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One-pot, three components, conventional and microwave-assisted synthesis of bisindolyl analogs is described. Michael addition of preformed 2,5-disubstituted indole-3-carboxaldehydes and 3-methyl-1H-pyrazol-5(4H)-one with 2,5-disubstituted indoles under solvent and catalyst-free conditions afforded the hitherto unreported 2,5-disubstituted bisindolyl analogs bearing a pyrazolone moiety in excellent yields. All the synthesized compounds were characterized using IR, 1H NMR, mass spectral, and analytical data. The analogs were screened for in vitro cytotoxic and DNA cleavage studies. Among the screened compounds 4c, 4f, and 4h-4j have emerged as most potent cytotoxic and 4c and 4f-4h as active DNA cleavage analogs.

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Development of small molecule drug-like inhibitors blocking both nitric oxide synthase and NFkappaB could offer a synergistic therapeutic approach in the prevention and treatment of inflammation and cancer. During the course of evaluating the biological potential of a commercial compound library, 2-phenylindole (1) displayed inhibitory activity against nitrite production and NFkappaB with IC50 values of 38.1 ± 1.8 and 25.4 ± 2.1 muM, respectively. Based on this lead, synthesis and systematic optimization have been undertaken in an effort to find novel and more potent nitric oxide synthase and NFkappaB inhibitors with antiinflammatory and cancer preventive potential. First, chemical derivatizations of 1 and 2-phenylindole-3-carboxaldehyde (4) were performed to generate a panel of N-alkylated indoles and 3-oxime derivatives 2-7. Second, a series of diversified 2-arylindole derivatives (10) were synthesized from an array of substituted 2-iodoanilines (8) and terminal alkynes (9) by applying a one-pot palladium catalyzed Sonogashira-type alkynylation and base-assisted cycloaddition. Subsequent biological evaluations revealed 3-carboxaldehyde oxime and cyano substituted 2-phenylindoles 5 and 7 exhibited the strongest nitrite inhibitory activities (IC50 = 4.4 ± 0.5 and 4.8 ± 0.4 muM, respectively); as well as NFkappaB inhibition (IC50 = 6.9 ± 0.8 and 8.5 ± 2.0 muM, respectively). In addition, the 6?-MeO-naphthalen-2?-yl indole derivative 10at displayed excellent inhibitory activity against NFkappaB with an IC50 value of 0.6 ± 0.2 muM.

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Described is an efficient oxidative dearomatization of indoles with TEMPO oxoammonium salt and a broad range of nucleophiles. Under very mild conditions, dearomative oxyalkynylation and oxyalkenylation of indoles to structurally diverse 2,2-disubstituted indolin-3-ones were developed for the first time with high atom-economy. In addition, dearomative oxyarylation, oxyallylation, and oxycyanation of indoles were also demonstrated. Mechanism studies indicated that TEMPO oxoammonium salt served as the sole oxidant source through an electron donor-acceptor (EDA) intermediate.

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The development of very high affinity, selective, and bioavailable h5-HT2A receptor antagonists is described. By investigation of the optimal position for the basic nitrogen in a series of 2-phenyl-3-piperidylindoles, it was found that with the basic nitrogen at the 3-position of the piperidine it was not necessary to further substitute the piperidine in order to obtain good binding at h5-HT2A receptors. This meant the compounds no longer had high affinity at the IKr potassium channel, an issue with previous series of 2-aryl-3-(4-piperidyl)indoles. Improvements could be made to oral bioavailability in this series by reduction of the pKa of the basic nitrogen, by adding a fluorine atom to the piperidine ring, leading to 3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (17). Metabolic studies with this compound identified oxidation at the 6-position of the indole as a major route in vitro and in vivo in rats. Blocking this position with a fluorine atom led to 6-fluoro-3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (22), an antagonist with 0.06 nM affinity for h5-HT2A receptors, with bioavailability of 80% and half-life of 12 h in rats.

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A novel and efficient method for the oxidation of 2-arylindoles to synthesize 2-arylbenzoxazinones utilizing oxone as the sole oxidant has been developed. The reaction tolerates a wide range of functional groups and allows quick and atom-economical assembly of a variety of valuable 2-arylbenzoxazinones in high yields.

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We report the synthesis, characterization, and cytotoxic and antimalarial activity of ferrocene-indole hybrids 8-14. The 2-phenylindole scaffold was chosen because of its potent antimitotic activity and ferrocene was chosen following the development of ferrocifens, ferrocene derivatives of tamoxifen, which are prototypes of a new family of organometallic anti-estrogens. Ferrocene-indole hybrids 8-14 and their corresponding organic analogues 1-7 showed only moderate antimalarial activities, while ferrocene-indole hybrids 11 and 12 showed excellent in vitro activities against the A549 human carcinoma cell line, with IC50 values of 5 and 7 muM respectively. These ferrocene-indole hybrids were up to 25-fold more potent as cytotoxic agents than their purely organic analogues.

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The invention discloses a method for synthesis of indole with the nitrile is straight, is characterized in that in order to 2 – iodo toluene derivatives as the substrate, the anhydrous copper sulfate and potassium tertiary butyl alcohol, nitrile derivatives with 2 – iodo toluene derivatives mol ratio of 0.02 – 0.1: 2 – 4:5 – 20:1, in the solvent for 60 – 105 C reaction 4 – 48 h, petroleum ether/dichloromethane/ethyl acetate according to volume 20 – 5:10: 1 mixed as eluant, over silica gel column separation, to obtain the target product. The method of the invention the operation is simple, mild condition, the yield is high, it is a green novel synthetic method. (by machine translation)

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An efficient metal-free strategy for the synthesis of pharmaceutically relevant benzo[a]carbazoles from the derivatives of readily available 2-phenylindole and bio-renewable acetol in an aqueous biphasic system was developed. This protocol employed a sulfone-containing Broensted acidic ionic liquid as the catalyst, which could be used for five times without a noticeable decrease in its activity and selectivity. Various substituted 2-phenylindoles and alpha-hydroxyketones participated in the reaction smoothly, with water as the sole byproduct. Mechanistically, the reaction involved the conventional carbon-nucleophile-induced Heyns-type rearrangement and downstream intramolecular olefination.

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A variety of 2-aminobenzonitriles were prepared from 2-arylindoles in good to excellent yields through tert-butylnitrite (TBN)-mediated nitrosation and sequential iron(III)-catalyzed C-C Bond cleavage in a one-pot fashion. The 2-aminobenzonitriles can be used to rapidly synthesize benzoxazinones by intramolecular condensation. The present method features an inexpensive iron(III) catalyst, gram scalable preparations, and novel C-C bond cleavage of indoles.

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A palladium-catalyzed expeditious synthesis of dibenzofused carbazoles from readily available 2-arylindoles and diaryliodonium salts is reported. Interestingly, after the electrophilic C3 palladation of indole, an unexpected “through-space” 1,4-palladium migration to the 2-aryl moiety, by remote C-H bond activation followed by C-H arylation with diaryliodonium salt, and an unprecedented 1,2-aryl shift take place. Finally, an intramolecular cross-dehydrogenative coupling (CDC) at the C2 position affords dibenzo[a,c]carbazoles in high yields. Remarkably, the present migratory annulation occurs through three C-H bond activation one C-C bond cleavage, and the simultaneous construction of three new C-C bonds in a single operation.

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