Synthesis of 6H-pyrrolo[3',4':2,3][1,4]diazepino[6,7,1-hi]indole-8,10(7H,9H)-diones using 3-bromo-4-(indol-1-yl)maleimide scaffold

Series of 3-arylalkyl- or 3-alkylamino-4-(indol-1-yl)maleimides and bis(indol-1-yl)maleimides were synthesised. The cyclization of the 3-substituted 4-(indol-1-yl)maleimides under the action of acids resulted in the formation of diazepine[1,4] derivatives with indoline and maleimide nuclei annelated. These compounds readily produced the corresponding indolomaleimidodiazepines[1,4] after dehydrogenation.     

Macrolactones built from the bis-3,4(indol-1-yl)maleimide scaffold

15, 16, and 17-Membered lactones based on the bis-3,4(indol-1-yl)maleimide framework were obtained using intramolecular esterification reaction starting from 3-(1-ω-carboxyalkyl-2,3-dihydroindol-1-yl)-4-(1-ω-hydroxyalkyl-2,3-dihydroindol-1-yl)-maleimides. 3,4-Dibromo-maleimide, ω-(2,3-dihydroindol-3-yl)alkanoic acids, and ω-(2,3-dihydroindol-3-yl)alkanoles were used as starting compounds. Substitution of Br for the substituted indolines followed by the intramolecular cyclization of O-silylated hydroxyl acids derivatives led to macrolactones that incorporated 4-(dihydroindol-1-yl)-3-(indol-1-yl)maleimide moieties. Indoline nuclei in these compounds were dehydrogenated by DDQ in refluxing toluene to give 15, 16 or 17-membered lactones 3-[(ω-3-carboxyalkylindol-1-yl)-4-(ω-hydroxyalkylindol-1-yl)maleimides. Quantum chemical calculations showed that the formation of macrolactones of smaller size (13-membered) corresponds to the higher Gibbs energy ΔG^# and correlates with the absence of the target reaction product.     

Quantum chemical study of the transformation of 2-(N-alkylamino)-3-(indol-1-yl)-and 2-(N-alkylamino)-3-(indol-3-yl)maleimides by protic acids: Tandem hydride transfer/cyclization mechanism

The geometric parameters, the charge distribution, and the energetics of N-methyl-2-(N-ethylanilino)-3-(indol-1-yl)-and N-methyl-2-(N-ethylanilino)-3-(indol-3-yl)maleimides and their conjugated acids were studied by density functional theory calculations at the B3LYP/6-31G(d) level. The mechanism of the tandem hydride transfer/cyclization sequence, which occurs after protonation of N-methyl-2-(N-ethylanilino)-3-(indol-1-yl)-and N-methyl-2-(N-ethylanilino)-3-(indol-3-yl)maleimides, was analyzed. The investigation of the potential energy surface for the tandem hydride transfer/cyclization of the iminium cation that formed upon protonation revealed that the hydride transfer followed by intramolecular cyclization at position 7 of the indole fragment in N-methyl-2-(N-ethylanilino)-3-(indol-1-yl)maleimide is the preferable process, unlike alternative intramolecular cyclization involving the cationic center at the C(2) atom of the indole fragment and the benzene ring of the N-ethylaniline fragment of the indoleninium cation in N-methyl-2-(N-ethylanilino)-3-(indol-3-yl)maleimide. A study of the key intermediates of the assumed reaction mechanism demonstrated that these intermediates are actually stationary points on the potential energy surface (minima and transition states). Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2069–2073, December, 2006.     

Cyclization of vicinally substituted heterocyclic analogs of 3,4-bis(indol-1-yl)maleimide under the action of protic acids: a quantum chemical study

B3LYP/6-31G(d) density functional quantum chemical calculations of vicinally substituted bis(indol-1-yl)derivatives of 1,5-dihydropyrrol-2-one, furan-2,5-dione, cyclopent-4-ene-1,3-dione, cyclobut-3-ene-1,2-dione, and pyrrolidine-2,5-dione were carried out to study the effect of modification of the maleimide moiety in 3,4-bis(indol-1-yl)maleimides on the direction of intramolecular cyclization under the action of protic acids. Geometric parameters, charge distributions, energy characteristics, and frontier orbital energies of these compounds and the corresponding indoleninium cations were determined. Alternative protonation routes of 3,4-bis(indol-1-yl)-1,5-dihydropyrrol-2-one have been studied. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1348–1352, July, 2008.     

Transformations of 3,4-bisindolylmaleimides with differently bonded indole and maleimide moieties under the action of protic acids: A quantum chemical study

Intramolecular cyclization reactions of 3,4-bis(indol-3-yl)maleimides 1, 3-(indol-1-yl)-4-(indol-3-yl)maleimides 2, and 3,4-bis(indol-1-yl)maleimides 3 under the action of protic acids were studied in order to estimate the parameters of the interaction between protonated and unprotonated indole moieties. Geometric parameters, charge distributions, energy characteristics, and information concerning the frontier orbitals of bisindolylmaleimides 1–3 were obtained from density functional B3LYP/6-31G(d) quantum chemical calculations. Alternative pathways of protonation of bisindolylmaleimides with differently bonded indole and maleimide moieties were studied and pathways of cyclization of corresponding conjugated acids leading to polyannelated compounds were analyzed. All the key intermediates of the cyclization reactions correspond to stationary points on the potential energy surfaces (minima and transition states). Analysis of the potential energy surfaces revealed almost linear dependences of the activation energies of the cyclization reactions under study on the distances between the reaction centers, on the angle of approach of intramolecular electrophile, and on the energy gap (energy difference between frontier orbitals). The key role in the cyclization reactions is played by structural similarity between the starting indoleninium cations and the activated complexes of the reactions under study. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 754–760, May, 2006.     

马来酰胺类糖原合成酶激酶-3β抑制剂的分子对接和三维定量构效关系

通过分子对接和三维定量构效关系(3D-QSAR)两种方法来确定两类马来酰胺类的糖原合成酶激酶-3β(GSK-3β)抑制剂的结合方式.首先,用分子对接确定抑制剂与GSK-3β的结合模式及其相互作用;然后用比较分子力场分析法(CoMFA)与比较分子相似性指数分析法(CoMSIA)对48个化合物做三维定量构效关系的分析.两种方法得出的交互验证回归系数分别为0.669(CoMFA)和0.683(CoMSIA),证明该模型具有很好的统计相关性,同时也说明该模型具有较高的预测能力.根据该模型提供的信息,设计出9个预测性较好的分子.     

马来酰胺类糖原合成酶激酶-3β抑制剂的分子对接和三维定量构效关系

通过分子对接和三维定量构效关系(3D-QSAR)两种方法来确定两类马来酰胺类的糖原合成酶激酶-3β(GSK-3β)抑制剂的结合方式. 首先, 用分子对接确定抑制剂与GSK-3β结合模式及其相互作用; 然后用比较分子力场分析法(CoMFA)与比较分子相似性指数分析法(CoMSIA)对48个化合物做三维定量构效关系的分析. 两种方法得出的交互验证回归系数分别为0.669(CoMFA)和0.683(CoMSIA), 证明该模型具有很好的统计相关性, 同时也说明该模型具有较高的预测能力.根据该模型提供的信息, 设计出9个预测活性较好的分子.     

Photochromic fluorescent indol-3-yl-substituted maleimides

New hetarylethenes, 3-(indol-3-yl)-4-thienyl(but-1-en-1-yl)-substituted pyrrole-2,5-diones containing coumarin or fluorene substituents on the pyrrole nitrogen atom, were synthesized by reactions of furan-2,5-diones with 9H-fluoren-2-amine and 6-amino-2H-chromen-2-one. Acyclic maleimide isomers showed fluorescence with quantum yields of 0.002 to 0.072. Their irradiation with UV light generates non-fluorescing cyclic isomer. The reverse ring opening occurs in the excited state.     

Zeolite-catalyzed synthesis of nicotinyl-fused indolo-pyrazoles and evaluation of their activities against Anopheles arabiensis and Lipoxygenase

A series of nicotyl-fused indolo-pyrazoles (NFIPs) were synthesized by a one-pot multicomponent reaction of aryl aldehydes, isoniazid, and indole in the presence of zeolite as a catalyst. Structures of all the synthesized compounds were established by IR, ¹H-NMR, ¹³C-NMR, 2D-NMR, TOF-MS, and elemental analysis. The products were obtained in excellent yields and high purity. All 10 compounds were screened for larvicidal and insecticidal properties against Anopheles arabiensis and tested for their lipoxygenase inhibitory activity. Compounds (3-(3-hydroxy-4-methoxyphenyl)-2,3-dihydropyrazolo[4,3-b]indol-1(4H)-yl)(pyridin-4-yl)methanone ( 4i ) and (3-(3-bromo-5-hydroxy-4-methoxyphenyl)-2,3-dihydropyrazolo[4,3-b]indol-1(4H)-yl)(pyridin-4-yl)methanone ( 4j) displayed highest larvae mortality at a 4 μg/ml dose in 24 h. Compounds (3-(4-methoxyphenyl)-2,3-dihydropyrazolo[4,3-b]indol-1(4H)-yl)(pyridin-4-yl)methanone ( 4h ) and (3-(3-hydroxy-4-methoxyphenyl)-2,3-dihydropyrazolo[4,3-b]indol-1(4H)-yl)(pyridin-4-yl)methanone ( 4i ) showed a significant knockdown activity after 24 h with 70% mortality. Furthermore, (3-(4-chlorophenyl)-2,3-dihydropyrazolo[4,3-b]indol-1(4H)-yl)(pyridin-4-yl)methanone ( 4c ) and (3-(3-bromo-5-hydroxy-4-methoxyphenyl)-2,3-dihydropyrazolo[4,3-b]indol-1(4H)-yl)(pyridin-4-yl)methanone ( 4j ) displayed promising lipoxygenase inhibitory activity with a mortality of 70% and 60%, respectively.     

Reactions of indoles with nitrogen dioxide and nitrous acid in an aprotic solvent

The reaction of 2-phenyl- and 1-methyl-2-phenylindole with nitrogen dioxide or with nitrous acid (NaNO2-CH3COOH) in benzene leads mainly to the formation of the isonitroso and 3-nitroso indole derivatives, respectively. When reacted with nitrous acid, 1-methyl-2-phenylindole gives also the corresponding azo-bis-indole in good yields. The reaction of indole with nitrogen dioxide leads to 2-(indol-3-yl)-3H-indol-3-one as the main product together with small amounts of 2-(indol-3-yl)-3H-indol-3-oxime; whereas the major product obtained when the same indole is reacted with nitrous acid is represented by 2-(indol-3-yl)-3H-indol-3-oxime. The reaction of 3-alkyl substituted indoles with nitrogen dioxide is rather complex and results in the formation of different nitro indoles, whereas nitrosation is observed when nitrous acid is used. Crystal structures of 2-(indol-3-yl)-3H-indol-3-one and of 4-nitro-N-acetyltryptamine have been determined by X-ray analysis.     

Uncatalyzed addition of indoles and N-methylpyrrole to 3-formylchromones: synthesis and some reactions of (chromon-3-yl)bis(indol-3-yl)methanes and E-2-hydroxy-3-(1-methylpyrrol-2-ylmethylene)chroman-4-ones

(Chromon-3-yl)bis(indol-3-yl)methanes and E-2-hydroxy-3-(1-methylpyrrol-2-ylmethylene)chroman-4-ones have been obtained in good yields from 3-formylchromones on reaction with indoles and N-methylpyrrole under solvent-free conditions. Reactions of (chromon-3-yl)bis(indol-3-yl)methanes with guanidine carbonate and hydrazine hydrate proceed with the participation of the chromone ring system and lead to the formation of the corresponding pyrimidines and pyrazoles bearing the bis(indol-3-yl)methyl moiety.     

Regioselective synthesis of 1-alkyl-5-(indol-3-yl- and -2-yl)pyrrolidin-2-ones from available reagents

The reaction under mild conditions of 1-alkyl-5-hydroxypyrrolidin-2-ones with different indoles having a free 3 position leads exclusively to 1-alkyl-5-(indol-3-yl)pyrrolidin-2-ones but if position 3 is occupied to 1-alkyl-5-(indol-2-yl)pyrrolidin-2-ones.     

Transformations of 3-formylindoles under the action of acids

Under the influence of acids 3-formylindole forms urorosein (the salt of di(indol-3-yl)methylium) which is unstable in solution and decomposes to give a series of indole derivatives, among which 6-(indol-3-yl)-5H,7H-indolo[2,3-b]carbazole and tri(indol-3-yl)methylium salt predominate. N,N′-Dimethylurorosein in solution also forms a mixture of indole derivatives, from which tri(1-methylindol-3-yl)methylium salt, 5N,11N-dimethylindolo[3,2-b]carbazole and its 6-(1-methylindol-3-yl) derivative were isolated. Research Institute of New Antibiotics, RAMN (Russian Academy of Medical Science), Moscow 119867, Russia; Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 631–639, May, 1999.     

Catalytic alkylation of cycloalkaneindoles and tetrahydro-γ-carboline with 9-oxiranylmethylcarbazole

Catalytic alkylation of substituted indoles such as cycloalkaneindoles and tetrahydro-γ-carboline using 9-oxiranylmethylcarbazole leads to the formation of 1-(carbazol-9-yl)-3-{dihydrocycloalkane[b]indol-4(1H)-yl}propan-2-ols and 1-(carbazol-9-yl)-3-{2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl}propan-2-ol, conjugates containing 2-hydroxypropylene spacer.     

Study of the transformations of 2-C-(indol-3-yl)methyl-α-l-xylo-hex-3-ulofuranosonic acid (the open form of ascorbigen) in an acidic medium

Transformation of ascorbigen in an acidic medium, which affects the carbohydrate moiety of the molecule and results in the formation of 2-hydroxy-4-hydroxymethyl-3-(indol-3-yl)cyclopent-2-enone, 5-hydroxymethyl-2-(indol-3-yl)methylidenetetrahydrofuran-3-one, and 2-(indol-3-yl)acetylfuran, was investigated. Isolation and identification of the intermediates allowed the elucidation of the mechanism of this domino-type reaction.     

Cyclic allylamine/enamine systems-6: Some reactions of 4-(indol-2-ylcarbonyl)-, 4-(indol-3-ylcarbonyl and 4-(indol- 3-ylmethyl)-1,2,5,6-tetrahydro-1 -methylpyridines

Indol-3-yl 1-methyl-1,2,5,6-tetrahydropyridin-4-yl ketone (1d) can be isomerised to indol-3-yl l-methyl-l,2,3,4-tetrahydropyridin-4-yl- ketone but the protonated form of this enamine could not be cyclised to the indole α-position. Both indol-2-yl l-methyl-l,2,5,6-tetrahydropyridin-4-yl ketone (1c) and its isomer (1d) were cyclised to 5-membered ketones by mineral acid catalysed Michael-type addition of indole β- and α-positions respectively onto the unsaturated ketone systems. Ketone (1d)was transformed to l-acetylindol-3-yl 3-acetyl-l,4,5,6-tetrahydropyridin-4-yl ketone by hot acetic anhydride. Strong base treatment of indol-3-yl(l,2,5,6-tetrahydropyridin-4-yl) methane caused isomerisation of the double bond into conjugation with the indole rather than into the endocyclic enamine position.     

Dual reactivity in 1,2-disubstituted dihydro-N-heteroaromatic systems. 12. Aromatization of 1-substituted-2-(indol-3-yl)-1,2-dihydroquinolines with 1,3,5-trinitrobenzene

As the electron-acceptor properties of the N-substituents in 1-R-2-(indol-3-yl)-1,2-dihydroquinolines decrease, their ability to undergo heterolysis of the internuclear C-C bond to give ion pairs of 1-R-quinolinium cations and indole anions decreases. Reaction of these ion pairs with 1,3,5-trinitrobenzene gives salts of 1-R-quinolinium cations and the 1-(indol-3-yl)-2,4,6-trinitrocyclohexadiene anion. With undissociated dihydroquinolines, aromatization under similar conditions gives salts of 1-R-2(indol-3-yl)quinolinium cations and the 1,1-dihydro-2,4,6-trinitrocyclohexadiene anion.For Communication 11, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 80–84, January, 1988.     

Convenient synthetic method for 3-(3-substituted indol-2-yl)quinoxalin-2-ones as VEGF inhibitor

It has already been reported that 3-(indol-2-yl)quinoxalin-2-ones have a potent inhibitory effect on the growth of tumor cells based on anti-angiogenesis activity. We have also carried out a structure-activity relationship (SAR) study of 3-(indol-2-yl)quinoxalin-2-ones, which showed a potent inhibitory activity toward the vascular endothelial growth factor (VEGF)-induced proliferation of human mesangial cells and the VEGF-induced auto-phosphorylation of human umbilical vein endothelial cells. Moreover, one of these compounds has a potent medicinal effect based on anti-angiogenic action, by oral administration (Chart 1, 9). However, since the existing synthetic methods for the preparation of 3-(indol-2-yl)quinoxalin-2-ones consist of multiple steps some of which require strict anhydrous conditions, a convenient and simple synthetic method in place of the existing method is desirable. As a result of the investigations into the synthetic procedures, 3-(3-substituted indol-2-yl)quinoxalin-2-ones can be easily prepared by the condensation of 3-substituted indoles with quinoxalin-2-ones in the presence of trifluoroacetic acid (TFA). Herein, we report the examination of these reaction conditions and the application of this new synthetic method to the synthesis of the derivatives as VEGF inhibitors.     

Synthesis and antimicrobial activity of N-(indol-5-yl)trifluoroacetamides and indol-5-ylaminium trifluoroacetates substituted in the pyrrole ring

Russian Chemical Bulletin - Based on a series of 1H-indol-5-ylamines substituted in the pyrrole ring, the corresponding N-(indol-5-yl)trifluoroacetamides and indol-5-ylaminium trifluoroacetates...     

Catalytic alkylation of substituted indoles with (phenothiazin-10-yl)propene-1-ones

Alkylation of substituted indoles (carbazoles, tetrahydrocarbazoles, and gamma-carbolines) with (phenothiazinyl)propenones catalyzed by cesium fluoride has led to the formation of 1-(phenothiazin-10-yl)-3-(carbazol-9-yl)propane-1-ones, (1-phenothiazin-10-yl)-3-(tetrahydrocarbazol-9-yl)propane-1-ones, and 3-(tetrahydropyrido[4,3-b]indol-5-yl)-1-(phenothiazin-10-yl)propane-1-ones, respectively.