Indazole Derivatives Research Articles

Discovery of highly potent and selective VEGFR2 kinase inhibitors for the treatment of rheumatoid arthritis

Synovial angiogenesis is essential for the development of rheumatoid arthritis (RA). Human vascular endothelial growth factor receptor 2 tyrosine kinase (VEGFR2) is a direct target gene that is notably elevated in RA synovium. Herein, we report the identification of indazole derivatives as a novel class of potent VEGFR2 inhibitors. The most potent compound, compound 25, displayed single-digit nanomolar potency against VEGFR2 in biochemical assays and achieved good selectivity for other protein kinases in the kinome. In addition, compound 25 dose-dependently inhibited the phosphorylation of VEGFR2 in Human Umbilical Vein Endothelial Cells (HUVECs) and showed an anti-angiogenic effect, as evidenced by the inhibition of capillary-like tube formation in vitro. Moreover, compound 25 reduced the severity and development of adjuvant-induced arthritis in rats by inhibiting synovial VEGFR2 phosphorylation and angiogenesis. Overall, these findings provide evidence that compound 25 is a leading potential drug candidate for anti-arthritic and anti-angiogenic therapy.

Design, Synthesis, In‐silico Studies and Antiproliferative Evaluation of Novel Indazole Derivatives as Small Molecule Inhibitors of B‐Raf

AbstractB‐Raf, a proto‐oncogene that encodes the B‐Raf protein in the Ras/Raf/Mek/Erk (MAPK) pathway, is important in directing cell development and differentiation, mutation of which results in various types of cancers. A series of novel indazole derivatives were synthesized employing scaffold‐based approach and characterized by the spectral data. All the synthesized compounds were subjected to molecular docking to assess their binding affinity with the protein. The physicochemical and pharmacokinetic profile of the compounds revealed their compliance with Lipinski's rule. The antiproliferative capacity of the synthesized derivatives was assessed by screening them against the human melanoma cell lines Skmel‐23 and A375, which express B‐Raf in wild‐type and mutant forms, respectively. Compounds with 2‐chloro and 2‐cyano‐4‐isoproxy substitutions elicited potent inhibition against melanoma cell lines with IC50 values of 40.11 and 13.37 μM against Skmel‐23 and 16.89, 15.57 μM against A375 cells respectively. The compounds manifested greater potential than the standard doxorubicin. In order to detect changes in cell morphology and evaluate their apoptotic potential; these substances were subjected to morphological screening. Both cell lines were shown to be strongly inhibited by the 2‐cyano‐4‐isoproxy substituted indazole derivative; making it a prospective therapeutic candidate for targeting both wild‐type and mutant B‐Raf forms.

Microwave‐Assisted PEG‐400 Medaited Synthesis of 4,5‐dihydro‐1H‐benzo[g]indazole Derivatives: An Enaminone Approach

AbstractA simple, rapid and conceptually new efficient protocol for the synthesis of 4,5‐dihydro‐1H‐benzo[g]indazole derivatives from novel enaminones prepared via Blaise reaction under catalyst free conditions is reported involving polyethylene glycol (PEG‐400) as an efficient recyclable medium without using any organic co‐solvent or additive by Microwave irridation with 91–95 % yields without chromatography.

Solvent-Dependent Selective Synthesis of CF3-Tethered Indazole Derivatives Based on Multiple Bond Activations

Presented herein is a solvent-dependent selective synthesis of CF3-tethered indazole derivatives via the cascade reactions of 1-arylpyrazolidinones with trifluoromethyl ynones. Mechanistically, the formation of the title products involves cascade N-H/C-H/C-N/C-C bond cleavage along with pyrazole ring formation and pyrazolidinone ring opening. For the formation of a pyrazole scaffold, 1-phenylpyrazolidinone acts as a C2N2 synthon, while trifluoromethyl ynone serves as a C1 synthon. Meanwhile, trifluoromethyl ynone also acts as an enol unit to facilitate the ring opening of the pyrazolidinone ring and provide a trifluoropropenoxy fragment via cleavage of the alkynyl triple bond and migration of the cleaved moiety. When the reaction was run in trifluoroethanol instead of DCE, it selectively afforded indazole derivatives tethered with a trifluoroethoxy moiety through in situ transesterification. To our knowledge, this is the first synthesis of CF3-tethered indazole derivatives via concurrent alkynyl activation, pyrazole formation, and CF3 migration.

The synthesis of novel 2, 3‐disubstituted 1,6‐dihydropyrrolo[2,3‐g]indazole derivatives via one‐pot three component reactions

AbstractA concise and efficient synthetic approach was developed for the synthesis of functionalized 2,3‐disubstituted 1,6‐dihydropyrrolo[2,3‐g]indazole via a one‐pot, three‐component reaction of 1H‐indazol‐6‐amine, arylglyoxal monohydrates, and 4‐hydroxy‐2H‐chromen‐2‐one or 4‐hydroxyquinolin‐2(1H)‐one promoted by acetic acid in ethanol under reflux conditions. The attractive features of this protocol are operational simplicity, short reaction time, easy purification of products, and good to excellent yields.

Antileishmanial activity of 5-nitroindazole derivatives.

Currently, there is no safe and effective vaccine against leishmaniasis and existing therapies are inadequate due to high toxicity, cost and decreased efficacy caused by the emergence of resistant parasite strains. Some indazole derivatives have shown in vitro and in vivo activity against Trichomonas vaginalis and Trypanosoma cruzi. On that basis, 20 indazole derivatives were tested in vitro against Leishmania amazonensis. To evaluate the in vitro activity of twenty 2-benzyl-5-nitroindazolin-3-one derivatives against L. amazonensis. For the selection of promising compounds, it is necessary to evaluate the indicators for in vitro activity. For this aim, a battery of studies for antileishmanial activity and cytotoxicity were implemented. These results enabled the determination of the substituents in the indazole derivatives responsible for activity and selectivity, through the analysis of the structure-activity relationship (SAR). In vitro cytotoxicity against mouse peritoneal macrophages and growth inhibitory activity in promastigotes were evaluated for 20 compounds. Compounds that showed adequate selectivity were tested against intracellular amastigotes. The SAR from the results in promastigotes was represented using the SARANEA software. Eight compounds showed selectivity index >10% and 50% inhibitory concentration <1 µM against the promastigote stage. Against intracellular amastigotes, four were as active as Amphotericin B. The best results were obtained for 2-(benzyl-2,3-dihydro-5-nitro-3-oxoindazol-1-yl) ethyl acetate, with 50% inhibitory concentration of 0.46 ± 0.01 µM against amastigotes and a selectivity index of 875. The SAR study showed the positive effect on the selectivity of the hydrophilic fragments substituted in position 1 of 2-benzyl-5- nitroindazolin-3-one, which played a key role in improving the selectivity profile of this series of compounds. 2-bencyl-5-nitroindazolin-3-one derivatives showed selective and potent in vitro activity, supporting further investigations on this family of compounds as potential antileishmanial hits.

Design, synthesis, and evaluation of indoleamin-2,3-dioxygenase 1 inhibition activity of novel 5/6-amino indazole derivatives with amide template

Design, synthesis, and evaluation of indoleamin-2,3-dioxygenase 1 inhibition activity of novel 5/6-amino indazole derivatives with amide template

Design, synthesis, and evaluation of indoleamin-2,3-dioxygenase 1 inhibition activity of novel 5/6-amino indazole derivatives with amide template

Design, synthesis, and evaluation of indoleamin-2,3-dioxygenase 1 inhibition activity of novel 5/6-amino indazole derivatives with amide template

Preparation and Characterization of 2,7-Diaminophenazine Supported on Nanocellulose as Novel Recyclable Nanocatalyst for Synthesis of Isoxazolo[4,3-e]indazole Derivatives and Theoretical Study on the Mechanism using a DFT Method

In this study, 2,7-Diaminophenazine supported on nanocellulose (DAP@CNC) was designed. The prepared nanocatalyst was characterized with various analytical techniques such as FTIR, XRD, TGA, SEM, TEM, and CHN. Nanocatalyst used for the synthesis of isoxazolo[4,3-e]indazole derivatives via the nucleophilic substitution of a hydrogen in 5-nitro-1-p-tolyl-1H-indazole with different 2-phenylacetonitrile derivatives in basic medium. Also, we did this reaction with KOH as other catalyst. The mechanism of the reaction investigated by density functional theory based modeling is also reported. Simple procedure, high yields, short reaction time and environmentally benign method are advantages of this protocol. The nanocatalyst was readily separated by filter and reusable without significant loss of its catalytic efficiency.

Hypervalent iodine mediated Pd(II)‐catalyzed ortho‐C(sp2−H) functionalization of azoles deciphering Hantzsch ester and malononitrile as the functional group surrogates

AbstractC−H bond activation has surfaced as a transformative toolbox for the efficient assembly of biologically important molecules. However, despite of major advances in palladium, rhodium and silver catalysis, yet palladium(II)‐ catalyzed, iodobenzene diacetate (PIDA) mediated C−H bond activation in azole skeleton has deluged with interesting wining outcome. Concentrating on that we herein report on the involvement of 4‐functionalized 1,4‐dihydropyridines (R‐DHPs) as the representative surrogates of benzoyl, pivalyl and ethoxycarbonyl groups and in presence of PIDA it releases appropriate functional radical (following single electron transfer oxidation of R‐DHPs under thermal condition)to become the part of ortho‐ functionalized azoles via Pd(II) catalysis. In case of cyanation reaction, malononitrile has served the key source of nitrile functionality by undergoing oxidative C−CN bond cleavage in presence of PIDA and with the help of Pd(II) catalyst it offers ortho‐cyanated azoles. Additionally, the selective formation of C‐3 benzoyl and ester functionalized indazole derivatives in absence of Pd(II)‐catalyst and the unprecedented formation of homo‐coupling products between two identical 2H‐indazoles are also notable outcome of present strategic access. Overall this protocol operates under mild condition, tolerates a wide range of structural moieties and gives versatile azole derivatives in high efficiency. The antioxidant properties of the synthesized 2‐thiophenyl benzoyl selenazole and isoselenazole are further evaluated using a chemically defined method. The Copper‐ascorbate (Cu−As) was utilized as an oxidative stress generator. Out of screened azoles, the 2‐benzoyl isoselenazole compound (3 i) displays magnificent antioxidant property as compared to the 2‐thiophenyl benzoyl selenazole (3 g).

Corrosion Inhibition by Indazole Derivatives in 1 M HCl Medium: Experimental and Computational Studies

Corrosion Inhibition by Indazole Derivatives in 1 M HCl Medium: Experimental and Computational Studies

N-Difluoromethylindazoles

Aim. To study the possibility of the N-difluoromethylation and separation of 1-difluoromethyl and 2-difluoromethyl isomers of C-substituted indazoles, as well as some possibilities of functionalization of such molecules.Results and discussion. The N-difluoromethylation of indazole derivatives containing bromine, iodine, and nitro groups in various positions of the heterocyclic ring was studied. In all cases, the conditions for the separation of isomers – N-difluoromethylation products – in positions 1 and 2 were found. The corresponding amines, esters of carboxylic and boric acids were obtained as a result of further functionalization of 1- and 2-difluoromethylindazole derivatives.Experimental part. The structure of the compounds synthesized was proven by 1H and 19F NMR spectroscopy methods, as well as by the elemental analysis. The structure of isomeric difluoromethylindazoles was finally confirmed by the SELNOESY and 1H-13C HMBC experiments.Conclusions. A convenient method for the difluoromethylation of substituted indazoles has been found; difluoromethyl derivatives in positions 1 and 2 of the indazole ring have been obtained in high yields. The method for the efficient separation of isomeric difluoromethylindazoles has been found; some possibilities of their further functionalization have been described.

Synthesis of 3‐(2‐Hydroxyaryl)indazole Derivatives through Radical O‐Arylation and [3,3]‐Rearrangement from N‐Hydroxyindazoles and Diaryliodonium Salts

AbstractA variety of functionalized 3‐(2‐hydroxyaryl)indazoles and N‐(tetrahydrofuran‐2‐yl)‐3‐(2‐hydroxyaryl)indazoles were prepared in moderate to good yields through a transition metal‐free radical O‐arylation and sequential [3,3]‐rearrangement cascade strategy from N‐hydroxyindazoles and diaryliodonium salts. The equivalents of diaryliodonium salts controlled the formation of the product structures. Mechanistic studies revealed that the O‐arylation and N−O bond cleavage via [3,3]‐rearrangement involved an intermolecular radical process. The reaction tolerated various sensitive functional groups, such as halides, ester, and aldehyde groups.magnified image

The behavior of two indazole derivatives on the copper/sulfuric acid interface in terms of adsorption and corrosion inhibition

BackgroundTo reduce the degree of copper corrosion by the pickling solution, the introduction of organic inhibitors into the pickling solution is a reasonably effective measure.5-fluoro-1H-indazole (5-FIA) and 5‑chloro-1H-indazole (5-CIA) may act as exceptional inhibitors. MethodsBased on experimental and theoretical methods, the antiseptic ability of two indazole derivatives on copper in sulfuric acid was researched. Significant findsThe results of electrochemical experiments show that in the test solution containing 1 mM inhibitors, the corrosion inhibition efficiency (η) of 5-FIA and 5-CIA was 90.4% and 94.3%, respectively, indicating that 5-FIA and 5-CIA have outstanding corrosion inhibition capabilities and their antiseptic effects are in the order of 5-FIA < 5-CIA, which is also confirmed by observations of Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM). Furthermore, both 5-FIA and 5-CIA are mixed-type inhibitors and their adsorption behavior follows Langmuir isothermal adsorption model. The results of X-ray Photoelectron Spectroscopy (XPS), theoretical calculations, and molecular dynamics simulations further reveal the mechanism that 5-CIA has stronger adsorption capacity than 5-FIA.

76P Modulation of mutant p53 activity using indazole derivatives

Oncogenic mutation p53 Y220C is the ninth most common mutation of p53 protein. The Y220C mutation creates an expanded surface pocket in the DNA-binding domain, rapidly unfolds and denatures under physiological conditions, which effectively cancels p53 signaling and leads to the development of a tumor. In this work the novel indazole derived compounds were tested. It was found that these molecules bind to the mutated p53 protein and stabilize its structure in vitro.

Synthesis of 3‐(Phenylcarbonyl)‐1H‐indazole Derivatives through Intramolecular Cyclization under Mild Conditions

AbstractThe synthesis of 3‐(phenylcarbonyl)‐1H‐indazole derivatives via the intramolecular cyclization of triazene derivatives substituted by a 2‐(phenylethynyl)phenyl group at the position 3 was developed. The azonium salt, the key intermediate in the reaction, was prepared under mild conditions from trimethylsilyl iodide (TMSI) obtained from an in situ mixture of trimethylsilyl chloride (TMSCl) and sodium iodide (NaI). The obtained 3‐(phenylcarbonyl)‐1H‐indazole derivatives exhibited interesting optical properties including phosphorescence, which was verified by theoretical calculations.

Multitarget drugs as potential therapeutic agents for alzheimer’s disease. A new family of 5-substituted indazole derivatives as cholinergic and BACE1 inhibitors

Multitarget drugs are a promising therapeutic approach against Alzheimer’s disease. In this work, a new family of 5-substituted indazole derivatives with a multitarget profile including cholinesterase and BACE1 inhibition is described. Thus, the synthesis and evaluation of a new class of 5-substituted indazoles has been performed. Pharmacological evaluation includes in vitro inhibitory assays on AChE/BuChE and BACE1 enzymes. Also, the corresponding competition studies on BuChE were carried out. Additionally, antioxidant properties have been calculated from ORAC assays. Furthermore, studies of anti-inflammatory properties on Raw 264.7 cells and neuroprotective effects in human neuroblastoma SH-SY5Y cells have been performed. The results of pharmacological tests have shown that some of these 5-substituted indazole derivatives 1–4 and 6 behave as AChE/BuChE and BACE1 inhibitors, simultaneously. In addition, some indazole derivatives showed anti-inflammatory (3, 6) and neuroprotective (1–4 and 6) effects against Aβ-induced cell death in human neuroblastoma SH-SY5Y cells with antioxidant properties.

Experimental and theoretical studies on prototropic tautomerism of 1-tetralone-2-carbothioamides and synthesis of regioselectively designed fused 2H-indazole derivatives

Condensation of 1-tetralones with phenylisothiocyanate in presence of sodium hydride produced 1-oxo-N-phenyl-1,2,3,4-tetrahydronaphthalene-2-carbothioamides 2a–b. The structure of carbothioamides 2 was established on the basis of spectral data. Prototropic tautomerism studies of carbothioamide 2a were investigated in solution by NMR (1H and 13C NMR), electronic spectroscopy and gas chromatography techniques. The proton transfer behaviour in solid state and gaseous phase was studied utilizing FT-IR and Mass spectral studies, respectively. DFT approach was used to accomplish the theoretical computations. The ground state geometries of different tautomers were optimized using B3LYP method and 6-31G(d) basis set. The vibrational and NMR spectra of different tautomers were calculated and correlated with the experimental results. HOMO-LUMO studies of different probable tautomers of carbothioamide 2a were employed in determination of chemical reactivity descriptors.The dynamic photoisomerization experiments were performed in chloroform under UV irradiation (UV lamp, 15W) and spectra were recorded to investigate the photo dynamic keto ⇌ enol ⇌ thioenol tautomerization. Further, condensation of carbothioamides 2 with hydrazine and its aryl derivatives regioselectively furnished 4,5-dihydro-2H-benzo[g]indazole derivatives 3. Spectrochemical characterizations and single crystal X-ray diffraction analysis of representative indazole derivative 3b resolved the structural ambiguity between the possible 2H-indazole 3 and 1H-indazole 4 regioisomers. Also, the optimized geometric bond lengths and bond angles, obtained by using DFT studies, were compared with the values obtained from X-ray diffraction. The regioselectivity of 3 was justified by root mean square deviations (RMSD) calculations which shows the minimum deviation for 2H-indazole derivative 3.

A review on synthetic strategy, molecular pharmacology of indazole derivatives, and their future perspective.

With different nitrogen-containing heterocyclic moieties, Indazoles earn one of the places among the top investigated molecules in medicinal research. Indazole, an important fused aromatic heterocyclic system containing benzene and pyrazole ring with a chemical formula of C7 H6 N2 , is also called benzopyrazole. Indazoles consist of three tautomeric forms in which 1H-tautomers (indazoles) and 2H-tautomers (isoindazoles) exist in all phases. The tautomerism in indazoles greatly influences synthesis, reactivity, physical and even the biological properties of indazoles. The thermodynamic internal energy calculation of these tautomers points view 1H-indazole as the predominant and stable form over 2H-indazole. The natural source of indazole is limited and exists in alkaloidal nature (i.e., nigellidine, nigeglanine, nigellicine, etc.) found from Nigella plants. Some of the FDA-approved drugs like Axitinib, Entrectinib, Niraparib, Benzydamine, and Granisetron are being used to treat renal cell cancer, non-small cell lung cancer (NSCLC), epithelial ovarian cancer, chronic inflammation, chemotherapy-induced nausea, vomiting, and many more uses. Besides all these advantages regarding its biological activity, the main issue about indazoles is the less abundance in plant sources, and their synthetic derivatives also often face problems with low yield. In this review article, we discuss its chemistry, tautomerism along with their effects, different schematics for the synthesis of indazole derivatives, and their different biological activities.

Recent Strategies in Transition-Metal-Catalyzed Sequential C-H Activation/Annulation for One-Step Construction of Functionalized Indazole Derivatives.

Designing new synthetic strategies for indazoles is a prominent topic in contemporary research. The transition-metal-catalyzed C–H activation/annulation sequence has arisen as a favorable tool to construct functionalized indazole derivatives with improved tolerance in medicinal applications, functional flexibility, and structural complexity. In the current review article, we aim to outline and summarize the most common synthetic protocols to use in the synthesis of target indazoles via a transition-metal-catalyzed C–H activation/annulation sequence for the one-step synthesis of functionalized indazole derivatives. We categorized the text according to the metal salts used in the reactions. Some metal salts were used as catalysts, and others may have been used as oxidants and/or for the activation of precatalysts. The roles of some metal salts in the corresponding reaction mechanisms have not been identified. It can be expected that the current synopsis will provide accessible practical guidance to colleagues interested in the subject.