Indolinone Derivatives Research Articles

Identification of novel indolinone derivatives as CTSC inhibitors to treat inflammatory bowel disease by modulating inflammatory factors

Novel inflammatory bowel disease (IBD) therapeutic drugs, mainly biologics that neutralize pro-inflammatory factors and janus kinase inhibitors that inhibit cytokine-mediated signal transduction, face problems including low efficacy rates, limited therapeutic benefits, and infection risks. It is an important task to find proteins that broadly regulate a variety of cytokines and to develop corresponding drugs. Cathepsin C (CTSC) mediates neutrophil-related inflammatory, participates in the recruitment and activation of inflammatory cells, and regulates cytokines levels, and is considered an ideal target for IBD treatment. In this study, starting from the in-house molecule, through medicinal chemistry and target-based design, a novel CTSC inhibitor B22 with IBD therapeutic efficacy was discovered. In vitro target verification and mechanism study indicated that B22 inhibit CTSC activity by binding to S2 pocket and S1 site, further inhibiting downstream serine protease activity. In addition, B22 exhibited anti-inflammatory activity and regulated various cytokines levels. In vivo studies highlighted B22 bears acceptable toxicity and suitable pharmacokinetic properties, and displays anti-inflammatory activity in IBD model. In conclusion, B22 is a potential anti-inflammatory molecule for IBD by targeting CTSC and deserves further research.

Physicochemical properties, pharmacokinetic studies, DFT approach, and antioxidant activity of nitro and chloro indolinone derivatives.

The process of developing of new drugs is greatly hampered by their inadequate physicochemical, pharmacokinetic, and intrinsic characteristics. In this regard, the selected chloro indolinone, (Z)-6-chloro-3-(2-chlorobenzylidene)indolin-2-one (C1), and nitro indolinone, (Z)-6-chloro-3-(2-nitrobenzylidene)indolin-2-one (C2), were subjected to SwissADME and density function theory (DFT) analysis. For compounds C1 and C2, the BOILED-Egg pharmacokinetic model predicted intestinal absorption, blood-brain barrier (BBB) penetration, and p-glycoprotein interaction. According to the physicochemical analysis, C1 has exceptional drug-like characteristics suitable for oral absorption. Despite only being substrates for some of the major CYP 450 isoforms, compounds C1 and C2 were anticipated to have strong plasma protein binding and efficient distribution and block these isoforms. The DFT study using the B3LYP/6-311G(d,p) approach with implicit water effects was performed to assess the structural features, electronic properties, and global reactivity parameters (GRP) of C1 and C2. The DFT results provided further support for other studies, implying that C2 is more water-soluble than C1 and that both compounds can form hydrogen bonds and (weak) dispersion interactions with other molecules, such as solvents and biomolecules. Furthermore, the GRP study suggested that C1 should be more stable and less reactive than C2. A concentration-dependent 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging activity was shown by both C1 and C2. In brief, this finding has provided a strong foundation to explore further the therapeutic potential of these molecules against a variety of human disorders.

A Mini-Review on the Synthesis of Substituted Isatins: From Early Approaches to Recent Advances with a Specific Focus on Sulfamoyl and Amino Derivatives

Abstract: As a member of heterocyclic compounds, indole possesses a diverse set of biological activities. Studies on the structure-activity relationship of 2-indolinones have shown that they are important bioactive compounds in the field of pharmaceutical chemistry. Isatin and structures bearing isatin scaffold are derivatives of indole, which have shown to be of biological and pharmacological significance. This review focuses on different ways of obtaining compounds containing isatin structure, considering both earlier and recent methods of synthesis. The syntheses given herein were grouped into three categories, syntheses using anilines as their starting substance, synthetic methods based on the oxidation of indoles, and finally, due to the extensive research going on 5-substituted isatins and their possible pharmacological efficacy, pathways for synthesizing 5-amino and 5-sulfamoylisatins were gathered to underline the importance of 2-indolinone and isatin derivatives as prospective therapeutic compounds in current and future drug discovery studies.

Novel 2-indolinone derivatives as promising agents against respiratory syncytial and yellow fever viruses.

Background: A vaccine or antiviral drug for respiratory syncytial virus (RSV) infections and a specific antiviral drug for yellow fever virus (YFV) infections has not yet been developed. Method: In this study, 2-indolinone-based N-(4-sulfamoylphenyl)hydrazinecarbothioamides were synthesized. Along with these new compounds, previously synthesized 2-indolinone-based N-(3-sulfamoylphenyl)hydrazinecarbothioamides were evaluated against various DNA and RNA viruses. Results: Some 2-indolinone compounds exhibited nontoxic and selective antiviral activities against RSV and YFV. Halogen substitution at the indole ring increased the anti-RSV activities. Moreover, 1-benzyl and 5-halogen or nitro-substituted compounds were the most effective compounds against YFV. Conclusion: Generally, the 3-sulfonamide-substituted compounds were determined to be more effective than 4-sulfonamide-substituted compounds against RSV and YFV.

An overview on 2-indolinone derivatives as anticancer agents

2-Indolinone nucleus is considered one of a promising heterocyclic core in medicinal chemistry that showed numerous range of activity among which antimicrobial, antioxidant, antiviral, antitubercular and anticancer activities. Cancer targeting is still an issue so there is a need for developing new agents that inhibit cancer growth without or low effect on normal body cells. Some derivatives of indolin-2-one are known to be a critical structure in some inhibitors of receptor tyrosine kinases (RTKs); a cancer target therapy, for example, Sunitinib. Herein in this review we focus on 2-indolinone derivatives as RTKs inhibitors as cancer targeting therapy.

5-Fluoro/(trifluoromethoxy)-2-indolinone derivatives with anti-interleukin-1 activity.

The pro-inflammatory cytokine interleukin-1 (IL-1) drives the pathogenesis of several inflammatory diseases. Recent studies have revealed that 2-indolinones can modulate cytokine responses. Therefore, we screened several 2-indolinone derivatives in preliminary studies to develop agents with anti-IL-1 activity. First, the putative efficacies and binding interactions of 2-indolinones were evaluated by docking studies. Second, previously synthesized 5-fluoro/(trifluoromethoxy)-1H-indole-2,3-dione 3-(4-phenylthiosemicarbazones) (compounds 47-69) which had the highest inhibitory effect in the screening were evaluated for inhibitory effects on the IL-1 receptor (IL-1R). Compounds 52 (IC50 = 0.09 µM) and 65 (IC50 = 0.07 µM) were selected as lead compounds for the subsequent synthesis of new derivatives. The novel 5-fluoro/(trifluoromethoxy)-1H-indole-2,3-dione 3-(4-phenylthiosemicarbazones) (compounds 70-116) were designed, synthesized, and in vitro studies were completed. The compounds 76, 78, 81, 91, 100, 105, and 107 tested showed nontoxic inhibitory effects on IL-1R-dependent responses in the range of 0.01-0.06 µM and stronger than the lead compounds 52 and 65. In vitro and in silico findings showed that compounds 78 (IC50 = 0.01 µM) and 81 (IC50 = 0.02 µM) had the strongest IL-1R inhibitory effects and the most favorable drug-like properties. Molecular modeling studies of the compounds 78 and 81 were carried out to determine the possible binding interactions at the active site of the IL-1R.

Pharmacological Effects of a New Indolinone Derivative in Experimental Pneumonitis in Rats.

We studied the effect of a new indolinone derivative GRS on animal survival and on functioning and histological structure of the lungs in rats with experimental pneumonitis. The rats of experimental groups were intratracheally administered 0.5% aqueous solution of carrageenan under intramuscular anesthesia. Compound GRS (10 mg/kg; a suspension in 0.5% aqueous solution of carboxymethyl cellulose) was orally administered for 4 days starting from the day of carrageenan administration; another rat group received the aqueous solution of carboxymethyl cellulose alone. Control rats received intratracheally isotonic solution of sodium chloride. Animal mortality was registered over 5 days; on day 5, the respiratory parameters were measured, the lungs were weighed, pulmonary edema was evaluated, and histological structure of the lungs was studied. GRS compound improved survival of animals with modeled pneumonitis, restored the respiratory parameters to the level of control animals, and reduced pulmonary edema by 35% and the severity of histological damage score in the lungs by 17% (p<0.05).

Biocatalytic synthesis of asymmetric water-soluble indirubin derivatives

A method for the synthesis of asymmetric carboxy-substituted indirubins is presented. It employs indole-5-carboxylic acid or indole-6-carboxylic acid and 2-indolinone derivatives as substrates for bacterial monooxygenase-driven enzymatic bioconversion in different bacterial hosts. This bioconversion system achieved the highest titer of monocarboxyindirubin production of up to 327 mg L−1 for 5-bromoindirubin-6′-carboxylic acid during the 16-h incubation period. The purified monocarboxyindirubins exhibited high solubility in water, up to three orders of magnitude higher than that of indirubin. In addition, several monocarboxyindirubins, namely 1-methylindirubin-5′-carboxylic acid, possess potent antiproliferative activity against different cancer cell lines. Therefore, the synthesis method for monocarboxyindirubins described herein is an efficient and environmentally friendly bioconversion system and the synthesized monocarboxyindirubins show great promise due to their high water solubility and potential antiproliferative activity.

Pharmacological effects of a new soluble guanylate cyclase stimulator in experimental pulmonary arterial hypertension

Aim. To assess the effect of an indolinone derivative (2-[2-[(5RS)-5-(hydroxymethyl)-3-methyl-1,3-oxazolidine-2yliden]-2-cyanoethylidene]-1H-indole-3(2H)-one (codename – GRS) on right ventricular contractility, endothelial vasodilator function, and histologic changes in the lungs and heart in a rat model of monocrotaline-induced pulmonary hypertension.Materials and methods. Pulmonary arterial hypertension (PAH) was induced in Wistar rats by a single subcutaneous administration of monocrotaline at a dose of 60 mg / kg. Starting from day 15 after PAH induction, the rats received either GRS at a dose of 10 mg / kg or riociguat at a dose of 1 mg / kg orally once a day. Blood pressure in the right ventricle, right ventricular weight, endothelial vasodilator function, and the histologic structure of the lungs and heart were studied after the last administration of test substances.Results. Twenty-eight days after monocrotaline administration, the rats developed PAH, as shown by the increase in the maximal blood pressure in the right ventricle and the right ventricular weight / total heart weight ratio. GRS after multiple administration reduced the maximal blood pressure in the right ventricle, had no significant effect on its contractility, improved endothelial vasodilator function, and normalized blood pressure. Riociguat had a hypotensive effect and did not alleviate endothelial dysfunction in experimental PAH.Conclusion. The indolinone derivative GRS and riociguat, both soluble guanylate cyclase stimulators, lowered blood pressure in the right ventricle. GRS also alleviated endothelial dysfunction in animals with experimental PAH.

Indolinone derivatives as promisming anti VEGFR-2 agents targeting tumor angiogenesis : A comprehensive in silico case study

Indolinone derivatives as promisming anti VEGFR-2 agents targeting tumor angiogenesis : A comprehensive in silico case study

Antihypertensive Effects of a Soluble Guanylate Cyclase Stimulator.

We studied antihypertensive activity of an indolinone derivative (compound GRS), a soluble guanylate cyclase stimulator and a drug with previously proven antiaggregant effects. Contraction activity of isolated aorta segments of Wistar-Kyoto (WKY) rats was assessed in vitro using a mechanographic method. Addition of GRS (0.1-100 μМ) resulted in dose-dependent relaxation of endothelium-denuded aorta segments. Pretreatment of aorta smooth muscle segments with a specific inhibitor of soluble guanylate cyclase (ODQ, 1 μM) weakened the vasodilatory effect of GRS. Antihypertensive activity of the indolinone derivative GRS was studied in spontaneously hypertensive SHR rats. Single oral administration of 5 and 10 mg/kg GRS was followed by a significant dose-dependent reduction of systolic and diastolic BP in SHR rats. Antihypertensive effect of GRS in a dose of 5 mg/kg was more potent than that of the reference drug isosorbide dinitrate. GRS in a dose of 10 mg/kg did not affect systolic and diastolic BP in normotensive WKY rats.

Selective C-O Bond Forming Reactions at Indole-C2-Position toward Polycyclic Indolone or Indolinone Derivatives Tethered with Medium-Sized Rings.

A methodology involving the chemoselective synthesis of tetracyclic [1,3]oxazino[3,2-a]indol-4-one or tetracyclic [1,3]oxazino[3,2-a]indoline-4-one tethered with a medium-sized ring by cross dehydrogenative coupling (CDC) or nucleophilic addition (NA) reaction has been developed. [1,3]Oxazino[3,2-a]indol-4-one compounds fused with a medium-sized ring were constructed through a CDC reaction in the presence of I2 and K2CO3. Whereas, [1,3]oxazino[3,2-a]indoline-4-ones tethered with a medium-sized ring were obtained with a TfOH system by NA reaction.

Influence of a new stimulator of soluble guanylate cyclase on platelet aggregation and vascular endothelial function in experimental ischemic stroke against the background of arterial hypertension

Background. Correction of endothelial dysfunction during arterial hypertension (AH) is an important measure in preventing cerebrovascular stroke. Drugs activating soluble guanylate cyclase (sGC) and 3’,5’-guanosine monophosphate (cGMP) production independently of nitric oxide (NO) were shown to be therapeutically useful in reducing the risk of stroke. The present work aims to study the antiaggregant and endothelium-protective activity of a new sGC stimulator, an indolinone derivative (2-[2-[(5RS)-5-(hydroxymethyl)-3-methyl-1,3-oxazolidine-2- yliden]-2-cyanoethylidene]-1H-indole-3(2H)-one (codename — GRS) in a model of ischemic stroke with AH. Prior studies have shown that GRS compound inhibits platelet aggregation, lowers blood pressure (BP) in spontaneouslyhypertensive SHR rats, prevents vascular occlusion in models of arterial and venous thrombosis. Antiplatelet drug clopidogrel, a P2Y12 receptor inhibitor, included in the standard of care for secondary prevention of ischemic stroke, was used as the reference drug.Objective. To assess the antiaggregant and endothelium-protective activity of a new indolinone derivative GRS, an sGC stimulator, compared to clopidogrel in a model of ischemic stroke concomitant with high arterial BP in spontaneously-hypertensive SHR rats.Design and methods. Focal brain ischemia/reperfusion was modelled in spontaneously-hypertensive SHR rats (n = 78). GRS in 10 mg/kg dose and clopidogrel in 10 mg/kg dose were administered orally once daily 3 days before modelling ischemia/reperfusion and for 5 days afterwards. Platelet aggregation and functioning of vascular endothelium were monitored.Results. Focal brain ischemia/reperfusion in SHR rats resulted in increased platelet aggregation and the development of endothelial dysfunction and disruption of vasodilatory function of endothelium. GRS compound and clopidogrel in repeated administration have prevented an increase in platelet aggregation (p &lt; 0,05), GRS compound also alleviated endothelial dysfunction (p &lt; 0,05).Conclusions. The indolinone derivative GRS, an sGC stimulator, inhibits increased platelet aggregation and prevents endothelial dysfunction in rats after focal brain ischemia/ reperfusion; the endothelium-protective effects of GRS aren’t related to its antiaggregant activity.

Distribution and Transmembrane transport as the basis of proper Pharmacodynamics of an Antithrombotic drug – An Indolinone derivative

The goal of the present study: assess the distribution and transmembrane transport of an antiaggregant drug GRS of indolinone series. The distribution of an indolinone derivative in organs, between blood plasma and blood cells was studied in Sprague Dawley rats. A Thermo Scientific Pierce dialysis system was used to study the binding to blood plasma proteins. A MultiScreen Caco-2 test system was used to study the transmembrane transfer of the indolinone derivative. Quantitative assay of GRS was performed by an HPLC/МS method. GRS was shown to pass into the liver, heart and kidneys, and doesn’t pass into the brain and skeletal muscle. The highest GRS accumulation occurs in the liver, the lowest in the kidneys. GRS has low plasma protein binding and its concentration is 1.6 times higher in blood cells than in blood plasma. GRS in 1 mcmol concentration has low cell membrane permeability from apical to basolateral membrane (A-B), increasing the concentration gradient by 10 times leads to a corresponding increase in transport efficiency. In the reverse direction (B-A) GRS permeability is 8.8 times higher, showing its participation in active transport. Pgp inhibitor cyclosporin A considerably decreases the transport efficiency of GRS in B-A direction.

One-Pot Synthesis of Dihydroxyindeno[1,2-d]Imidazoles and Naphthoquinone Substituted Indandione and Oxindole Derivatives

A series of potentially bioactive compounds having either indole or indene frameworks such as dihydroindenone and indolinone derivatives were synthesized in good to high yields by one-pot, multi-component reaction of various amines, trichloroacetonitrile, ninhydrin or isatin, and 2-hydroxy-1,4-naphthoquinone. The present method offers desirable advantages including mild conditions, absence of catalyst, simple workup procedure, and easy purification process with no chromatographic technique.

Фармакокинетика нового антиагреганта – производного индолинона в эксперименте

Introduction. More than 18 million people die every year from complications (the most common of them are thrombosis of the cerebral, coronary and peripheral vessels) caused by diseases of the cardiovascular system. Optimal prevention of thrombosis (antiplatelet therapy) requires the use of drugs that would be able to effectively prevent thrombus formation without increasing the risk of bleeding. A new indolinone derivative (codenamed GRS) has potent antiaggregant action and low toxicity (LD50 for rats &gt; 5000 mg/kg). However, selecting the effective dose and dosage regimen for GRS requires data on its pharmacokinetics in oral and intravenous administration. Aim. To determine the pharmacokinetics of a new antiplatelet agent, an indolinone derivative (GRS) after a single intravenous and oral administration to rats. Materials and methods. The GRS compound was administered as a 1 mg/kg aqueous solution into the tail vein or as a 10 mg/kg suspension in carboxymethyl cellulose aqueous solution for oral (intragastrical) administration. Blood samples were taken at 5, 10, 20, 40 min, 1, 2, 4, and 8 h, and urine samples were collected at 2, 4, 8, 12, and 24 h after administration. GRS was detected in biological samples using high-performance liquid chromatography with ultraviolet detection. Results. The study has demonstrated that with both routes of administration, the antiaggregant effect of GRS lasts for at least 8 hours, being lipohpilic, GRS is rapidly distributed in organs and tissues by passive diffusion, undergoes biotransformation and is excreted in the urine mostly as metabolites, since at most 2.5% of the initial compound is excreted in the urine. Bioavailability of GRS does not exceed 12%. Conclusion. After intravenous and oral administration to rats, the GRS compound is excreted in the urine mostly as metabolites; metabolic clearance is more prominent after GRS oral administration.

Synthesis, biological evaluation and molecular docking of new sulfonamide-based indolinone derivatives as multitargeted kinase inhibitors against leukemia

Series of novel sulfonamide-based 3-indolinones 3a-m and 4a-f were designed, synthesized and then their cytotoxic activity was evaluated against a panel of sixty cancer cell lines. This screening indicated that 4-(2-(5-fluoro-2-oxoindolin-3-ylidene)acetyl)phenyl benzenesulfonate (4f) possessed promising cytotoxicity against CCRF-CEM and SR leukemia cell lines with IC50 values 6.84 and 2.97 µM, respectively. Further investigation of the leukemic cytotoxicity of compound 4f was carried out by performing PDGFRα, VEGFR2, Aurora A/B and FLT3 enzyme assays and CCRF-CEM and SR cell cycle analysis. These investigations showed that compound 4f exhibited pronounced dual inhibition of both kinases PDGFRα and Aurora A with potency of 24.15 and 11.83 nM, respectively. The in vitro results were supported by molecular docking studies in order to explore its binding affinity and its key amino acids interactions. This work represents compound 4f as a promising anticancer agent against leukemia.

Pharmacophore modeling and 3D-QSAR study for the design of novel α-synuclein aggregation inhibitors

Alpha-synuclein (α-syn), as a highly soluble presynaptic protein expressed in the brain, plays an important role in recycling synaptic vesicles and regulating the synthesis, storage, and release of neurotransmitters. Accumulation of α-syn in Lewy bodies and Lewy neurites is the pathological hallmark of Parkinson's disease (PD), so inhibition of α-syn aggregation may provide a novel approach for treating PD. In this study, the 3D structure of α-syn was downloaded from Protein Data Bank (PDB ID: 2N0A). A ligand-based pharmacophore model was conducted on a set of 43 diverse α-syn ligands, and the results suggested that two hydrogen-bond acceptors, one hydrophobic group, and two aromatic rings were significant to the inhibition of α-syn aggregation. A ligand-based 3D-QSAR model was also established with good statistical significance (R2 = 0.920) and excellent predictive ability (Q2 = 0.752). Novel indolinone derivatives were designed and synthesized based on the pharmacophore model. Subsequently, the 3D-QSAR model was used to predict the inhibitory activities towards α-syn aggregation, and the actual inhibitory activities were evaluated by thioflavin-T assay in vitro with the best inhibitory activity reaching 45.08%. The fitting results indicated that the built pharmacophore and 3D-QSAR models provided better reliability and accuracy for compound modification and prediction of the activity thereof. A ligand-based pharmacophore modeling and 3D-QSAR study have been performed on a set of 43 diverse ligands for α-synuclein for the first time. Based on the best pharmacophore modeling, novel indolinone derivatives were designed and synthesized, and the inhibitory activities for α-synuclein aggregation were evaluated by thioflavin-T assay in vitro, which preliminary indicated that five pharmacophore sites (two hydrogen bond acceptors (A), a hydrophobic group (H), and two aromatic rings (R)) in compounds contribute to the inhibitory activities. In the study, the built pharmacophore modeling and 3D-QSAR provided better reliability and accuracy for compound modification and prediction of the activity thereof.

Metabolic Study of Stable Isotope Labeled Indolinone Derivative in Hepatocyte Cell by UPLC/Q TOF MS

The aggregation process of α-synuclein (α-syn) is substantial in the pathogenesis of Parkinson's disease. Indolinone derivatives are inhibitors of α-syn aggregates and can be used as PET-based radiotracers for imaging α-syn fibrils. However, no investigations on the metabolism of indolinone derivatives have been reported until now. In the present research, a 13C and 15N isotope labeling strategy was developed to synthesize compound [13C2,15N]-(Z)-1-(4-aminobenzyl)-3-((E)-(3-phenyl)allylidene)indolin-2-one (M0'), which was then used in a study of metabolism in hepatocytes. The metabolites were characterized using accurate mass and characteristic ion measurements. In the metabolic system, compound M0' was the main component (accounting for 97.5% of compound-related components) after incubation in hepatocytes for 3 h, which indicated that compound M0' possessed great metabolic stability. Seven metabolites have been successfully verified by UPLC/Q TOF MS in metabolic studies, including hydroxyl M0' (M1'), hydroxyl and methylated M0' (M2'), N-acetylated M0' (M3'), sulfate of hydroxyl M0' (M4'), the glucose conjugate of M0' (M5'), glucuronide conjugate of M0' (M6'), and glucuronide conjugate of hydroxyl M0' (M7'). The study on metabolism provides the important information to develop effective α-syn aggregate inhibitors and new PET-tracer-related indolinone derivatives.

Insight on a new indolinone derivative as an orally bioavailable lead compound against renal cell carcinoma

A series of novel 3-indolinone-thiazolidinones and oxazolidinones 4a-k was synthesized via molecular hybridization approach and sequentially evaluated to explore its cytotoxic activity. The cytotoxicity screening pointed toward the N-cyclohexyl thiazolidinone derivative 4f that revealed promising renal cytotoxicity against CAKI-1 and UO-31 renal cancer cell lines with IC50 values 4.74 and 3.99 µM, respectively, which were comparable to those of sunitinib along with good safety threshold against normal renal cells. Further emphasis on compound 4f renal cytotoxicity was achieved via different enzyme assays and CAKI-1 and UO-31 cell cycle analysis. The results were supported by in silico studies to explore its physicochemical, pharmacokinetic and drug-likeness properties. Finally, compound 4f was subjected to an in vivo pharmacokinetic study through two different routes of administration showing excellent oral bioavailability. This research represents compound 4f as a promising candidate against renal cell carcinoma.