Indolone Derivatives Research Articles

Synthesis and biological studies of acetophenone-based novel chalcone, semicarbazone, thiosemicarbazone and indolone derivatives: Structure-Activity relationship, molecular docking, molecular dynamics, and kinetic studies

This study presents the synthesis and evaluation of nine acetophenone derivatives (1–9), with compounds 2, 4, 5, 6, 7, and 9 being novel and synthesized for the first time. These derivatives encompass diverse structural motifs including chalcone, thiosemicarbazone, semicarbazone, and indolone derivatives. The structures of synthesized compound were confirmed by NMR analysis. The synthesized compounds were assessed for their in vitro enzyme inhibition against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-Glycosidase enzymes, as well as their antioxidant capacities using the DPPH radical scavenging assay. With Ki values ranging from 8.96±0.40 to 44.16±4.25 nM, these showed effective inhibition of AChE. However, the inhibitory characteristics of all drugs were almost the same. The Ki values of the two most active compounds, (3) and (4), were 8.96±0.40 and 11.33±0.58 nM, respectively. Regarding α-Glycosidase, they demonstrate that all novel compounds (1–9) have IC50 values between 30.16 and 133.98 µM, whereas the Ki values vary from 42.71±5.90 to 128.78±8.03 µM. Compound 4 emerged as a notable inhibitor, displaying significant inhibition against all used enzymes. Molecular docking studies revealed its exceptional binding affinities, corroborated by MM-GBSA ΔG binding free energies, and Glide Emodel scores. Compound 7 also exhibited promising inhibitory potential against α-Glycosidase. Docking scores for hAChE -12.207, for hBChE -10.140 and for α-Glycosidase -10.590 kcal/mol. The 250 ns molecular dynamics simulations confirmed the stability of the ligand-protein complexes, particularly with compound 4. The ligand-protein complexes were found extremely stable according to the MD simulations. Additionally, ADME predictions indicated favorable pharmacokinetic properties and drug-likeness for all compounds, further supporting their potential as orally active agents. Compound 4, in particular, stands out as a multitarget drug candidate, with strong inhibition against key enzymes implicated in neurodegenerative diseases and diabetes, suggesting its therapeutic potential in these conditions.

Structural Optimization, Anti‐TNBC Activities Evaluation, and Molecular Docking of an Indolone Derivative from Periplaneta americana

AbstractIn our previous work, an indolone derivative ZL170 was isolated and identified from Periplaneta americana (P. americana). Based on its characteristic structure, we used it as a lead compound to carry out structural optimization and subsequent antitumor activity evaluation. In the present study, a series of novel indolone derivatives bearing thiazole scaffold were designed and synthesized, and their antitumor activities against triple‐negative breast cancer (TNBC) were determined. The preliminary screening results showed that LJ3, LJ8, LJ23, and LJ27 display inhibition rates of over 60 % against MDA‐MB‐231cells at the concentration of 50 μM. Notably, LJ23 demonstrated an IC50 value of 32.19 μM against MDA‐MB‐231, prompting further evaluation of its inhibitory effect on TNBC cell motility. Results revealed that LJ23 effectively hindered TNBC cell migration through downregulation of the EMT process. Additionally, molecular docking was employed to predict the interaction mode between LJ23 and phosphoinositide 3‐kinase (PI3K).

Immobilization of ionic liquids (ILs) on magnetic mesoporous silica nanotubes: A high throughput and reusable nanocatalyst for the green synthesis of indeno[1,2-b]indolone derivatives

The acidic ionic liquid supported on the magnetic mesoporous silica nanotubes (M-MSNTs/IL) was prepared as a new magnetic catalyst and fully characterized with FE-SEM, HR-TEM, EDS, TGA, BET, VSM, FT-IR, EDX, elemental mapping and XPS. The template of catalyst was magnetic aminated MWCNTs (M-MWCNTs/CONHBu), which removed through calcination process and magnetic mesoporous silica nanotubes (M-MSNTs) were obtained and functionalized using adenine based ionic liquid. The prepared catalyst was successfully applied as a new reusable heterogeneous catalyst for the one-pot three-component indeno[1,2-b]indole-9,10-dione derivatives in water at 75 °C. All of desired products were obtained in good to excellent yields (79–96 %) after relatively short reaction times. M-MSNTs/IL also exhibited a remarkable performance with TOF of 61.2 h-1 and TON of 86.7. The use of M-MSNTs/IL catalyst in the synthesis of indeno[1,2-b]indole-9,10-dione derivatives revealed several advantages including mild reaction conditions, high yield of pure products, clean reaction conditions, avoiding the production of toxic waste, chemical stability of the catalyst, low amount and reusability of catalyst. In addition, the applied nanocatalyst was recovered with an external magnet and reused 6 times without considerable reduction in its catalytic activity.

Sonocatalysis green synthesis of indeno[1,2‐b]indolone derivatives using CuFe2O4@CS‐SB nanocomposite as a reusable catalyst under mild conditions

In this literature, the synthesis of indeno[1,2‐b]indolone from starting materials of ninhydrin, derivatives of aniline, and dimedone by using copper ferrite anchored to chitosan bearing Schiff base (CuFe2O4@CS‐SB) as a catalyst in water solvent under ultrasound irradiation was described. This catalyst was designed, fabricated, and characterized by the FT‐IR, 1H NMR, XRD, SEM, TGA, mapping scan, EDX, and BET techniques. This prepared acidic, effective heterogeneous catalyst catalyzed green synthesis of indeno‐indolone derivatives in a very short reaction times between 1 and 7 min with excellent yields between 95% and 99%. Also, the FT‐IR, 1H NMR, and melting point analyses are used to identify the synthesis of the indolones as organic products.

Fabrication and characterization of inorganic-organic hybrid copper ferrite anchored on chitosan Schiff base as a reusable green catalyst for the synthesis of indeno[1,2-b]indolone derivatives.

This study presents a description of the catalytic synthesis of indeno[1,2-b]indolone derivatives. In this method, initially, a Schiff base compound was synthesized from the reaction of acetylacetone with 2-hydroxyaniline. Then, the prepared Schiff base was immobilized on chelated magnetic copper ferrite nanoparticles with a chitosan surface to design and prepare the CuFe2O4@CS-SB nanocomposite. Further, the one-pot multi-component cyclization reaction of aniline, dimedone and ninhydrin was conducted using the synthesized nanocomposite as a heterogeneous acid catalyst in water solvent under thermal conditions. In this reaction, the products were obtained in excellent yields and short reaction times, and the catalyst could be recycled and reused six times without any loss in product yields. By conducting FT-IR spectroscopy, 1H NMR spectroscopy, XRD, FE-SEM, TGA, elemental mapping scanning, EDX and BET analyses, the structure of the nanocatalyst was characterized. In addition, for the identification of organic compounds, FT-IR, 1H NMR, and 13C NMR spectroscopies and melting point analysis were used, which confirmed the synthesis of this class of derivatives.

Potassium persulfate mediated oxidative dearomatization and C–H functionalization of indoles in water: Green and transition metal free approach for the synthesis of indolone derivatives

An operationally simple, transition metal-free “Greener Approach” for the synthesis of 2-(1H-indol-3-yl)-2,3’- bisindolin-3-one derivatives using K2S2O8 as an eco-friendly oxidant in water is described for electron rich and deficient indoles. Reactions in water and acetonitrile are done for confirming the intermediate and yield. The reaction proceeds through a radical pathway, confirmed by EPR, with C3 oxidative dearomatization followed by trimerization. Preliminary photophysical studies are done for selected compounds with donor-acceptor functional groups.

An efficient one-pot synthesis of acenaphtho[1,2-b]indolindeneone and acenaphtho[1,2-b]indoldione derivatives

A simple method for the synthesis of acenaphtho[1,2-b]indolindenedione derivatives and acenaphtho[1,2-b]indolone derivatives via four-component reaction is described. The reaction between dimedone, arylamines, acenaphthoquinone, and 1,3-indondione in refluxing ethanol under catalyst-free conditions are produced the title compounds. The advantages of this method are: environmental friendly, short reaction time, easy work-up, and high yield.

Design, synthesis, and biological evaluation of a series of indolone derivatives as novel FLT3 inhibitors for the treatment of acute myeloid leukemia

FLT3-ITD mutant has been extensively studied as a drug discovery target for acute myeloid leukemia. Based on our previous discovered FLT3 inhibitor (2), a series of urea group based indolone derivatives were designed, synthesized, and biological evaluated as novel FLT3 inhibitors for the treatment of FLT3-ITD positive AML. Among them, compound LC-3 exhibited potent inhibitory effects against FLT3 (IC50 = 8.4 nM) and significantly inhibited the proliferation of FLT3-ITD positive AML cells MV-4-11 (IC50 = 5.3 nM). In the cellular context, LC-3 strongly inhibited FLT3-mediated signaling pathways and induced cellular apoptosis by arresting cell cycle in G1 phase. In the in vivo studies, LC-3 significantly suppressed the tumor growth on MV-4-11 xenograft models (10 mg/kg/day, TGI = 92.16%) without exhibiting obvious toxicity. These results suggested that compound LC-3 might be a potential drug candidate for FLT3-ITD positive AML.

Synthesis and Biological Evaluation of Novel Synthetic Indolone Derivatives as Anti-Tumor Agents Targeting p53-MDM2 and p53-MDMX.

A series of novel indolone derivatives were synthesized and evaluated for their binding affinities toward MDM2 and MDMX. Some compounds showed potent MDM2 and moderate MDMX activities. Among them, compound A13 exhibited the most potent affinity toward MDM2 and MDMX, with a Ki of 0.031 and 7.24 μM, respectively. A13 was also the most potent agent against HCT116, MCF7, and A549, with IC50 values of 6.17, 11.21, and 12.49 μM, respectively. Western blot analysis confirmed that A13 upregulated the expression of MDM2, MDMX, and p53 by Western blot analysis. These results indicate that A13 is a potent dual p53-MDM2 and p53-MDMX inhibitor and deserves further investigation.

2D-QSAR modeling, drug-likeness studies, ADMET prediction, and molecular docking for anti-lung cancer activity of 3-substituted-5-(phenylamino) indolone derivatives

2D-QSAR modeling, drug-likeness studies, ADMET prediction, and molecular docking for anti-lung cancer activity of 3-substituted-5-(phenylamino) indolone derivatives

Visible light promoted polyhalomethylation of alkenes: alkylation and cyclization

The report describes a visible light promoted carbochloromethylation of 2-bromomethyl acrylate and N-arylmethacrylamide, and a series of trihalomethyl substituted allylic acid esters and indolone derivatives were synthesized.

Design, Synthesis, and Biological Evaluation of a Series of Indolone Derivatives as Novel Flt3 Inhibitors for the Treatment of Acute Myeloid Leukemia

Design, Synthesis, and Biological Evaluation of a Series of Indolone Derivatives as Novel Flt3 Inhibitors for the Treatment of Acute Myeloid Leukemia

Transition Metal-Free, Methoxide-Catalyzed Synthesis of Pyridoindolones.

A simple transition metal-free strategy for the synthesis of pyrido[1,2-a]indolone derivatives has been devised through sodium methoxide-catalyzed intramolecular cyclization of 2-alkenylated N-pyrimidyl indoles. The reactions involved a Smiles rearrangement/cyclization cascade, which resulted in a new series of N-fused indoles, potentially applicable skeletons in medicinal chemistry. This reaction presents simple eco-friendly reaction conditions, a high atom- and cost-economy, a short reaction time, and a broad range of substrate scope with high reaction efficiency.

Synthesis of Fused Pyrimido[1,6-a]indolones via Rhodium(III)-Catalyzed Cascade Annulations

AbstractA novel method for the synthesis of fused pyrimido[1,6-a]-indolone derivatives by annulation of 2-alkynylaryl aldehydes/2-alkynyl­arylidene ketones with N-(pivaloyloxy)-1H-indole-1-carboxamide catalyzed by rhodium has been accomplished. The reaction proceeds through C–H activation based annulation with alkyne moiety followed by addition of nitrogen on to aldehyde/activated alkene to give the products in moderate to good yields. Highly fluorescent dipyrrinone analogues could be synthesized from the derived products.

Zinc-Catalyzed Alkyne-Carbonyl Metathesis of Ynamides with Isatins: Stereoselective Access to Fully Substituted Alkenes.

A zinc-catalyzed intermolecular alkyne-carbonyl metathesis reaction of ynamides with isatins followed by an amide to esterconversion has been developed, which produces the indolone derivatives with a fully substituted alkene species in good to high yields. The salient features of this reaction include the following: mild reaction conditions, aninexpensive zinc catalyst, a broad substrate scope, theexcellent regiocontrol and stereoselectivity, andamenable to the gram scale.

Dual inhibitors of RAF-MEK-ERK and PI3K-PDK1-AKT pathways: Design, synthesis and preliminary anticancer activity studies of 3-substituted-5-(phenylamino) indolone derivatives.

The dysfunction and mutual compensatory activation of RAF-MEK-ERK and PI3K-PDK1-AKT pathways have been demonstrated as the hallmarks in several primary and recurrent cancers. The strategy of concurrent blocking of these two pathways shows clinical merits on effective cancer therapy, such as combinatory treatments and dual-pathway inhibitors. Herein, we report a novel prototype of dual-pathway inhibitors by means of merging the core structural scaffolds of a MEK1 inhibitor and a PDK1 inhibitor. A library of 43 compounds that categorized into three series (Series I-III) was synthesized and tested for antitumor activity in lung cancer cells. The results from structure-activity relationship (SAR) analysis showed the following order of antitumor activity that 3-hydroxy-5-(phenylamino) indolone (Series III) > 3-alkenyl-5-(phenylamino) indolone (Series I) > 3-alkyl-5-(phenylamino) indolone (Series II). A lead compound 9za in Series III showed most potent antitumor activity with IC50 value of 1.8 ± 0.8 µM in A549 cells. Moreover, antitumor mechanism study demonstrated that 9za exerted significant apoptotic effect, and cellular signal pathway analysis revealed the potent blockage of phosphorylation levels of ERK and AKT in RAF-MEK-ERK and PI3K-PDK1-AKT pathways, respectively. The results reported here provide robust experimental basis for the discovery and optimization of dual pathway agents for anti-lung cancer therapy.

Fe3O4 magnetic nanoparticles in the layers of montmorillonite as a valuable heterogeneous nanocatalyst for the one-pot synthesis of indeno[1,2-b]indolone derivatives in aqueous media

In the present work, iron oxide nanoparticles (Fe3O4-NPs) were prepared using a chemical coprecipitation method. At room temperature, Fe3O4-NPs are put in interlamellar space and external surfaces of montmorillonite (MMT) as a supported solid. The MMT@Fe3O4 was characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), vibrating sample magnetometer (VSM), thermogravimetric analysis (TGA) and Fourier transform infrared spectrophotometry (FT-IR). Then, indeno[1,2-b]indolone derivatives were catalyzed by magnetic MMT@Fe3O4-NPs. MMT@Fe3O4-NPs were found to be a recoverable organocatalyst for the effective synthesis of the indeno[1,2-b]indolone derivatives via one-pot multicomponent cyclocondensation of ninhydrin, 1,3-diketo compound and amine derivatives in water. The significant advantages of this method are excellent yield, mild conditions, eco-friendly catalyst, low expense, and not using an environmentally harmful catalyst or solvent.

Catalyst‐free Synthesis of Tetrahydroacenaphtho[1,2‐b]indolone Derivatives via One‐pot Four‐component Reaction

A simple and efficient one‐pot synthesis of tetrahydroacenaphtho[1,2‐b]indolone derivatives via four‐component reaction of 5,5‐dimethylcyclohexane‐1,3‐dione (dimedone), arylamines, acenaphthoquinone, and active methylene compounds under catalyst‐free conditions is described. The reactions were carried out under mild conditions using ethanol as solvent. Advantages of this method include simple experimental and workup procedure, readily available starting materials, and high yields.

Role of Quinone Reductase 2 in the Antimalarial Properties of Indolone-Type Derivatives

Indolone-N-oxides have antiplasmodial properties against Plasmodium falciparum at the erythrocytic stage, with IC50 values in the nanomolar range. The mechanism of action of indolone derivatives involves the production of free radicals, which follows their bioreduction by an unknown mechanism. In this study, we hypothesized that human quinone reductase 2 (hQR2), known to act as a flavin redox switch upon binding to the broadly used antimalarial chloroquine, could be involved in the activity of the redox-active indolone derivatives. Therefore, we investigated the role of hQR2 in the reduction of indolone derivatives. We analyzed the interaction between hQR2 and several indolone-type derivatives by examining enzymatic kinetics, the substrate/protein complex structure with X-ray diffraction analysis, and the production of free radicals with electron paramagnetic resonance. The reduction of each compound in cells overexpressing hQR2 was compared to its reduction in naïve cells. This process could be inhibited by the specific hQR2 inhibitor, S29434. These results confirmed that the anti-malarial activity of indolone-type derivatives was linked to their ability to serve as hQR2 substrates and not as hQR2 inhibitors as reported for chloroquine, leading to the possibility that substrate of hQR2 could be considered as a new avenue for the design of new antimalarial compounds.

A Cascade C–H‐Functionalization/Cyclization Reaction of Indoles with α‐Halo or α‐Sulfonyloxy Ketones for the Synthesis of Dihydropyrimidoindolone Derivatives

A new cascade C–H‐functionalization/cyclization reaction of N‐carbamoylindoles 1 with α‐halo, α‐mesyloxy, or α‐tosyloxy ketones 2 has been developed under rhodium(III) catalysis, leading to dihydropyrimido[1,6‐a]indolone derivatives 3 in moderate to excellent yields.