S, an intra­molecular N—H⋯N hydrogen bond generates an S(5) ring, whereas N—H⋯O and C—H⋯S inter­actions complete S(6) ring motifs. The dihedral angle between the isatin ring system and the fluoro­benzene ring is 5.96 (6)° and the complete mol­ecule is close to planar (r.m.s. deviation for all the non-H atoms = 0.112 Å). In the crystal, mol­ecules are linked by N—H⋯O hydrogen bonds to form C(8) chains along the [100] direction and C—H⋯O inter­actions are also observed.

Synthesis and In vitro antioxidant activity of new 3-substituted-2-oxindole derivatives

A series of new 1,3-dihydro-3-hydroxy-3-(2-phenyl-2-oxoethyl)-2H-indol-2-ones (1a-g) and 1,3-dihydro-3-(2-phenyl-2-oxoethylidene)-2H-indol-2-ones (2a-g) were synthesised by Knoevenagel condensation of substituted indole-2,3-diones (isatins) with various acetophenones. The synthesised compounds were characterised by their physical data, elemental, IR, 1H NMR, 13C NMR and mass spectral analyses and their in vitro antioxidant activity was determined by 2,2-diphenyl-1-picrylhydrazyl free radical scavenging assay. These compounds showed moderate to good antioxidant activities as compared with the standard, ascorbic acid. The antioxidant potential of 3-hydroxy-3-substituted oxindoles (1a-g) increased in a concentration-dependent manner from 10 to 500 μg/ml with 5-fluoro and 5-methyl analogues showing maximum activity. Of 3-aroyl methylene indol-2-ones (2a-g), majority of compounds with halogen substitution at position 5 of isatin ring exhibited good antioxidant activity within a concentration range of 5-100 μg/ml and the maximum activity was observed at 20 and 25 μg/ml concentrations. Thus, our study provides evidence that some newly synthesised isatin derivatives exhibit substantial antioxidant activity at low concentrations.

Inhibition of monoamine oxidase by C5-substituted phthalimide analogues

Literature reports that isatin as well as C5- and C6-substituted isatin analogues are reversible inhibitors of human monoamine oxidase (MAO) A and B. In general, C5- and C6-substitution of isatin leads to enhanced binding affinity to both MAO isozymes compared to isatin and in most instances result in selective binding to the MAO-B isoform. Crystallographic and modeling studies suggest that the isatin ring binds to the substrate cavities of MAO-A and -B and is stabilized by hydrogen bond interactions between the NH and the C2 carbonyl oxygen of the dioxoindolyl moiety and water molecules present in the substrate cavities of MAO-A and -B. Based on these observations and the close structural resemblances between isatin and its phthalimide isomer, a series of phthalimide analogues were synthesized and evaluated as MAO inhibitors. While phthalimide and N-aryl-substituted phthalimides were found to be weak MAO inhibitors, phthalimide homologues containing C5 substituents were potent reversible inhibitors of recombinant human MAO-B with IC50 values ranging from 0.007 to 2.5μM and moderately potent reversible inhibitors of recombinant human MAO-A with IC50 values ranging from 0.22 to 9.0μM. By employing molecular docking the importance of hydrogen bonding between the active sites of MAO-A and -B and the phthalimide inhibitors are highlighted.

Synthesis, Characterization and Cytotoxic Activity of S-Benzyldithiocarbazate Schiff Bases Derived from 5-Fluoroisatin, 5-Chloroisatin, 5-Bromoisatin and Their Crystal Structures

Schiff bases were prepared from S-benzyldithiocarbazate with 5-fluro-, 5-chloro- and 5-bromoisatin. All are potential tridentate nitrogen, oxygen, sulfur donors. They were found to be selectively active against MCF-7 cell line (Human non-metastatic mammary gland adenocarcinoma cell line). The bromide and fluoride compounds were the most active with IC50 values of 6.40 μM (2.6 μg/mL) and 9.26 μM (3.2 μg/mL) respectively while the chloride derivative was weakly active with an IC50 value of 38.69 μM (14.0 μg/mL). The cytotoxic activity of the halo substituted isatins against the breast cancer cell lines tested is in the order of Br > F > Cl. Planarity of the isatin ring in the Schiff bases can be arranged in the following order SB5FISA > SB5ClISA > SB5BrISA while the perpendicularity of the benzyl ring towards the dithiocarbazate plane can be ordered as follows, SB5FISA > SB5BrISA > SB5ClISA. Schiff bases were prepared from S-benzyldithiocarbazate with 5-fluro-, 5-chloro- and 5-bromoisatin. They were found to be selectively active against MCF-7 cell line (Human non-metastatic mammary gland adenocarcinoma cell line) with the bromide compound was the most active with IC50 value of 6.40 μM (2.6 μg/mL).

5-Fluoro-3-(2-phenylhydrazinylidene)indolin-2-one

In the title compound, C14H10FN3O, the six- and five-membered rings of the isatin moiety and the six-membered ring of phenyl­hydrazone are nearly planar with r.m.s. deviations of 0.0003, 0.0004 and 0.007 Å, respectively. The dihedral angle between the phenyl ring and the isatin ring system is 6.09 (9)°. The mol­ecular structure is stabilized by a strong intra­molecular N—H⋯O hydrogen bond, leading to the formation of a pseudo-six-membered ring, generating an S(6) ring. The crystal structure features inter­molecular N—H⋯O inter­actions.

Impact of Substituents on the Isatin Ring on the Reaction Between Isatins with Ortho-Phenylenediamine

The reaction of different substituted isatins with ortho-phenylenediamine in acetic acid has been investigated. While electron-donor substituents on isatin shift the reaction toward classical 6H-indolo[2,3-b]quinoxaline ring closure, electron-withdrawing groups enhance the formation of 3-(2′-amino-5′-substituted)-quinoxaline-2(1H)-ones. The structures of all synthesized compounds were assigned by using infrared, mass, 1H NMR, 13C NMR, 13C-1H HSQC, and 13C-1H heteronuclear multiple bond correlation (HMBC) spectroscopic data.

A Crystallographic Study of S-Methyl 2-(5-Chloro-2-Oxoindolin-3-ylidene)Hydrazinecarbodithioate

S-methyl 2-(5-chloro-2-oxoindolin-3-ylidene)hydrazinecarbodithioate (SM5ClISA) has been prepared from S-methyldithiocarbazate and 5-chloroisatin. The compound crystallized in monoclinic crystal system with space group P 21/n, Z = 4, V = 1201.85(7) Å3 and unit cell parameters a = 6.5466(2) Å, b = 7.5056(3) Å, c = 24.6509(8) Å, α = γ = 90° and β = 97.1434(18)°. The crystal structure reveals that the compound exists in the thione form with the chlorine occupies the fifth position in the isatin ring with the bond length of 1.739(2) Å. The 5-chloroisatin moiety is trans with respect to the C3–N2 and C3–S4 bonds whereas the methyl group of the dithiocarbazate moiety is cis with respect to the C3–N2 and C3–S5 bonds. The crystal structure of S-methyl 2-(5-chloro-2-oxoindolin-3-ylidene)hydrazinecarbodithioate .

Design, synthesis, and QSAR study of novel 2-(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)-N-phenylacetamide derivatives as cytotoxic agents

This study deals with the synthesis of novel 2-(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)-N-phenylacetamide derivatives (6a–j) from isatin (3) and 5,7-dibromoisatin (4). All newly synthesized compounds were characterized using IR, 1H NMR, MS, and elemental analysis followed by evaluation of their cytotoxic activity by XTT assay on breast cancer cell line MCF-7 and non-cancer African green monkey cell line VERO. Correlation study for QSAR and in vitro assay was performed. The outcomes indicated that electron withdrawing substitutions at para position of phenyl ring and 5, 7 positions of isatin ring and increasing lipophilicity of the compound increased the cytotoxic activity. The 2-(5,7-dibromo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)-N-(4-nitrophenyl)acetamide (6b) was found to be the most active compound in the series and demonstrated higher selectivity toward MCF-7 cell line. The IC50 values were 1.96 and 1.90 μM for test compound (6b) and vinblastin (reference drug), respectively. This indicates compound (6b) may possess equipotent cytotoxic activity to vinblastine. The compound (6b) is particularly promising, since it could kill cancer cells 19–20 times more effectively than the non-cancer cells. This property of (6b) may enable us to effectively control tumors with low side effects. Hence, we propose that 2-(5,7-dibromo-2,3-dioxo-2,3-dihydro-1H- indol-1-yl)-N-(4-nitrophenyl)acetamide may be used as lead for further development.

18F]- and [11C]-Labeled N-benzyl-isatin sulfonamide analogues as PET tracers for Apoptosis: synthesis, radiolabeling mechanism, and in vivo imaging study of apoptosis in Fas-treated mice using [11C]WC-98

The radiolabeled isatin sulfonamide caspase-3 inhibitor, [18F] 2 (WC-II-89), is a potential PET radiotracer for noninvasive imaging of apoptosis. The radiolabeling mechanism was studied by 13C NMR, ESI/MS, and computational calculations. It was found that the high electrophilicity of the C3 carbonyl group in the isatin ring, which served as a trap for [18F]fluoride, was responsible for the failure of the radiolabeling via nucleophilic substitution of the mesylate group in 7a by [18F]fluoride. Once treated with a strong base, 7a opened the isatin ring completely to form an isatinate intermediate 16, which lost the ability to trap [18F]fluoride, thereby allowing the displacement of the mesylate group to afford the 18F-labeled isatinate 17. [18F] 17 can be converted to isatin [18F] 2 efficiently under acidic conditions. The ring-opening and re-closure of the isatin ring under basic and acidic conditions were confirmed by reversed phase HPLC analysis, ESI/MS and 13C NMR studies. Computational studies of model compounds also support the above proposed mechanism. Similarly, the ring-opening and re-closure method was used successfully in the synthesis of the 11C labeled isatin sulfonamide analogue [11C] 4 (WC-98). A microPET imaging study using [11C] 4 in the Fas liver apoptosis model demonstrated retained activity in the target organ (liver) of the treated mice. Increased caspase-3 activation in the liver was verified by the fluorometric caspase-3 enzyme assay. Therefore, this study provides a useful method for radio-synthesis of isatin derivative radiotracers for PET and SPECT studies, and [11C] 4 is a potential PET radiotracer for noninvasive imaging of apoptosis.

Synthesis and structures of monomeric [chloro(isatin-3-thiosemicarbazone)bis(triphenylphosphine)]copper(I) and dimeric [dichlorobis(thiophene-2-carbaldehyde thiosemicarbazone)bis(triphenylphosphine)]dicopper(I)] complexes

Reaction of copper(I) chloride with thiophene-2-carbaldehyde thiosemicarbazone (Httsc) in acetonitrile in the presence of Ph3P yielded a sulfur-bridged dimer [Cu2Cl2(μ2-S-Httsc)2(PPh3)2]·2CH3CN (1), while a similar reaction with isatin-3-thiosemicarbazone (H2itsc) formed a monomer, [CuCl(H2itsc)(Ph3P)2]·2CH3CN (3). Furan-2-carbaldehyde thiosemicarbazone (Hftsc) also formed a compound of the composition [Cu2Cl2(Hftsc)2(PPh3)2]·2H2O (2). Complexes 1–3 have been characterized using elemental analysis, IR, 1H and 31P NMR spectroscopy and single crystal X-ray crystallography (1 and 3). Acetonitrile is engaged in hydrogen bonding with the chlorine atom {NCCH2–H⋯Cl)}, which is necessary for the stabilization of the bridging sulfur in 1. In compound 3, however, acetonitrile is strongly hydrogen bonded to the NH hydrogen of the isatin ring {CH3CN⋯NH(isatin)} and not to the chlorine atom. The Cu⋯Cu contact of 2.7719(5)Å in dimer 1 is close to twice the van der Waals radius of the Cu atom (2.80Å).

1′-Benzyl-1-(2,4-dimethoxyphenyl)-3-phenoxyspiro[azetidine-2,3′(3H)-indole]-2′,4(1H)-dione

The title compound, C31H26N2O5, is a compound with a spiro junction between β-lactam and isatin ring systems. Its four- and five-membered rings are nearly planar, with maximum deviations of −0.020 (1) and 0.050 (1) Å for their carbonyl C atoms, respectively. The dihedral angle between these two rings is 86.44 (5)°. The crystal structure is stabilized by intra­molecular C—H⋯O hydrogen-bonding and van der Waals inter­actions.

Total Synthesis of Nigellicine and Nigeglanine Hydrobromide

[reaction: see text] The first syntheses of the pyridazinoindazolium alkaloids nigellicine and nigeglanine hydrobromide via a common intermediate are described. Ortho-lithiation/acylation and the direct amination of an isatin ring system are the key steps in the synthesis.

A New Insight into the Pfitzinger Reaction. A Facile Synthesis of 6‐Sulfamoylquinoline‐4‐carboxylic Acids.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A new insight into the Pfitzinger reaction. A facile synthesis of 6-sulfamoylquinoline-4-carboxylic acids

The unusual formation of 6-sulfamoylquinoline-4-carboxylic acids from 5-sulfamoylisatins under the conditions of Pfitzinger reaction is described. Key step in the suggested mechanism is the reaction of in situ generated acetaldehyde with the hydrolytically cleaved isatin ring. The suggested mechanism has been confirmed by dynamic LCMS measurements and by reactions with isotopically labeled reactants.

Kinetics and mechanism of isatin ring opening in aqueous binary mixtures of methanol and acetonitrile cosolvents

Solvent effects on the kinetics of hydrolysis of isatin by sodium hydroxide have been investigated within the temperature range (30–55°C) in methanol-water and acetonitrile-water media of varying solvent compositions up to 70% (v/v) of the organic solvent component. The thermodynamic activation parameters were calculated and discussed in terms of solvation effects. The determined isokinetic temperatures, in both systems, revealed the existence of compensation effect arising from strong solute-solvent interactions; log k was correlated with both log [H2O] and the reciprocal of the dielectric constant. The first correlation was observed to be linear while the second was nonlinear. Finally a mechanism for the isatin ring opening was proposed, which accounts for the role and the effect of the solvent on the reaction rate. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 463–469, 1998

Kinetics and mechanism of isatin ring opening in aqueous binary mixtures of methanol and acetonitrile cosolvents

Kinetics and mechanism of isatin ring opening in aqueous binary mixtures of methanol and acetonitrile cosolvents

Process for controlling a series of flotation cells

Isatin methyl derivatives have several pharmacotherapeutic applications, such as antibacterial, antifungal, antiviral, anticonvulsants and anticancer activities. The electrochemical behaviours of thirteen isatin-substituted derivatives with different functional groups, such as isatin 1-morpholinomethyl, isatin 1-hydroxymethyl, and isatin 1-, 5- or 7-methyl, and their halogenated derivatives, in phosphate buffer pH = 7.2, at a glassy carbon electrode, by cyclic, differential pulse and square wave voltammetry, were investigated. The oxidation mechanism of all isatin derivatives occurred in two consecutive irreversible charge transfer pH-dependent reactions. The first anodic reaction was on the benzene ring, with the generation of one hydroxyl group attached to the ring, which was oxidized in the second step to para- and/or ortho-quinone derivatives, and/or polymeric products. The reduction mechanism of all isatin derivatives, was an irreversible cathodic process, dependent on pH and the presence/absence of attached halogenated groups. The isatin derivatives reduction, in the absence of halogens, caused the irreversible cleavage of the carbonyl group, at the position C3, in the heterocyclic ring, and, in the presence of halogens, the cathodic peak corresponded to the carbon-halogen bond reduction. The functional groups attached to the isatin ring at the 1-position, morpholinomethyl-, hydroxymethyl- and methyl- are not electroactive, and do not affect considerably the isatin derivatives redox mechanism, since the oxidation occurs at the benzene ring, and the reduction at the carbonyl C3-position.

Cathodic Reduction of Isatin-3-oxime

The molecule of isatin-3-oxime was studied polarografically over the region of pH 1 to 13. Cathodic reduction within the region of pH 1 to 10.5 gives rise to a single four-electron polarographic wave due to the reduction of the oxime group, whereas two polarographic waves are observed at pH 10.5 to 13: one is due to the reduction of the isatin-3-oxime anion, the other, more negative wave is associated with the reduction of the oxime group in the α-oxime isatinic acid anion, which is the product of hydrolytic cleavage of the isatin ring in the basic pH region. The experimental results give evidence that the substance can exist as seven ionic and molecular species in dependence on pH. The species have been confirmed polarographically, by IR and electronic spectroscopy, potentiometrically and by paper electrophoresis.

ChemInform Abstract: 5‐(2‐OXO‐3‐INDOLINYLIDENE)THIAZOLIDINE‐2,4‐DIONE‐1,3‐DI‐MANNICH BASE DERIVATIVES: SYNTHESIS AND EVALUATION FOR ANTILEUKEMIC ACTIVITY

A novel series of 5-(2-oxo-3-indolinylidene)thiazolidine-2,4-dione, having the 1- and 3-positions of the isatin and thiazolidine rings respectively, substituted by various Mannich bases, was prepared. Five compounds were evaluated for antileukemic activity against P388 lymphocytic leukemia in the mouse. The di-Mannich base with a dimethylamino component exhibited the highest activity of the tested compounds. Introduction of bromine into the aromatic moiety of isatin ring (position 5) increased the activity of the parent molecule to a smaller extent.