N-substituted Indole Derivatives Research Articles

Design, synthesis and antibacterial evaluation of N-substituted indole derivatives containing 1,3,4-thiadiazole and amide moieties

A total of eighteen novel 2-(1H-indol-1-yl)-N-(5-phenyl-1,3,4-thiadiazol-2-yl) acetamide derivatives were synthesized through the condensation reaction of 2-(1H-indol-1-yl) acetic acid and 5-phenyl-1,3,4-thiadiazol-2-amine via fragment-based design strategy. The target compounds were subjected to screening for antibacterial activity against Xanthomonas oryzae pv. Oryzae, Xanthomonas axonopodis pv. Citri and Pseudomonas syringae pv. Actinidiae. The preliminary antibacterial evaluation of the target compounds showed that some target compounds possessed moderate to good activities against Xoo and Xac. Among them, compound 3p exhibited best inhibition effects against Xoo (77.85% and 62.15%, respectively) and Xac (52.51% and 36.48%, respectively) at 100 μg/mL and 50 μg/mL, which were superior to Thiodiazole-copper and Bismerthiazol. To the best of our knowledge, it is the first report on the design, synthesis, and antibacterial evaluation of novel indole-derived compounds containing 1,3,4-thiadiazole and amide moieties.

Synthesis and investigation of the structure, thermal, optical, and electrical properties of poly (indol-thiazolo-thiadiazole) derivatives at room temperature

This research work is intended for the novel synthesis and study of structural, thermal, optical, electrical, and dielectric properties of semiconductor poly (2-amino-5-(1H-indolyl)-5H-thiazolo[4,3-b]-1,3,4-thiadiazole) (PAITTD) and its N-substituted indole derivatives with a side chain containing chlorobenzoyl (PACBITTD) and bromobenzene sulphonyl (PABBSITTD). The characterization techniques such as H1NMR, FTIR, SEM, and TGA/DSC ensured the structural and thermal properties of the as-synthesized polymers. In addition, the molecular weight of the PAITTD, PACBITTID, and PABBSITTD was calculated via H1NMR technique. The optical band gap as obtained from the absorbance study was found to be in the range of 1.5 eV to 2.58 Ev. Moreover, the ground-state geometries and the absorption wavelengths for the studied compounds were investigated by DFT and TD-DFT, where the theoretical results show coincidence with these of the experimental where the calculated (λmax) values are approximately near to the experimental (λmax) values for the PAITTD, PACBITTID, and PABBSITTD. The impedance ac conductivity and dielectric properties of the PAITTD, PACBITTID, and PABBSITTD were performed in the frequency ranges from 20 Hz to 10 MHz at room temperature, where their values were 3.0 × 10−7, 8.7 × 10−7, and 2.6 × 10−6, respectively. The Nyquist plot confirmed the presence of both grain and grain boundary effects for conducting PAITTD, PACBITTID, and PABBSITTD, and Double relaxation behavior was also observed. The variation of ac conductivity with frequency obeys the modification of Jonscher’s universal power law (JUPL). Based on the optical and electrical properties, synthetic PAITTD, PACBITTID, and PABBSITTD are promising materials in the design of optoelectronic semiconductor devices.

Synthesis, Molecular Docking and ADME Prediction of 1H-indole/5- substituted Indole Derivatives as Potential Antioxidant and Anti- Inflammatory Agents.

Inflammation is a protective biological process, but under extreme conditions, it can become highly dreadful to the body. Antioxidant and anti-inflammatory agents treat similar disease conditions as inflammation and oxidative stress commonly follow similar causative pathways. The goal of this study was to synthesize N-substituted indole derivatives with different heterocyclic moieties through propyl linker with the aim of getting highly potent anti-inflammatory and antioxidant agents. Synthesized compounds were analyzed by analytical techniques such as IR, 1H NMR, 13C NMR spectra, and mass spectrometry. Molecular docking and ADME calculation were employed on synthesized compounds to estimate their COX-2 enzyme inhibition and drug like properties, respectively. Antioxidant activity was evaluated by the DPPH assay and the reducing power assay. Selected derivatives were evaluated for anti-inflammatory activity at an acute (carrageenan-induced paw edema method) and chronic level (formalin-induced inflammation method) using indomethacin as a standard drug. Herein, twelve indole derivatives (11a-c, 12a-c, 13a-c, and 14a-c) were synthesized. Among all, compound 12c was found to be the best inhibitor of the COX-2 enzyme as it displayed good interaction energy. Zero violations of Lipinski's rule were found in the ADME investigation, confirming the drug-like qualities of synthesized compounds. The compounds 11a and 12c were found to be the most potent as compared with standard ascorbic acid in antioxidant evaluation. From the collected results, compounds 12c and 13b were the most potent against acute and chronic inflammation. The novel synthetic indole derivatives could act as potent leads for the development of novel antioxidant and anti-inflammatory agents.

Synthesis, Molecular Docking and Biological Evaluation of N‐Substituted Indole Derivatives as Potential Anti‐Inflammatory and Antioxidant Agents

Novel N-substituted Indole derivatives with various hetero-cyclic moieties were synthesized via an ethyl linker in order to obtain highly potent anti-inflammatory and antioxidant agents. The structure of the obtained chemical compounds was determined using IR, 1 H-NMR, and mass spectroscopy. Molecular docking was used to create selective and efficient COX-2 inhibitors from twelve novel indole derivatives (11a-c, 12a-c, 13a-c, and 14a-c). The compounds 13b and 14b had a high interaction energy, which inhibited the COX-2 enzyme. There is a relationship between anti-inflammatory activity and antioxidants, which is also defined by COX-2 inhibition, according to the mechanism of action. The Swiss ADME online programme was used to determine the drug-like properties of synthesized compounds. Two common and reliable methods were adopted to determine the antioxidant effect. In the DPPH assay, compounds 11a, 11b, and 14b, whereas compounds 11b, 13b, and 14b in the reducing power assay, were the most potent as compared with standard ascorbic acid. To evaluate the anti-inflammatory effect at an acute and chronic level, the carrageenan-induced paw edema method along with the formalin-induced inflammation method were used both at low dose and high dose. From the collected results, compounds 13b and 14b were the most potent against acute and chronic inflammation. The results showed that the synthesized compounds are unique as anti-inflammatory and antioxidant agents, and that they could be useful for drug discovery in the future.

Synthesis and Evaluation of Antimicrobial Activity of N-Substituted Indole Derivatives and Molecular Docking Studies

Abstracts: The increasing burden of microbial infection and emerging resistance against the available antimicrobial drugs drives the development of new agents. Two different series of indole-based compounds (VN-1 to VN-18) were synthesized and analyzed for antimicrobial activity by calculating the diameter of the inhibition zone using the broth dilution method and well diffusion method against Escherichia coli (E. coli) and environmental microbes. Most of the compounds displayed good to moderate activity against E. coli, and VN-4 and VN-9 displayed good inhibitory activity against the tested microbes. Molecular docking and binding energy calculation studies of all the synthesized compounds have been performed for targeting FabI, where most of the compounds showed significant interactions with the aromatic nicotinamide moiety of NAD+. In molecular dynamics studies, VN-9 stays inside the binding cavity for sufficient time to induce antimicrobial activity. Thus, these indole-based derivatives may lead to the development of new antimicrobial agents that may act as FabI inhibitors.

Synthesis and Absorption Properties of Trisubstituted Hetarylazo Indole Dyes

In this study, as a result of azo coupling of diazonium salts prepared with various aromatic amines with 2-(4-methylphenyl)-1H-indole and 2-(4-chlorophenyl)-1H-indole compounds, a series of new hetarylazo indole dyes were synthesized. N-substituted indole derivatives were synthesized by alkylation of the prepared dyes with the isopropyl alcohol from the N-position by Mitsunobu reaction. The chemical structures of the synthesized compounds were determined by NMR, FT-IR, UV-vis, mass spectrometry and elemental analysis. In order to determine the photophysical properties of the dyes obtained, visible region absorption spectra were examined in solvents of different polarity. In addition, the behavior of acid and base addition on absorption maxima were examined in detail.

Synthesis and Evaluation of Antimicrobial Activities of Novel N-Substituted Indole Derivatives

Indole motifs are one of the most significant scaffolds in the discovery of new drugs. We have described a synthesis of new N-substituted indole derivatives (1-3), and their in vitro antimicrobial activities were investigated. The synthesis of titled compounds has been demonstrated by utilizing commercially available starting materials. The antibacterial and antifungal activities were performed using new strains of bacteria Staphylococcus aureus, Escherichia coli, and Candida albicans using the disc diffusion method. Notably, the compound 4-(1-(2-(1H-indol-1-yl) ethoxy) pentyl)-N,N-dimethyl aniline (1) was found to be most potent than the other analogues (2 and 3), which has shown higher inhibition than the standard drug chloramphenicol.

Synthesis of N-substituted indole derivatives as potential antimicrobial and antileishmanial agents.

Leishmaniasis and microbial infections are two of the major contributors to global mortality and morbidity rates. Hence, development of novel, effective and safer antileishmanial and antimicrobial agents having reduced side effects are major priority for researchers. Two series of N-substituted indole derivatives i.e. N-substituted indole based chalcones (12a-g) and N-substituted indole based hydrazide-hydrazones (18a-g, 19a-f, 21 a-g) were synthesized. The synthesized compounds were characterized by 1H NMR, 13C NMR, Mass and FT-IR spectral data. Further these derivatives were evaluated for their antimicrobial potential against Escherichia coli, Bacillus subtilis, Pseudomonas putida and Candida viswanathii, and antileishmanial potential against promastigotes of Leishmania donovani. Compounds 18b, 18d and 19d exhibited significant activity with an IC50 of 0.19±0.03µM, 0.14±0.02µM and 0.16±0.06µM against B. subtilis which was comparable to chloramphenicol (IC50 of 0.25±0.03µM). Compounds 12b and 12c exhibited an IC50 of 24.2±3.5µM and 21.5±2.1µM in the antileishmanial assay. Binding interactions of indole based hydrazide-hydrazones were studied with nitric oxide synthase in silico in order to understand the structural features responsible for activity.

Discovery and structure-activity relationship studies of N-substituted indole derivatives as novel Mcl-1 inhibitors

Myeloid cell leukemia-1 (Mcl-1) is an important antiapoptotic protein functioning through protein-protein interactions. We discovered LSL-A6 (2-((2-carbamoyl-1-(3-(4-methoxyphenoxy)propyl)-1H-indol-6-yl)oxy)acetic acid) with a novel N-substituted indole scaffold to interfere Mcl-1 binding as a novel Mcl-1 inhibitor. Molecular modeling indicated that this compound binds with Mcl-1 by interaction with P2 and R263 hot-spots. Structure modification focused on several moieties including indole core, hydrophobic tail and acidic chain were conducted and structure-activity relationship was analyzed. The most potent compound 24d which exhibited Ki value of 110nM for interfering Mcl-1 binding was obtained after hit-to-lead modification.

Novel N-substituted indole Schiff bases as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase enzymes: Synthesis, biological activities in vitro and docking study

Two new series of N-substituted indole derivatives 4a–l and 5a–h were synthesized. Their chemical structures were confirmed using spectroscopic tools including IR, 1H NMR, 13C NMR mass spectroscopy and elemental analyses. The results showed no significant cytotoxic activity on either cancer or normal human cells. Anti-inflammatory activity for all target compounds was evaluated in vitro. Compounds 5a–h were found to have better anti-inflammatory activity than 4a–l. The inhibitory activity of COX-2 and 5-LOX were tested for 5a–h. Three compounds, 5c, 5d and 5f showed excellent COX-2 inhibitory activity with IC50 ranging from 0.98 to 1.23 μM compared to the reference celecoxib (1.54 μM). These compounds had a reasonable selectivity index between 7.03 and 8.05. Additionally, p-methylbenzoyl derivative 5g (IC50 = 5.78 μM) had superior 5-LOX inhibitory activity, higher than quercetin. 5e was close to quercetin in its LOX inhibitory activity. Compounds 5a–h were docked inside the active site of COX-2 and 5-LOX enzymes.

ChemInform Abstract: Direct Fluoroalkylation of Indoles with Fluoroalkyl Halides Mediated by Copper.

An efficient and mild copper-mediated reaction for the direct perfluoroalkylation and difluoromethylation of indoles with perfluoroalkyl halides and ICF2COOEt to produce 2-substituted indoles was developed. Both free indole derivatives and N-substituted indole derivatives could be used in this process to obtain the desired products in moderate to good yields.

Palladium‐Catalyzed One‐Pot Three‐ or Four‐Component Coupling of Aryl Iodides, Alkynes, and Amines through CN Bond Cleavage: Efficient Synthesis of Indole Derivatives

An efficient synthesis of N-substituted indole derivatives was realized by combining the Pd-catalyzed one-pot multicomponent coupling approach with cleavage of the C(sp(3))-N bonds. Three or four components of aryl iodides, alkynes, and amines were involved in this coupling process. The cyclopentadiene-phosphine ligand showed high efficiency. A variety of aryl iodides, including cyclic and acyclic tertiary amino aryl iodides, and substituted 1-bromo-2-iodobenzene derivatives could be used. Both symmetric and unsymmetric alkynes substituted with alkyl, aryl, or trimethylsilyl groups could be applied. Cyclic secondary amines such as piperidine, morpholine, 4-methylpiperidine, 1-methylpiperazine, 2-methylpiperidine, and acyclic amines including secondary and primary amines all showed good reactivity. Further application of the resulting indole derivatives was demonstrated by the synthesis of benzosilolo[2,3-b]indole.

Bifunctional cinchona alkaloid-squaramide-catalyzed highly enantioselective aza-Michael addition of indolines to α,β-unsaturated ketones.

An enantioselective aza-Michael addition of indolines to α,β-unsaturated ketones was achieved using a bifunctional cinchona alkaloid-derived chiral squaramide derivative. Various β-indolinyl ketone derivatives were obtained in good to excellent yields and with high enantioselectivity. DDQ or MnO2 oxidation of indoline derivatives provided convenient access to various enantioenriched N-substituted indole derivatives.

Ir(I)-Catalyzed C–H Bond Alkylation of C2-Position of Indole with Alkenes: Selective Synthesis of Linear or Branched 2-Alkylindoles

A cationic iridium-catalyzed C2-alkylation of N-substituted indole derivatives with various alkenes has been developed, which selectively gives linear or branched 2-alkylindoles in high to excellent selectivity. This protocol relies on the use of the carbonyl group on the nitrogen atom of indole as a directing group: a linear product was predominant when an acetyl group was used as a directing group, and a branched product was predominant with a benzoyl group.

ChemInform Abstract: Synthesis of Some N-Substituted Indole Derivatives and Their Biological Activities.

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Synthesis of N-Substituted Indole Derivatives via PIFA-Mediated Intramolecular Cyclization

[Structure: see text] A variety of N-arylated and N-alkylated indole derivatives were synthesized by way of a phenyliodine bis(trifluoroacetate) (PIFA)-mediated intramolecular cyclization. This novel method allows for the construction of an indole skeleton by joining the N-atom on the side chain to the benzene ring at the last synthetic step. Other novel pyrrole-fused aromatic compounds can also be achieved by this method.