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An efficient method was developed for the construction of N -short-chain ether-attached carbonyl group-substituted indazoles. The visible-light-induced three-component reactions of α-diazoesters, indazoles, and cyclic ethers, under extremely mild conditions, led to the corresponding mixture of N1 and N2 short-chain ether-substituted indazoles in good to excellent yields. [ABSTRACT FROM AUTHOR]

New EA-sulfonamides and indazole-sulfonamides were synthesized, characterized, and evaluated for their anticancer activities. The target compound structures were elucidated using various spectroscopic techniques such as NMR-{1H and 13C}, infrared spectroscopy, and high-resolution mass spectrometry. The anticancer activities of the novel compounds were evaluated against four human cancer cell lines, namely A-549, MCF-7, Hs-683, and SK-MEL-28 as well as the normal cell line HaCaT, using 5-fluorouracil and etoposide as reference drugs. Among the tested compounds, 9, 10, and 13 exhibited potent anticancer activities which are better than or similar to the reference compounds 5-fluorouracil and etoposide, against the A-549, MCF-7, and Hs-683 cancer cell lines, with IC50 values ranging from 0.1 to 1 μM. Molecular docking studies of compounds 9, 10, and 13 showed a strong binding with selected protein kinase targets, which are linked to the tested cancer types. Furthermore, the analysis of the molecular dynamics simulation results demonstrated that compound 9 exhibits significant stability when bound to both JAK3 and ROCK1 kinases. This new compound has the potential to be developed as a novel therapeutic agent against various cancers. [ABSTRACT FROM AUTHOR]

We report a method to furnish substituted 1H‐indazoles via a coupling of 3‐acetyl substituted nitroarenes and arylhydrazines. Reactions progressed in the presence of cobalt(II) acetylacetonate catalyst, TEMPO oxidant, and Cs2CO3 base. Functional groups including bromo, chloro, nitro, and trifluoromethoxy groups were compatible with reaction conditions. The proposed mechanism was based on a nucleophilic substitution of hydrogen para to nitro group. Our method feature a convenient pathway to directly obtain substituted 1H‐indazoles which avoid the use of pre‐functionalized starting materials. Indazole could play a role as the directing group for a palladium‐catalyzed C(sp2)─H arylation with iodobenzene. [ABSTRACT FROM AUTHOR]

Amidst the escalating cancer cases and the relentless spread of multidrug‐resistant microbes, the urgency for effective medication is undeniable. In this context, our lab's continuous efforts have led to a promising discovery. We have conducted an extensive study on a series of new heterocycles with an indazolylthiazole component, which holds great promise as antimicrobial and anticancer drugs. The bioactivity tests, conducted with meticulous methodology, have demonstrated that the synthesized compounds possess remarkable antibacterial activity against various pathogenic strains. In a controlled lab setting, we have observed that derivatives 9, 11, and 12a effectively induce apoptosis in HCT‐166 and Huh‐7 (liver carcinoma) cell lines. Among these, derivative 11 has shown the highest selectivity (SI=14.54±1.2 and 16.51±1.4) and the lowest IC50 value. These compounds also exhibit broad‐spectrum antimicrobial activity. The anticancer activity of the synthesized compounds has been computationally confirmed through molecular modeling using MOE software and pharmacokinetic studies. Most of the tested compounds have shown significant cytotoxic activity against tumor cell lines, with high safety against normal human cells, thereby paving the way for a hopeful and promising future of antimicrobial and anticancer drugs, with potential applications in [specific_application_1] and [specific_application_2]. [ABSTRACT FROM AUTHOR]

The medicinal importance, natural rarity, and challenges associated with the synthesis of C3-functionalized 1 H -indazoles have propelled the development of novel and practical 1 H -indazole N-oxides for the production of diverse arrays of C3-functionalized 1 H -indazoles. The use of 1 H -indazole N-oxides has been remarkably effective for the selective introduction of diverse functional groups, including amino (NHAr), chloro (Cl), hydroxy (OH), sulfonyl (SO2 Ar), aromatic (Ar), olefin, alkyl, and N-formyl (NRCHO) groups, to indazole pharmacophore molecules. This review offers a concise overview of the synthetic approaches and practical applications of 1 H -indazole N-oxides, including recent studies conducted by the authors. Transformative reactions involving 1 H -indazole N-oxides not only offer strategies for synthesizing C3-functionalized 1 H -indazoles but also hold significant potential in medicinal chemistry. 1 Introduction 2 Synthetic Approaches and Applications of 1 H -Indazole N -Oxides 3 Summary and Outlook [ABSTRACT FROM AUTHOR]

Indazoles are a very important group of nitrogen-containing heterocycles with a wide range of biological and medicinal applications. These properties make them highly attractive for drug development, particularly when combined with sulfonamides to enhance their medicinal potential. In this work, we synthesized an indazole-based sulfonamide, namely the 1-((2-chloro-5-methoxyphenyl)sulfonyl)-5-nitro-1H-indazole (3). The reduction of the nitro group of 5-nitroindazole (1) to its corresponding amine was also performed to yield compound (4). Both compounds' structures were elucidated using various spectroscopic techniques such as 1H NMR, 13C NMR, infrared (IR), and high-resolution mass spectrometry (HRMS). Our molecular docking studies suggest that compounds (3) and (4) have a strong affinity for MAPK1, indicating their potential as cancer treatments. [ABSTRACT FROM AUTHOR]

Synthesis of 6,7-dihydro-2H-indazoles by iodobenzene diacetate mediated intramolecular C–N coupling cyclization of acylhydrazones derived from (E)-2-methylidenecyclohex-3-enones was reported for the first time. Oxidative aromatization of these dihydroindazole intermediates with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone followed by in situ deprotection of the indazole nitrogen produced a series of 3-aryl-1H-indazoles in moderate to high yields. The cyclization method has the advantages of mild reaction conditions, broad substrate scope, and operational simplicity, which provides a novel synthetic route toward indazole derivatives and enriches the application of hypervalent iodine reagents in the synthesis of N-heterocyclic compounds. [ABSTRACT FROM AUTHOR]

Antibiotic resistance is a critical public health issue. Among the multi-drug resistant microorganisms in question, Pseudomonas aeruginosa has been designated by the WHO as a priority threat. Its virulence is orchestrated through quorum sensing (QS). This sophisticated communication network relies on the release and perception of autoinducers acting as population density indicators. Therefore, the interest of a quorum silencing pharmacological approach has unfolded to quench bacterial pathogenicity without impairing growth. In this article, we reported the development of a family of indazole–quinolone hybrids as anti-virulence agents. These new biaromatic compounds were designed as potential specific QS quenchers against P. aeruginosa. Our transdisciplinary research methodology included their synthesis using palladocatalyzed cross-coupling reactions, as well as their in silico physicochemical and in vitro biological evaluation. The hit 7-chloro-2-indazolyl-4-quinolone Ie shows a promising anti-biofilm and anti-pyocyanin efficiency (35% inhibition at 25 µM and 35% inhibition at 100 µM, respectively) without an anti-pseudomonal bacteriostatic effect. It also demonstrated a moderate eukaryotic cytotoxicity. Its anti-QS properties have been investigated using metabolomic and molecular modelling studies. [ABSTRACT FROM AUTHOR]

A theoretical study of the formation of carbamic acids of pyrazole and indazole has been carried out using DFT computational methods. The effects of the substituents and the solvent (using explicit and implicit solvent models) have been considered. In addition, the deprotonation of the carbamic acid and its influence on the stability of the system has been calculated. In the neutral systems, only the formation of indazole-1-carbamic acid derivatives is favored vs. the non-covalent complexes between pyrazole or indazole with CO2. The deprotonation of the carbamic acid highly stabilizes the system preventing its dissociation. [ABSTRACT FROM AUTHOR]

Aim of the study was designed for the design of novel indazole derivatives and evaluation of their docking against topoisomerase-II DNA gyrase enzyme for the antibacterial screening. Different novel substituted indazol-3-yl benzenesulfonamide derivatives were designed for the synthesis from o-chlorobenzonitrile and phenyl hydrazine reaction and further, with benzene sulphonyl chloride reaction. These were evaluated for their docking targeting topoisomerase-II DNA gyrase enzyme for the antibacterial screening. A range of binding affinity (-12.2 to -9.6 kcal/mol) was observed. Compound, 4-chloro-N-(1-phenyl-1H-indazol-3-yl)benzenesulfonamide had the highest binding affinity (-12.2 kcal/mol) which is better than the standard norfloxacin (-10.7 kcal/mol). Compounds (12a, 12c, 12e and 12g) with chloro-substitution at para position of sulfonamide had higher affinity as compared to the compounds (12b, 12d, 12f and 12h) with methyl substitution. A convenient method for the synthesis of indazole derivatives has been developed. 4-chloro-N-(1-phenyl-1H-indazol-3-yl)benzenesulfonamide had shown the best binding affinity. Further, more diverse bioactive moieties may be incorporated into indazole scaffold in the near future by future researchers and a great amount of effort may be dedicated to the exploration of medicinal approaches for their preparation and evaluation of their biological activities. [ABSTRACT FROM AUTHOR]

Indazole is a very significant group of heterocyclics. Aim of the research was thus planned to synthesize novel derivatives of indazole and evaluate their anti-inflammatory activity. Novel compounds of indazole were first synthesized from reaction of 2-chlorobenzonitrile with phenylhydrazine in presence of catalyst potassium tbutoxide (t-BuOK) and the solvent diglyme. Synthesized derivatives of indazole were analyzed by ¹H-NMR and MS spectroscopic techniques. All the synthesized derivatives of indazole were evaluated for their antiinflammatory activity in Sprague Dawley rats by carrageenan-induced rat paw edema method. All the synthesized derivatives of indazole had shown very good activity in both docking and anti-inflammatory activity in rats in comparison to the standard etoricoxib. Compound 1a in a dose of 30 mg/kg body weight had shown most significant inhibition of edema as compared to toxic group and the inhibition was comparable to that of the standard drug, etoricoxib in a dose of 10 mg/kg body weight. A convenient means for the synthesis of derivatives of indazole was developed which may find applications in heterocyclic synthesis of derivatives of indazole. Compound 1a i.e., 3-(4-carboxyphenyl)amino-1-phenyl-1H-indazole had shown best anti-inflammatory activity amongst all the synthesized compounds. [ABSTRACT FROM AUTHOR]

Aim of the study was designed to synthesize and evaluate antibacterial activity of novel heterocyclic compounds, 3-methyl-1H-indazole derivatives. The heterocyclic compounds, 3-methyl-¹H-indazole derivatives (1a-1d and 2a- 2d) were synthesized; all of them characterized physically by melting point, Rf value, appearance & solubility; and some of them characterized spectroscopically by IR and 1H NMR spectroscopy. All the synthesized derivatives were evaluated for their antibacterial activity against both Gram positive bacteria, Bacillus subtilis and Gram negative bacteria, Escherichia coli by cup plate method using ciprofloxacin as a standard drug. All the synthesized heterocyclic compounds, 3-methyl-1H-indazole derivatives (1a-1d and 2a-2d), had shown antibacterial activity against the B. subtilis and E. coli. Compound 1d i.e., 1-(2-(piperidin-1-yl)ethan-1-oyl)-3-methyl-1H-indazole at the concentration of 300 μg/ml showed best antibacterial activity against the bacteria B. subtilis and E. coli as compared to standard drug, ciprofloxacin. The methodology for the synthesis of heterocyclic compounds, 3- methyl-1H-indazol-1-yl derivatives was simple as well as economical and gave better yield of the synthesized compounds. The compound, 1-(2-(piperidin-1-yl)ethan-1-oyl)-3-methyl-1H-indazole had shown best antibacterial activity against the bacteria B. subtilis and E. coli. [ABSTRACT FROM AUTHOR]

The oxidant‐controlled divergent synthesis of C‐2′ formyl 2H‐indazoles and indazoloindazolediones has been developed through Mn(I)‐ catalyzed ortho C−H functionalization of 2H‐indazoles with para‐formaldehyde to afford C‐2′ hydroxymethylated 2H‐indazoles and subsequently oxidation with varying the amount of DDQ in one‐pot. By employing selectfluor as the oxidant instead of DDQ, this reaction exclusively provided indazolebenzoxazine derivatives. This strategy delivered unsymmetrical indazoloindazoledione and indazolobenzoxazine with varied functional group tolerance in moderate to good yields. [ABSTRACT FROM AUTHOR]

A new series of 1,2,4-oxadiazole incorporated indazole-isoxazole (12a-j) derivatives were designed, synthesized and confirmed their structures by ¹HNMR, 13CNMR and mass spectral analysis. Further, all compounds were evaluated for their anticancer activity against a panel of human cell lines like breast cancer (MCF-7), lung cancer (A549), prostate cancer (DU-145) and breast cancer (MDA MB-231) by using MTT assay. The etoposide used as a reference drug and the results were expressed with IC50 (µM). Most of the compounds were showed good to moderate activity with respective cell lines. Among them, compounds 12b, 12e, 12 g, 12h and 12i have exhibited more potent activity as compared with the reference drug etoposide. In which one of the compound 12i has showed most significant activity. Molecular docking studies were carried out using PyRx tool and visualized through Chimera and Pymol visualization tools, revealed that the interactions between the active site of the tubulin with the selected compound 12i exhibited good interactions with the active site amino acids. These findings suggested that the 12i compound acts as a potential binder to the tubulin complex. These results revealed that the selected synthesized compounds were used in anticancer therapies. [ABSTRACT FROM AUTHOR]

A hybrid library of compounds based on indazole-based thiadiazole containing thiazolidinone moieties (1–17) was synthesized. The synthesized compounds were screened in vitro for their inhibition profile against targetedacetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities. All the derivatives demonstrated a varied range of inhibitory activities having IC50 values ranging from 0.86 ± 0.33 μM to 26.73 ± 0.84 μM (AChE) and 0.89 ± 0.12 μM to 27.08 ± 0.19 μM (BuChE), respectively. The results obtained were compared with standard Donepezil drugs (IC50 = 1.26 ± 0.18 μM for AChE) and (1.35 ± 0.37 μM for BuChE), respectively. Specifically, the derivatives 1–17, 1, 9, and 14 were found to be significantly active, with IC50 values of 0.86 ± 0.30, 0.92 ± 0.10, and 1.10 ± 0.37 μM (against AChE) and 0.89 ± 0.12, 0.98 ± 0.48 and 1.19 ± 0.42 μM (against BuChE), respectively.The structure–activity relationship (SAR) studies revealed that derivatives bearing para-CF3, ortho-OH, and para-F substitutions on the phenyl ring attached to the thiadiazole skeleton, as well as meta-Cl, -NO2, and para-chloro substitutions on the phenyl ring, having a significant effect on inhibitory potential. The synthesized scaffolds have been further characterized by using 1H-NMR, 13C-NMR, and (HR-MS) to confirm the precise structures of the synthesized compounds. Additionally, the molecular docking approach was carried out for most active compounds to explore the binding interactions established by most active compounds, with the active sites of targeted enzymes and obtained results supporting the experimental data. [ABSTRACT FROM AUTHOR]

Indazole-based HDAC6 inhibitors with novel zinc-binding modifications were synthesized and evaluated to determine their potential to inhibit HDAC6. The analogs were subjected to a histone deacetylase (HDAC) enzyme assay, which led to identification of compounds 3a and 3b. Both compounds demonstrated higher potency and selectivity as HDAC6 inhibitors with IC50 values of 9.1 nM and 9.0 nM, respectively, and highlighted the importance of the hydroxamic acid moiety for binding to Zn2+ inside the catalytic pocket of HDAC enzymes. In the neuroblastoma SH-SY5Y cell line, both compounds efficiently acetylated α-tubulin but not histone H3 at a low concentration of 0.5 µM. Moreover, compounds 3a and 3b effectively reversed the deacetylation of α-tubulin caused by methamphetamine in the SH-SY5Y cell line, suggesting the potential usefulness of HDAC6 selective inhibition in restoring blood brain barrier integrity by reversing methamphetamine-induced deacetylation. [ABSTRACT FROM AUTHOR]

Herein, we report the synthesis of cyclic ketone‐fused pyrazoles via [3+2] annulation reaction between hydrazones and cyclic enones (five‐, six‐ and seven‐membered) catalyzed by Cu(II) under aerobic conditions. These compounds were further functionalized by reactions such as Suzuki‐Miyaura cross‐coupling, Heck coupling, and Aldol reaction to afford diverse molecular scaffolds in good yield, selectivity and functional group tolerance. [ABSTRACT FROM AUTHOR]

The synthesis of N‐methyl‐5‐nitroindazolylacrylonitriles 2 a–l by a Knoevenagel condensation reaction with a series of aldehydes in the presence of piperidine allowed the preparation of the desired products the yields are good to excellent. N‐Methyl‐5‐nitroindazolylacrylonitriles (2 a–l) were verified by 1H, 13C NMR and mass spectrometry. In this current work, the reactivity indices defined within the Conceptual DFT of the targeted molecules through DFT/B3LYP/6‐311G(d,p) calculations were studied. The 1H NMR, UV‐vis and IR spectroscopy chemical shifts of all synthesized 5‐nitroindazoles 2 a–l were calculated and the results were compared to the results of the experimental data. In this series of compounds, the 2 e has the lowest hyperpolarizability, which results being the most stable and having the least response to nonlinear optics (NLO). In contrast, the compound 2 l has the highest hyperpolarizability, which fallouts being the least stable and having a high response to NLO. Every chemical has a significant three‐dimensional p‐electronic delocalization, which is crucial for understanding NLO responses. [ABSTRACT FROM AUTHOR]

N-heterocyclic compounds are a natural and rich source of pharmacologically active molecules displaying anti-cancer properties through various antiproliferative mechanisms. Some of these N-heterocyclic compounds are already being utilized or evaluated in clinical settings for cancer treatment, highlighting their potential significance in discovering new anticancer agents. This study aims to gather information from articles published between 2019 and 2021 on the recent advancements in N-heterocyclic derivatives such as indazole, triazolopyrimidine, pyrazolopyrimidine, quinoxaline, benzimidazole, benzodiazepine, indole, and quinoline as promising anticancer agents, including their structure-activity relationships and mechanisms of action. [ABSTRACT FROM AUTHOR]

Multi-drug resistant bacterial strains (MDR) have become an increasing challenge to our health system, resulting in multiple classical antibiotics being clinically inactive today. As the de-novo development of effective antibiotics is a very costly and time-consuming process, alternative strategies such as the screening of natural and synthetic compound libraries is a simple approach towards finding new lead compounds. We thus report on the antimicrobial evaluation of a small collection of fourteen drug-like compounds featuring indazoles, pyrazoles and pyrazolines as key heterocyclic moieties whose synthesis was achieved in continuous flow mode. It was found that several compounds possessed significant antibacterial potency against clinical and MDR strains of the Staphylococcus and Enterococcus genera, with the lead compound (9) reaching MIC values of 4 µg/mL on those species. In addition, time killing experiments performed on compound 9 on Staphylococcus aureus MDR strains highlight its activity as bacteriostatic. Additional evaluations regarding the physiochemical and pharmacokinetic properties of the most active compounds are reported and showcased, promising drug-likeness, which warrants further explorations of the newly identified antimicrobial lead compound. [ABSTRACT FROM AUTHOR]

A 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. [ABSTRACT FROM AUTHOR]

In a basic medium, 5-Mercapto-1,2,4-triazoles pass into the thiol form, allowing their transformation into sodium salts, which, in reaction with sodium monochloroacetate, lead to sodium 5-thioacetates of 1,2,4-triazoles-3,4-disubstituted. Sulfur derivatives converted to pivalic mixed anhydrides were used as active forms in the acylation of 6-amino penicillanic acid (6-AP) to obtain new semisynthetic penicillins. They contain in the molecule, together with the β-lactam ring, the nucleus 3-[(5-nitroindazol-1′-yl-methyl)]-4-aryl-5-mercapto-1,2,4-triazole, both contributing to an important antibacterial effect. The structure of the new antibiotics was confirmed by the results of elemental and spectral analysis (FT-IR, 1H- and 13C-NMR). The synthetic penicillins were tested for toxicological action and antibacterial activity and the obtained results were close to those for amoxicillin, the reference drug. [ABSTRACT FROM AUTHOR]

Fms-like tyrosine kinase 3 (FLT3) has been verified as a therapeutic target for acute myeloid leukaemia (AML). In this study, we report a series of 2-(1H-indazol-6-yl)-1H-benzo[d]imidazol-5-yl benzamide and phenyl urea derivatives as potent FLT3 inhibitors based on the structural optimisation of previous FLT3 inhibitors. Derivatives were synthesised as benzamide 8a-k, 8n-z, and phenyl urea 8l-m, with various substituents. The most potent inhibitor, 8r, demonstrated strong inhibitory activity against FLT3 and FLT3 mutants with a nanomolar IC50 and high selectivity profiles over 42 protein kinases. In addition, these type II FLT3 inhibitors were more potent against FLT3 mutants correlated with drug resistance. Overall, we provide a theoretical basis for the structural optimisation of novel benzimidazole analogues to develop strong inhibitors against FLT3 mutants for AML therapeutics. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A 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. [ABSTRACT FROM AUTHOR]

A new solvent/ligand-controlled switchable C–H arylation of 1-methyl-4-nitro-1 H -indazole catalyzed by Pd(OAc)2 was achieved. A bidentate ligand in DMA promoted the activation at C7 position, while a phosphine ligand in H2 O oriented the arylation at C3 position. The C3 and C7 arylation products were obtained in moderate to good yields and with high regioselectivity. [ABSTRACT FROM AUTHOR]

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 C7H6N2, 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. [ABSTRACT FROM AUTHOR]

The 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. [ABSTRACT FROM AUTHOR]

We contribute with the design and synthesis of novel 2,3‐diphenyl‐2H‐indazole hybrids series (1–14). Compounds 4 and 6 had the highest antiproliferative activity against the cancer cell lines, HeLa, SK‐LU‐1, K‐562, PC‐3, SW620 and MCF‐7 (CC50 values from 3 to 5.4 μM). Their activity was also evaluated against a normal human cell line, showing their higher Selectivity Index against the cancer cell lines than the reference drug CA‐4. The inhibition of tubulin assembly by compounds 4 and 6 was determined using in vitro tubulin polymerization assay and Western Blotting. The induction of mitotic catastrophe was observed with immunofluorescence assays. Besides, it was demonstrated by flow cytometry that compounds 4 and 6 arrest HeLa cell cycle at G2/M and promote apoptotic cell death. The mitotic arrest was also associated with elevated levels of cyclin B1 protein. We have identified two hybrids that behave as microtubule‐destabilizing agents on different cancer cell lines. [ABSTRACT FROM AUTHOR]

From the last two decades, Cadogan cyclization reaction is considered as one of the best routes for the preparation of various azaheterocycles comprising carbazoles, indoles, coumarins, carbolines, pyrazoloquinoxalines, S,N‐heterotetracenes from the nitro‐based substrates by using a variety of tetravalent phosphorus‐based reagents. To date the majority of Cadogan reactions are found to be intramolecular reactions, however, interestingly, a case of intermolecular Cadogan reaction is also reported, resulting in the widening of the reaction scope for futuristic perspectives. We report the Cadogan cyclization reactions for the synthesis of azaheterocycles from 2018 to present according to multiple classes of chemical frameworks including its scope (FDA approved drugs), along with the possibilities and mechanistic developments for unexpected products. [ABSTRACT FROM AUTHOR]

The current work presents an objective overview of the impact of one important heterocyclic structure, the pyrazole ring, in the development of anti-proliferative drugs. A set of 1551 pyrazole derivatives were extracted from the National Cancer Institute (NCI) database, together with their growth inhibition effects (GI%) on the NCI's panel of 60 cancer cell lines. The structures of these derivatives were analyzed based on the compounds' averages of GI% values across NCI-60 cell lines and the averages of the values for the outlier cells. The distribution and the architecture of the Bemis–Murcko skeletons were analyzed, highlighting the impact of certain scaffold structures on the anti-proliferative effect's potency and selectivity. The drug-likeness, chemical reactivity and promiscuity risks of the compounds were predicted using AMDETlab. The pyrazole ring proved to be a versatile scaffold for the design of anticancer drugs if properly substituted and if connected with other cyclic structures. The 1,3-diphenyl-pyrazole emerged as a useful scaffold for potent and targeted anticancer candidates. [ABSTRACT FROM AUTHOR]

Electrochemical synthesis offers a mild, simple, and efficient tool for the preparation of interesting and useful molecules, thus eluding severe chemical oxidizing and reducing agents used in conventional synthetic methods. In particular, electrochemical C-H activation is expected to play an important role in the direct functionalization of heterocyclic compounds. Over the past few decades, the research interest in imidazopyridine and indazole has increased significantly due to their multipurpose uses in medicinal and industrial chemistry. Therefore, structural modification of these heterocycles using electro-oxidation has become one of the important research topics among synthetic organic chemistry in recent time. This review provides a comprehensive discussion of electrochemical functionalization of indazoles and imidazopyridines published so far. A summary of the current challenges and the future direction for the development of efficient and green electrochemical methods for functionalization of these heterocycles is also presented. [ABSTRACT FROM AUTHOR]

Herein we described the synthesis of indazole derivatives through C-N cyclization and evaluated for their anticancer activities against three human cancer cell lines such as HeLa, MCF-7, and SKOV3 using MTT assay. The synthesized indazole hybrids are characterized based on 1H NMR, 13C NMR spectral data, and elemental analysis. The results indicated that the most potent molecule in this series is compound 3b against MCF-7, compound 3h against HeLa, and compound 3d against SKOV3, which showed the highest activity with an IC50 value of 32.92 μg/ml, 12.08 μg/ml, and 29.06 µg/ml respectively. [ABSTRACT FROM AUTHOR]

Indazole is known as an important structural motif in medicinal chemistry and, recently, has also gained attention in other areas, such as materials chemistry, with many studies showing different potential applications for their regioisomers. Phosphonates are also a class of compounds with diverse applications, ranging from medicinal to material applications. Here we present the synthesis of 1H‐ and 2H‐indazolephosphonic acid derivatives substituted at C‐3, involving mono‐ or bisphosphonic acids, from their corresponding carboxylic acid and esters. These compounds were fully characterized, and their spectroscopic data were evaluated to identify and distinguish the structural scaffold of each phosphonic acid. Crystallization of [hydroxy(1‐methyl‐1H‐indazol‐3‐yl)methanediyl]bis(phosphonic acid) 7 afforded crystals suitable for single crystal X‐ray diffraction studies and its crystal structure details are also discussed. [ABSTRACT FROM AUTHOR]

Tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate is a significant intermediate of 1H-indazole derivatives. In this paper, the title compound is acquired through two substitution reactions. The structure is corroborated by FTIR, 1H and 13C NMR spectroscopy, and MS. In the meantime, the single crystal is detected by means of X-ray diffraction, calculated by exerting density functional theory (DFT), and subjected to the crystallographic and conformational analysis. The results of comparing the DFT calculated value with the X-ray diffraction value display that the optimized molecular structure does cohere with the single crystal structure ascertained via the experiment. The 98.28% stable conformer and 1.72% unstable conformers are found in the DFT calculations. Furthermore, to reveal the physicochemical features of the title compound, the molecular electrostatic potential and frontier molecular orbitals are investigated through DFT. [ABSTRACT FROM AUTHOR]

The inhibitory effect of a new derivative of the indazole family, namely, (Z)-2-(1-methyl-5-nitro-1H-indazol-4-yl)-3-(3-nitrophenyl) acrylonitrile (51K2) against corrosion of carbon steel in 1 M HCl medium at a temperature of 25°C has been evaluated by different techniques such as gravimetric methods, potential-intensity curves, and electrochemical impedance spectroscopy. The impact of the concentration on the inhibition efficiency was also studied. The results of weight loss measurements and electrochemical analyses obtained showed that the addition of 51K2 increases the inhibition efficiency by decreasing the corrosion rate, with a maximum inhibitory efficacy of 80%. In other words, 51K2 is a good anodic-type corrosion inhibitor of carbon steel in 1 M HCl. [ABSTRACT FROM AUTHOR]

A simple and efficient strategy for the C–N cross-coupling of indazole with a variety of substituted aryl bromides is reported. Under the optimized conditions, a broad scope of N-arylated products were obtained in good to excellent yields (up to 87%) under the ligand-free conditions. [ABSTRACT FROM AUTHOR]

Depending on the reactant property and reaction mechanism, one major regioisomer can be favored in a reaction that involves multiple active sites. Herein, an orthogonal regulation of nucleophilic and electrophilic sites in the regiodivergent hydroamination of isoprene with indazoles is demonstrated. Under Pd‐hydride catalysis, the 1,2‐ or 4,3‐insertion pathway with respect to the electrophilic sites on isoprene could be controlled by the choice of ligands. In terms of the nucleophilic sites on indazoles, the reaction occurs at either the N1‐ or N2‐position of indazoles is governed by the acid co‐catalysts. Preliminary experimental studies have been performed to rationalize the mechanism and regioselectivity. This study not only contributes a practical tool for selective functionalization of isoprene, but also provides a guide to manipulate the regioselectivity for the N‐functionalization of indazoles. [ABSTRACT FROM AUTHOR]

Depending on the reactant property and reaction mechanism, one major regioisomer can be favored in a reaction that involves multiple active sites. Herein, an orthogonal regulation of nucleophilic and electrophilic sites in the regiodivergent hydroamination of isoprene with indazoles is demonstrated. Under Pd‐hydride catalysis, the 1,2‐ or 4,3‐insertion pathway with respect to the electrophilic sites on isoprene could be controlled by the choice of ligands. In terms of the nucleophilic sites on indazoles, the reaction occurs at either the N1‐ or N2‐position of indazoles is governed by the acid co‐catalysts. Preliminary experimental studies have been performed to rationalize the mechanism and regioselectivity. This study not only contributes a practical tool for selective functionalization of isoprene, but also provides a guide to manipulate the regioselectivity for the N‐functionalization of indazoles. [ABSTRACT FROM AUTHOR]

The In vitro antimicrobial properties of a series of N-methyl-3-aryl indazoles (5a-5j) were screened. In this present work, we describe our efforts towards the development of potent antimicrobial activity of synthesized indazole derivatives. The antimicrobial activities of the prepared compounds were investigated against four bacterial strains: Xanthomonas campestris, Escherichia coli, Bacillus cereus, Bacillus megaterium, and a fungal strain Candida albicans. The biological evaluation studies of these indazole derivatives revealed that some of these tested compounds have shown moderate to good In vitro antimicrobial activities. [ABSTRACT FROM AUTHOR]

More and more attention has been paid to the structurally diverse indazole analogs in recent years which are widely present in numerous commercially available drugs. Indazole-containing derivatives are endowed with a broad range of biological properties, such as anti-inflammatory, antibacterial, anti-HIV, antiarrhythmics, antifungal and antitumor activities. This review is a guide for pharmacologists who are in search of valid preclinical/clinical drug compounds where the progress, from 1966 to the present day, of approved marketed drugs containing indazole scaffold is examined. [ABSTRACT FROM AUTHOR]

In this work, catalytic activity of a series of copper(I) complexes containing dihydrobis(2‐mercapto‐benzimidazolyl) borate (Bb), and phosphine co‐ligands was investigated in the synthesis of N‐heterocycle compounds including 2H‐indazoles and 5‐substituted 1H‐tetrazoles. The copper(I) complex containing tricyclohexylphosphine co‐ligand, [Cu(Bb)(PCy3)], displayed the highest catalytic activities for the formation of 2H‐indazoles and 1H‐tetrazoles. Apart from the nontoxicity and strong σ‐donating ability of the introduced ligands, the introduced catalyst required easy handling processes. The catalytic reactions were successfully performed at low catalyst loadings in either PEG‐200 or DMF and in relatively short reaction times. The diversity of these reactions was also explored with 20 and 12 examples. Finally, the current catalytic system is amenable to large‐scale production of these N‐heterocycle compounds. [ABSTRACT FROM AUTHOR]

An efficient protocol providing easy access to highly functionalized heterocyclic compounds as novel organic building blocks was developed by coupling alkyl pyrazole-, indazole- and indolecarboxylates with N-Boc-3-iodoazetidine. The synthesized compounds are representatives of constrained non-chiral synthetic azole carboxylates in their N-Boc protected ester forms. Diversification of the prepared heterocyclic building blocks was achieved via application of palladium-catalyzed Suzuki–Miyaura cross-coupling reactions. In total, 34 building blocks were obtained to form a highly diversified small molecule collection. The structure of the novel heterocyclic compounds was investigated and verified by advanced NMR spectroscopy methods. [ABSTRACT FROM AUTHOR]

Indazole is an important heterocyclic scaffold exhibiting a wide range of biological and pharmacological properties and plays a crucial role in drug design. In recent years, indazoles have gained attention in materials chemistry owing to their promising photophysical properties. The biomedical importance and natural rarity inspire the development of new practical syntheses of the indazole core. In this review, we are presenting a comprehensive overview of recent developments in the transition metal‐catalyzed synthesis of indazole during the last decade. [ABSTRACT FROM AUTHOR]

Indazoles are a very important class of N‐containing heterocycles with a wide range of biological and medicinal properties. The presence of different functionalities on indazole moieties enhances its biological activities. Hence, the preparation of indazole compounds bearing functional groups has gained a significant interest to the organic synthetic chemists. A large effort has been made to develop efficient and new methods for the functionalization of indazoles. Direct catalytic functionalization is a very powerful tool for facile synthesis of important indazole derivatives due to its straightforwardness. This review summarizes developments on direct functionalizations of indazoles published in the last two decades. [ABSTRACT FROM AUTHOR]

The molar standard enthalpy of formation in condensed and gas phases of indazole, 1H-indazole-3-carboxylic acid, 1H-indazole-5-carboxylic acid, 1H-indazole-6-carboxylic acid and 1-methyl-1H-indazole-6-carboxylic methyl ester is reported. These properties were obtained indirectly from experimental determinations of the compounds using isoperibolic calorimetry and thermogravimetry. The values obtained for enthalpy of formation in the gas phase were compared with the computational results by means of the auxiliary density functional theory using deMon2k. The influence of the carbonyl and acetate groups on this type of compounds is analyzed energetically and structurally. The results obtained were compared and discussed with the data found in the literature. [ABSTRACT FROM AUTHOR]

A series of 3-aryl indazoles and 1-methyl-3-aryl indazole derivatives are prepared with exceptional yields by coupling with several arylboronic acids and methylation by two dissimilar approaches. The as-prepared indazole derivatives (3a–3j) and their N-methyl derivatives (5a–5j) are evaluated for in vitro anticancer activity against two cancer cell lines, HCT-116 and MDA-MB-231. The results reveal that the indazole derivatives tested display mild to moderate anticancer activities against the cell lines tested. [ABSTRACT FROM AUTHOR]

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Rational ligand design is crucial for achieving widespread applications of coordination polymers. The preparation, structural characterisation, and catalytic applications of zirconium (IV) coordination polymer (Zr-IDA), which was derived from 1-(carboxymethyl)-1H-indazole-5-carboxylic acid are reported. The Zr-IDA catalyst contains porous and highly crystalline particles with a quasi-spherical morphology around 100 nm in size, and Zr was coordinated with both O and N as shown by FT-IR and XPS measurements. Importantly, the Zr-IDA catalyst shows great activity, selectivity and stability in the oxidative coupling of benzyl cyanides with tert-butyl hydroperoxide to afford tertbutyl peresters, and the dehydrogenation cyclization of ophenylenediamines with aromatic alcohols to afford 1,2-disubstituted benzimidazole derivatives. Mechanistic investigations were carried out to study these reactions and the developed catalytic system in more detail. [ABSTRACT FROM AUTHOR]

The [4+1] cycloaddition reaction of bifunctional amino reagents has been achieved with in situ formed aza‐ortho‐quinone methides. Specifically, N‐(tosyloxy)carbamates were used as an N1 synthon and bifunctional amino reagents for this transformation, which provides a metal‐free, catalyst‐free, and oxidant‐free strategy to form nitrogen‐nitrogen bonds. [ABSTRACT FROM AUTHOR]