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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]

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]

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]

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]

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]

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]

The study reports on the synthesis and in vitro assessment of the antimycobacterial activity of a series of new indole- and indazole-based aroylhydrazones evaluated against Mycobacterium tuberculosis H37Rv. Isoniazide and ethambutol were used as reference drugs. The most active compounds 3a (MIC 0.4412 μM) and 3e (MIC 0.3969 μM) demonstrated excellent antimycobacterial activity, a very low toxicity against the human embryonic kidney cell line HEK-293T and high selectivity index values (SI = 633.49 and SI > 1978.83, respectively). Importantly, the oral administration of compound 3e at the highest dose of 2000 mg/kg b.w. resulted in no mortalities or evidence of adverse effects, implying that compound 3e is nontoxic. The other derivatives with an indole and indazole scaffold also exhibited high antimycobacterial activity with exception of indole derivatives with Br substituents at the 5th position which exhibited activity weaker than that of ethambutol. The molecular docking investigations performed in an enoyl-ACP reductase (InhA) displayed good docking scores and promising insights on possible interactions with the InhA receptor. [ABSTRACT FROM AUTHOR]

Novel 4'-aryl-1,2',5'-triphenyl-2',4',6,7-tetrahydrospiro[indazole-5,3'-pyrazol]-4(1H)-ones have been synthesized in moderate yields by 1,3-dipolar cycloaddition of 5-arylmethylidene-1-phenyl-1,5,6,7-tetrahydro-4H-indazol-4-ones and diphenylnitrilimine, generated in situ from N-phenylbenzohydrazonoyl chloride and triethylamine. According to structural analyses by NMR spectroscopy and single crystal X-ray diffraction method, the reaction proceeds regioselectively affording products with C(5)-C(3') connectivity at the spiro center. [ABSTRACT FROM AUTHOR]

A novel series of indazole 13a-13j derivatives has been synthesized. Their structures are confirmed by 1H and 13C NMR, and mass spectral analysis. The compounds are tested for their anticancer activity against four human cancer cell lines including A549 (Lung), MCF7 (Breast), A375 (Melanoma), and HT-29 (Colon), using combretastatin-A4 as a positive control. Most of the synthesized compounds demonstrate potent activity against the above cell lines. Here IC50 values of target compounds range from 0.010±0.0042 to 12.8±3.77 μM and the control drug from 0.11±0.02 to 0.93±0.034 μM. The compounds 13a, 13b, 13e, 13g, 13h, and 13j are determined to be more potent than the positive control. [ABSTRACT FROM AUTHOR]

A series of ten novel hydrazide-hydrazones linked indole and indazole moieties were designed and synthesized. All the synthesized compounds were evaluated for their cytotoxicity against four human cancer cell lines (HeLa, MDA-MB-231, MCF-7, and A549). Three of the synthesized compounds showed promising cytotoxicity specifically on some of the tested cell lines with IC values ranging between 1.93 and 25.6 µM. Further, one compound was identified as a promising drug lead which showed promising cytotoxicity with IC value of 1.93 µM towards MCF-7 breast cancer cell line as compared to the standard drug doxorubicin ( IC value 0.98 µM). While, all these new compounds showed no cytotoxicity on the normal human embryonic kidney cell line, HEK-293. Graphical abstract: [ABSTRACT FROM AUTHOR]

Mechanical force from ball milling was used for efficient and quantitative preparation of a series of cyclohexenones and indazoles. The method is environmentally friendly, simple, short, and solventless. Unambiguous structural assignments of the obtained cyclohexenones were achieved based on single-crystal X-ray diffraction. The structures of the indazoles were characterized using Fourier-transform infrared spectroscopy, hydrogen and carbon nuclear magnetic resonance (NMR) spectroscopy, homonuclear correlation spectroscopy, distortionless enhancement by polarization transfer (DEPT) NMR, and gas chromatography-mass spectrometry. The synthesized compounds were screened for antimicrobial activity against two Gram-positive bacteria (methicillin-resistant staphylococcus aureus and Micrococcus luteus), three Gram-negative bacteria ( Klebsiella oxytoca, Salmonella typhimurium, and Shigella sonnei), and three fungi ( Candida albicans, Aspergillus niger, and A. flavus). The effects that different substituents on the synthesized compounds had on the antibacterial and antifungal activities were evaluated. Cyclohexenone derivatives with thiophene moiety at 4-position showed antibacterial activity comparable to the antibiotic tetracycline. Graphical Abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

[Figure not available: see fulltext.] The new heterocyclic system isoxazolo[4,3- e]indazole was synthesized via the nucleophilic substitution of a hydrogen in 1-methyl-5-nitro-1 H-indazole with different aryl acetonitriles in basic medium. The fluorescence properties and antibacterial activities of the new compounds against Gram-positive and Gram-negative bacterial species were also studied. [ABSTRACT FROM AUTHOR]

Cyclocondensation reactions of 3-phenyl-1-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl) prop-2-en-1-one ( 2) with active methylene reagents such as ethyl cyanoacetate, malononitrile, ethyl acetoacetate, and acetoacetanilide afforded pyrazolinyl pyridine derivatives ( 3 and 12), pyrazolinyl pyran derivative ( 9), and pyrazolinyl cyclohexene derivatives ( 10 and 11). Reaction of 11 with hydrazines and hydroxyl amine led to the formation of indazole derivatives ( 13 and 14), and benzisoxazole derivative 15. Also, reaction of 9 with different reagents gave pyrano[2,3- d][1,2,3]triazine ( 19) and pyrano[2,3- d]pyrimidine derivatives ( 20 and 21). The anti-inflammatory, analgesic, and antimicrobial activities of these compounds were determined. Compounds 13 and 14 showed good anti-inflammatory activity in comparison with the standard indomethacin, whereas compounds 4, 7, and 12 showed higher analgesic activity than the reference aspirin drug. In addition, compounds 7, 11, and 15 exhibited broad spectrum activities against all bacterial and fungal species tested. Graphical Abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

New indazole derivatives were synthesized by reacting hydrazine hydrate and its derivatives with cyclohexenone derivatives, which in turn prepared from respective chalcones. The chemical structure of newly synthesized compounds was well characterized by using H NMR, C NMR, IR and mass spectral data. All the synthesized products were screened for their antioxidant properties. All indazole derivatives exhibited noticeable DPPH radical scavenging activity, reducing power capacity and total antioxidant capacity in comparison with the respective standards. [ABSTRACT FROM AUTHOR]

By means of DFT calculations [B3LYP/6-311++G(d,p), GIAO], the properties of the three tautomers of 1:9,5:10-anthradipyrazole were analyzed and compared with Maspero's crystal structures and NMR results. The agreement is fairly good and in agreement with indazole tautomers. Besides, the aromaticity of these interesting five-membered ring systems was explored. [ABSTRACT FROM AUTHOR]

Background: Head and neck squamous cell carcinoma (HNSCC) is the 11th leading cancer by incidence worldwide. Surgery and radiotherapy have been the major treatment for patients with HNSCC while chemotherapy has become an important treatment option for locally advanced HNSCC. Understanding of the molecular mechanisms underlying HNSCC impelled the development of targeted therapeutic agents. The development and combinations of targeted therapies in different cellular pathways may be needed to fulfill the unmet needs of current HNSCC chemotherapy. Results: A series of N3-acyl-N5-aryl-3,5-diaminoindazoles were synthesized and their anti-proliferative activities were evaluated against human cancer cell lines, Caki, A549, AMC-HN1, AMC-HN3, AMC-HN4, AMC-HN6, and SNU449. The cellular selectivity of compound was obtained by the modification of substituent at N5-aryl group of 3,5-diaminoindazole. Compound 9a and 9b showed more than 7-fold selectivity for AMC-HN4 and AMC-HN3, respectively. Conclusions: N3-acyl-N5-aryl-3,5-diaminoindazole analogues can be used as hits in the development of anticancer drug for HNSCC. [ABSTRACT FROM AUTHOR]

New functionalized derivatives were prepared using alkyl 4,6-bis(4-fluorophenyl)-2-oxocyclohex-3-ene-1-carboxylate as a building block. Newly prepared compounds were well characterized using H NMR, IR, and mass spectral data. All the synthesized products were screened for their antioxidant properties. Among the tested compounds, indazole derivatives exhibited noticeable DPPH radical scavenging activity and reducing power capacity in comparison with the standard Glutathione. [ABSTRACT FROM AUTHOR]

This article reveals the various biological activities of the heterocyclic compound, indazole, including anti-inflammatory, antimicrobial, antiHIV, anticancer, hypoglycemic, antiprotozoal, antihypertensive, and other activities. From the observed biological activities of the indazole moiety, it is concluded that the medicinal properties of indazole have to be explored in the near future for the treatment of various pathological conditions. [ABSTRACT FROM AUTHOR]

Examples of intramolecular cyclizations of functionalized diacetylenes are considered in the review. Cyclizations occur with the participation of one of the triple bonds that leads to ethynyl-substituted heterocycles, or of two triple bonds that is used in the synthesis of polycondensed heterocyclic systems and ensembles. [ABSTRACT FROM AUTHOR]

The influence of injection periods of 3-(1 H-pyrrol-2-yl)-1 H-indazole regarding vitamins A, E, C, selenium (Se), malondialdehyde (MDA) levels, and glutathione peroxidase (GSH-Px) activity in rats has been investigated. The substance was given by subcutaneous injection at 20 mg/kg every other day for a total of 15 injections. At the end of the treatment, Se levels in serum were determined by fluorimetry, and those of vitamins A, E, C, and malondialdehyde in serum, liver, and kidney were determined by high-performance liquid chromatography. GSH-Px activities in erythrocytes were determined spectrophotometrically. Vitamins A, E, C, and Se levels were generally lower than in the controls, while GSH-Px activity at the third injection period was maximally increased, with the activities after the other injection periods being higher than in the control group. In addition, vitamins A, E, and C levels were generally lower than the control groups, while serum, liver, and kidney MDA levels gradually increased depending on injection periods. On the other hand, GSH-Px activity was higher than in the control group. Thus, the results show that while vitamins A, E, C, and Se levels decreased, MDA levels and GSH-Px activities increased after administration of 3-(1 H-pyrrol-2-yl)-1 H-indazole to the rats. These findings might be related to the increased amount of free radicals caused by 3-(1 H-pyrrol-2-yl)-1 H-indazole injection. [ABSTRACT FROM AUTHOR]

The review covers the use of formazans in the synthesis of azoles. [ABSTRACT FROM AUTHOR]

Ferrocenylmethylation and α-ferrocenylethylation of indazole were carried out for the first time. Both reactions afforded two isomers, which were characterized by physical and physicochemical methods, among them by X-ray diffraction analysis. 1-(α-Ferrocenylethyl)indazole is thermally more stable than the 2-substituted isomer. Both isomers serve as ferrocenylalkylating agents with respect to s-triazole. [ABSTRACT FROM AUTHOR]

N-(2-Azido-5-nitrobenzylidene)-3,5-di- tert-butyl-4-hydroxyaniline ( 3a) and N-(2-azido-5-nitrobenzilidene) aniline ( 3b), when heated in dimethylformamide yielded 2-(3,5-di- tert-butyl-4-hydroxyphenyl)-5-nitroindazole ( 4a) and 2-phenyl-5-nitroindazole ( 4b), respectively. The structure of 4b was confirmed by X-ray analysis. A stable phenoxyl radical was shown to originate from the oxidation of 4a with lead (IV) dioxide. [ABSTRACT FROM AUTHOR]