Indazolone Derivatives Research Articles

In Vitro Evaluation of New 5-Nitroindazolin-3-one Derivatives as Promising Agents against Trypanosoma cruzi

Chagas disease is a prevalent health problem in Latin America which has received insufficient attention worldwide. Current treatments for this disease, benznidazole and nifurtimox, have limited efficacy and may cause side effects. A recent study proposed investigating a wide range of nitroindazole and indazolone derivatives as feasible treatments. Therefore, it is proposed that adding a nitro group at the 5-position of the indazole and indazolone structure could enhance trypanocidal activity by inducing oxidative stress through activation of the nitro group by NTRs (nitroreductases). The study results indicate that the nitro group advances free radical production, as confirmed by several analyses. Compound 5a (5-nitro-2-picolyl-indazolin-3-one) shows the most favorable trypanocidal activity (1.1 ± 0.3 µM in epimastigotes and 5.4 ± 1.0 µM in trypomastigotes), with a selectivity index superior to nifurtimox. Analysis of the mechanism of action indicated that the nitro group at the 5-position of the indazole ring induces the generation of reactive oxygen species (ROS), which causes apoptosis in the parasites. Computational docking studies reveal how the compounds interact with critical residues of the NTR and FMNH2 (flavin mononucleotide reduced) in the binding site, which is also present in active ligands. The lipophilicity of the studied series was shown to influence their activity, and the nitro group was found to play a crucial role in generating free radicals. Further investigations are needed of derivatives with comparable lipophilic characteristics and the location of the nitro group in different positions of the base structure.

Theoretical investigation of Cp*Rh(III)-catalyzed allylation and cyclization reactions of 1-arylindazolones with carbonates

By employing DFT calculations and analysis, we have conducted a comprehensive theoretical investigation on the Rh(III)-catalyzed C-H functionalization/cyclization reaction of indazolone derivatives, elucidating the mechanistic pathways leading to different products under varying solvent and reaction conditions. After the formation of allyl alcohol intermediate, two distinct reaction pathways emerge primarily due to differences in solvent properties. The calculation results indicate that the additive AgSbF6 plays a pivotal role in facilitating Cl-departure through dehalogenation to promote the generation of catalytically active species.

Aerobic Cu(I)‐Catalyzed Site‐Selective 1,3‐Difunctionalization of Indazole through Cascade C−N and C−O Bond Formation

AbstractA Cu(I)‐catalyzed 1,3 oxo alkylation of indazole has been developed for constructing N‐1‐alkylated indazolone derivatives. This cascade reaction involves the formation of C−N and C−O bonds through the sequential functionalization of N1 and C3 positions of indazole in 41–89% yields. The photo‐physical studies of the synthesized compounds showed efficient quantum yields with high Stoke shift values. The preliminary experimental results suggest an aerobic manifold of the present protocol through single electron transfer.magnified image

Synthesis and characterization of some new Indazolone and Carbohydrazide derivatives from azachalcones

Pyridine-4-carboxaldehyde can be used for the synthesis 1-aryl-3-(2-pyridyl)-2-propenone(4-azachalcone)(m1-m3) by coupling with acetophenone, 4-methyl acetophenone and 4-amino acetophenone in basic medium. The compounds (m1-m3) converted by Robinson annulation reaction to form the corresponding cyclohexenone derivatives (m4-m6) by coubling with ethyl acetoacetate after mandate reflux. Reaction of cyclohexenone derivatives (m4-m6) with hydrazine hydrate (99%) in presence of some drops glacial acetic acid gives Indazolone derivatives (m7-m8). On the other side, the synthesized cyclohexenone (m4-m6) were treated with hydrazine hydrate (99%) in absolute ethanol to yield carbohydrazide derivatives (m9-m11).The chemical structures of the new compounds (m1-m11) were established on the basis of some physical properties and some spectroscopy methods like, FT-IR, 1HNMR and 13C-NMR spectra. Also, all these reactions followed by thin layer chromatography (TLC) technique.

Hypervalent iodine(III)-mediated oxidative dearomatization of 2H-indazoles towards indazolyl indazolones.

A new iodine(III)-mediated oxidative dearomatization of 2H-indazoles has been developed to afford N-1 indazolyl indazolones. In this methodology, PIFA plays a dual role: as an oxidant and as a carbonyl oxygen source. A series of indazolone derivatives was promptly synthesized in good to excellent yields through sequential C-heteroatom bond formation. Mechanistic studies indicate that the reaction likely takes place through an SET pathway.

Copper-Catalyzed Oxidative Cyclization of 2-Aminobenzamide Derivatives: Efficient Syntheses of Quinazolinones and Indazolones

AbstractA simple copper-catalyzed assembly to formulate quinazolinone and indazolone derivatives in a single protocol manner is reported. These transformations are based on the fact that DMF can serve as a reaction solvent and one carbon synthon for the construction of heterocyclic rings. Moreover, this protocol features base-free and Brønsted acid free environmentally benign conditions with broad synthetic scope. A good scalability is demonstrated.

An efficient protocol for synthesis of novel polyheterocyclic chromeno pyrimido[1,2-b]indazolone derivatives using [Et3NH][HSO4] as a reusable catalyst under solvent-free conditions

A convenient and highly efficient method for the synthesis of novel polyheterocyclic chromeno pyrimido[1,2-b]indazolone derivatives via a three-component condensation of 1H-indazol-3-amine, aldehydes and 4-hydroxycoumarin catalyzed by Bronsted acid ionic liquid [Et3NH][HSO4] under solvent-free reaction conditions is presented. This ionic liquid is air and water stable and easy to prepare from amine and acid. The main advantages of this protocol includes short reaction time, excellent yield, easy work-up, operational simplicity, a wide range of functional group tolerance and column chromatography-free method. The catalyst can be recovered and reused for at least four runs without any significant impact on the product yields.

Rapid and halide compatible synthesis of 2-N-substituted indazolone derivatives via photochemical cyclization in aqueous media.

Indazolone derivatives exhibit a wide range of biological and pharmaceutical properties. We report a rapid and efficient approach to provide structurally diverse 2-N-substituted indazolones via photochemical cyclization in aqueous media at room temperature. This straightforward protocol is halide compatible for the synthesis of halogenated indazolones bearing a broad scope of substrates, which suggests a new avenue of great importance to medicinal chemistry.

IBX-mediated synthesis of indazolone via oxidative N-N bond formation and unexpected formation of quinazolin-4-one: in situ generation of formaldehyde from dimethoxyethane.

Synthesis of indazolone derivatives, which exhibit diverse biological and pharmaceutical activities, were achieved by hypervalent λ(5) iodine reagents, such as iodoxybenzoic acid (IBX),-mediated oxidative N-N bond forming cyclization. In this study, the equivalence of IBX was optimized to promote the formation of N-N bond by oxidatively generated acylnitrenium ion. Dimethoxyethane and dichloroethane were discovered as alternative solvents and the reaction could be conducted in more concentrated condition. Some unprecedented substrates successfully afforded the corresponding indazolone in new condition discovered in this study. When the reactions were conducted in DME solvent, substrates with no electron-rich phenyl substituted amides afforded the unanticipated quinazolin-4-ones in moderate yields, which were not formed in DCE solvent. The formation of quinazolin-4-ones was attributed to the in situ generation of formaldehyde from DME. Therefore, the reaction might undergo different pathway in DME when the substrate aryl amides have phenyl rings without electron donating substituents.

Efficient synthesis of highly substituted tetrahydroindazolone derivatives.

A straightforward and efficient method for the synthesis of novel highly substituted and diversely functionalized indazolone derivatives has been developed. The transformation consists of a cyclocondensation of selected 1,3,3'-tricarbonyls with monosubstituted hydrazines. The starting β-triketones were prepared by an efficient chemo- and regioselective method under MW irradiation, exploiting the oxazolone chemistry. The reaction is easily accomplished under mild conditions and appears versatile, providing a synthetic diversification method with potential for drug-like compounds preparation.

Design and synthesis of 2-N-substituted indazolone derivatives as non-carboxylic acid glycogen synthase activators

Glycogen synthase (GS) catalyzes the transfer of glucose residues from UDP-glucose to a glycogen polymer chain, a critical step for glucose storage. Patients with type 2 diabetes normally exhibit low glycogen levels and decreased muscle glucose uptake is the major defect in whole body glucose disposal. Therefore, activating GS may provide a potential approach for the treatment of type 2 diabetes. In order to identify non-carboxylic acids GS activators, we designed and synthesized a series of 2-N-alkyl- and 2-N-aryl-indazolone derivatives and studied their activity in activating human GS.

Facile and efficient synthesis of indazole derivatives by 1,3-cycloaddition of arynes with diazo compounds and azomethine imides

N-Unsubstituted indazoles 3 and 1-arylindazoles 4 are readily available in good to high yields through [3+2] cycloaddition of 2-(trimethylsilyl)aryl triflates 1 and diazo compounds in the presence of KF or CsF under mild reaction conditions. Furthermore, we found that azomethine imides also underwent cycloaddition reaction with 2-(trimethylsilyl)phenyl triflates (1a) in the presence of KF to afford indazolone derivatives 6 in moderate yields.

The search for novel TRPV1-antagonists: From carboxamides to benzimidazoles and indazolones

Based on a series of diaryl amides the corresponding inverse amides have been found to be potent TRPV1 receptor antagonists. Benzimidazole and indazolone derivatives prepared retained good potency in vitro and indazolone 4a was identified as a novel TRPV1 receptor antagonist suitable for evaluating orally in animal models of analgesia.

Novel Alternative for the N−N Bond Formation through a PIFA-Mediated Oxidative Cyclization and Its Application to the Synthesis of Indazol-3-ones

The synthesis of a series of N,N'-disubstituted indazolone derivatives starting from methyl anthranilates is presented. This general approach features a novel and easy way for access to the target N-heterocycles by formation of a new N-N single bond. The key cyclization step embraces the formation of an N-acylnitrenium intermediate, mediated by the hypervalent iodine reagent PIFA, and its succeeding intramolecular trapping by the amine moiety under rather mild experimental conditions.

Biological Activity of the Hypolipidemic Agent, N2-n-Butylindazolone

Previously, a series of N-substituted indazolone derivatives proved to be effective hypolipidemic agents in rodents. The most effective agent, N2-n-butylindazolone, at 20 mg/kg/d was shown to suppress the levels of cytoplasm acetyl coenzyme A required for cholesterol and fatty acid synthesis as well as sn-glycerol-3-phosphate acyl transferase and phosphatidate phosphohydrolase activities. Lipid content of the liver, small intestine, and serum lipoprotein fractions was lowered, whereas lipid content was increased in fecal excretions by drug treatment for 14 d. The absorption of orally administered cholesterol from the intestine was severely reduced after drug administration. The mode of action of N2-n-butylindazolone appears to be similar to cyclic imides possessing hypolipidemic activity.

Hypolipidemic activity of phthalimide derivatives. 7. Structure-activity studies of indazolone analogues.

The apparent benefit of limiting serum cholesterol and triglyceride levels either by dietary restriction or drug therapy has prompted work in our laboratories toward development of a suitable antihyperlipidemic agent. We have demonstrated the antihyperlipidemic activity of a series of phthalimide derivatives in rodents to be significantly greater than that of clofibrate at a dose of 20 mg/(kg day), intraperitoneally. Here we report the synthesis and biological evaluation of a series of indazolone derivatives, which are heterocycles that are structurally related to the phthalimides . In general, structure-activity relationships within the phthalimide series may be extended to the indazolones . While indazolone itself is only moderately active, N1-carbethoxy substitution produced a more active compound. Substitution of the N2 position with an n-butyl group afforded the most active compound, as also seen in the phthalimide series. Aromatic substitution with electron-releasing and -withdrawing groups lessened the antihyperlipidemic activity.

Studies on Indazolone Derivatives

The reactions of indazolone with dialkylaminoalkyl halides have been studied under various reaction conditions, using several kinds of solvents and condensing agents. It has been found that the C-3-O of indazolone is substituted by a dialkylaminoalkyl group selectively.The reaction of indazolone with dimethylaminopropyl chloride has been studied in detail in this reaction, 3- (γ-dimethylaminopropoxy) -1H-indazole was found to be mainly produced together with minor formations of the 1, 3-disubstituted derivative of the enol-form and the 1, 2-disubstituted derivative of the keto-form.