Indazole Compounds Research Articles

An efficient and simple approach for synthesizing indazole compounds using palladium-catalyzed Suzuki-Miyaura cross-coupling.

A series of indazole derivatives (6a-6i and 7a-7i) has been synthesized using Suzuki Miyaura cross-coupling with a palladium catalyst from readily available starting materials. An efficient and reliable methodology was employed for the synthesis, and the compounds were thoroughly characterized using 1H NMR, 13C NMR, FT-IR, and HRMS analysis to confirm their structural integrity and purity. Density function theory (DFT) computation identified four compounds (6g, 6h, 7g, and 7h) with significant energy band gaps. Additionally, the molecular electrostatic potential study highlighted the distinct electrical characteristics of these indazole molecules. Subsequent molecular docking investigations were carried out using the AUTODOCK method with two separate protein data bank (PDB) structures (6FEW, 4WA9) involved in renal cancer pathways. The results showed that eight substances PDB: 6FEW (6g, 6h, 7g, and 7h) and PDB: 4WA9 (6a, 6c, and 7c, 7g) had the highest binding energies, indicating their potential as therapeutic agents for treating kidney cancer.

Probing into the Flap-dimer Dynamics of the Mycobacterium tuberculosis Kasa Enzyme Binding Landscape Provides the Underlying Inhibitory Mechanisms of JSF-3285 and 5G.

β-ketoacyl-ACP synthase I (KasA I) enzyme is crucial in mycolic acid synthesis via catalytic condensation reactions, hence implicated in M. tuberculosis's virulence and drug resistance. Presently, there is no known potent KasA inhibitor; thiolactomycin lacks potency. Recently reported indazole compounds JSF-3285/tr1DG167 and 5G/tr2DG167 inhibit the KasA through binding to the substrate cavity. However, the molecular mechanism is still unclear, and the unknown resistance mechanisms raise concerns about JSF-3285's novelty. This study is the first to report the flap dimer opening and closing of the KasA pocket using combined metrics to define the symmetry impact of the flap-dimer motions and investigate the underlying inhibitory mechanism of tr1DG167 andtr2DG167 using all-atom MD simulation. The distance/d1 between the flap (PRO147) and dimer (LEU205) residues; TriC-α angle (θ1: PRO147-VAL83-LEU205 & θ2: PRO147-GLU199-LEU205); and the dihedral angle (Φ) were applied to investigate the flap "twisting" and dimer shift closing due to concerted motion by adjacent glycine-rich and glutamic acid-rich loops around the active site during the binding pocket's opening. The full flap-dimer of the unbound opens at 230 ns (d1 = 21.51 Å), corresponding to the largest TriC-α angle θ1 44.5° as θ2 is unreliable to describe the flap-dimer motion. The overall averages θ1 and θ2 for the bounds were ~23.13° and ~23.31°, respectively. Thus, the degree of KasA flap dimer opening is best investigated by distance and θ1. BFE (Kcal/mol) of -44.05 (tr1DG167) showed a higher affinity for the pocket than tr2DG167-KasA (-32.16). Both tr1DG167 and tr2DG167 formed hydrophobic interactions with LEU116, GLY117, ALA119, and tr1DG167 formed strong H-bonds with GLU199. The average RMSD of 2.80 Å (Apo) and RoG of 20.97 Å showed that KasA is less stable and less tightly packed without the inhibitors. These findings provide a background for a new structure-based design of novel KasA inhibitors.

Theoretical Studies on Selectivity of HPK1/JAK1 Inhibitors by Molecular Dynamics Simulations and Free Energy Calculations.

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T cell receptor, which has been regarded as a potential target for immunotherapy. Yu et al. observed the off-target effect of the high-throughput screening HPK1 kinase inhibitor hits on JAK1 kinase. The off-target effect is usually due to the lack of specificity of the drug, resulting in toxic side effects. Therefore, exploring the mechanisms to selectively inhibit HPK1 is critical for developing effective and safe inhibitors. In this study, two indazole compounds as HPK1 inhibitors with different selectivity towards JAK1 were used to investigate the selectivity mechanism using multiple computational methods, including conventional molecular dynamics simulations, binding free energy calculations and umbrella sampling simulations. The results indicate that the salt bridge between the inhibitor and residue Asp101 of HPK1 favors their selectivity towards HPK1 over JAK1. Information obtained from this study can be used to discover and design more potent and selective HPK1 inhibitors for immunotherapy.

Propitious Indazole Compounds as β‐ketoacyl‐ACP Synthase Inhibitors and Mechanisms Unfolded for TB Cure: Integrated Rational Design and MD Simulations

AbstractMycobacterium tuberculosis β‐ketoacyl‐ACP synthase I (KasA) involves in mycolic acid biosynthesis for cell wall maintenance; hence, it is a critical target in TB drug design. Thiolactomycin (TLM) and derivatives are the known standard KasA enzyme activity inhibitors. However, TLM analogues have poor activity against KasA protein. Indazole sulphonamide chemotype (JSF‐3285/JFX) was recently reported as a promising KasA enzyme inhibitor. JSF‐3285 mechanism is unclear; thus, it provides a means for designing KasA inhibitors. This study unfolds six hits as unprecedented KasA inhibitors. The inhibitory mechanisms of the screened compounds were investigated and compared with a standard inhibitor (TLM) using integrated molecular informatics and dynamics. JFX, M1, M2, and M5 molecules showed stronger interactions with KasA, having binding energy (kcal/mol) of −44.05, −41.52, −39.51, and −35.9, respectively, against −11.69 for TLM. Molecules showed good predicted inhibitory constants, drug‐likeness, ADME, and synthetic accessibility. KasA complex C‐α atoms RMSD and RMSF showed stable and erratic fluctuations compared to apo KasA. The findings provide potential antimycobacterial lead‐like molecules for future TB drugs.

Metabolism studies of 4'Cl-CUMYL-PINACA, 4'F-CUMYL-5F-PINACA, and 4'F-CUMYL-5F-PICA using human hepatocytes and LC-QTOF-MS analysis.

4'Cl-cumyl-PINACA (SGT-157), 4'F-cumyl-5F-PINACA (4F-cumyl-5F-PINACA, SGT-65), and 4'F-cumyl-5F-PICA (4F-cumyl-5F-PICA, SGT-64) are a series of new halogenated cumyl synthetic cannabinoid receptor agonists (SCRAs). Due to rapid metabolism, monitoring and screening for SCRAs in biological matrices requires identification of their metabolites. It is an essential tool for estimating their spread and fluctuations on the global illicit market. The purpose of this study was to identify human biotransformations of 4'Cl-cumyl-PINACA, 4'F-cumyl-5F-PINACA, and 4'F-cumyl-5F-PICA in vitro and characterize for the first time the metabolic pathways of halogenated cumyl SCRAs. 4'Cl-cumyl-PINACA, 4'F-cumyl-5F-PINACA, and 4'F-cumyl-5F-PICA were incubated with human hepatocytes in duplicates for 0h, 1h, 3h, and 5h. The supernatants were analysed in data-dependent acquisition on a UHPLC-QToF-MS and the potential metabolites were tentatively identified. A total of 11 metabolites were detected for 4'Cl-cumyl-PINACA, 21 for 4'F-cumyl-5F-PINACA, and 10 for 4'F-cumyl-5F-PICA. The main biotransformations were oxidative defluorination, followed by hydroxylation with dehydrogenation, N-dealkylation, dihydrodiol formation, and glucuronidation. Hydroxylations were most common at the tail moieties with higher abundancy for indole than indazole compounds. N-dealkylations were more common for fluorinated tail chain compounds than the non-fluorinated 4'Cl-cumyl-PINACA. In conclusion, many metabolites retained halogen groups at the cumyl moieties which, in various combinations, may be suitable as analytical biomarkers.

Photoredox-catalyzed trifluoromethylation of 2H-indazoles using TT-CF3+OTf- in ionic liquids.

A protocol for metal and oxidant free photoredox catalyzed trifluoromethylation of 2H-indazoles was developed by using Eosin Y as the photocatalyst and recoverable ionic liquids as the solvents. A series of trifluoromethylated products were obtained in moderate to good yields in this protocol under mild conditions. The reaction proceeded via a free-radical mechanism with a broad substrate range, excellent regioselectivity, and good functional group tolerance. Furthermore, the utility of this protocol was demonstrated by the synthesis of a highly selective ligand for estrogen receptor beta (ERβ) and the drug granisetron. The protocol provides a mild and environmentally friendly solution for trifluoromethylation reaction.

Exploring the inhibitory mechanisms of indazole compounds against SAH/MTAN-mediated quorum sensing utilizing QSAR and docking.

The world is under the great threat of antimicrobial resistance (AMR) leading to premature deaths. Micro-organisms can produce AMR via quorum sensing mechanisms utilizing S-adenocylhomocystiene/methiothioadenosine nucleosidase (SAH/MTAN) biosynthesis. But there is no specific drug developed till date to stop theSAH/MTAN which is a crucial target for the discovery of anti quorum sensing compound. It has been shown that the indazole compounds causes inhibition of SAH/MTA nucleosidase mediated quorum sensing, but the biochemical mechanisms have not yet been explored.Therefore, in this original research, an attempt has been made to explore essential structural features of these compounds by QSAR and molecular docking of indazole compounds having inhibition of SAH/MTA nucleosidase mediated quorum sensing. The validated QSAR predicted five essential descriptors and the molecular docking helps to identify the active binding amino acid residues involved in ligand receptor interaction are responsible for producing the quorum sensing inhibitory mechanisms of indazole compounds against SAH/MTAN-mediated antimicrobial resistance.

Facile synthesis of new N1-alkylated 1H-indazole-3-carboxamide derivatives as potential anticancer agents: In vitro, ADMET prediction, and SAR studies

This work is focused on the synthesis and characterization by spectroscopic methods of new indazole compounds containing carboxamide and acetamido N-substituted moieties on C3 and N1 atoms, respectively, where acetamido moiety has been considered a linker essential for different biological activities including anticancer activity. In this context, the antiproliferative activity of all these compounds was investigated over MDA-MB-231, A-549, and MCF-7 cancer cell lines and their cytotoxicity activity over normal fibroblast cell lines (NIH-3T3). The result showed that compounds SN-1.1, SN-2.1, and SN 3.2 bearing electron-withdrawing group at the fourth position on phenyl rings exhibited the most potent activity against MCF-7 cell line with GI50 value 2.34±0.036, 3.21±0.033, and 4.93±0.038 µM respectively. Further synthesized compounds were evaluated by various in silico screening technologies to better understand the drug-likeness features. All the compounds displayed optimal physicochemical features as excellent lead molecules. In the toxicity profiling study, all compounds were predicted to lack mutagenicity and cytotoxicity. This work provides a new class of safer indazole molecules with anticancer potential.

Search for biologically active compounds in the series of indazole derivatives

Indazole compounds are intensively used in the synthesis of new active substances for pharmacological purposes. The present work includes methods of modification and preparation of new indazole compounds, determination of their biological activity (antibacterial properties, antiprotozoal and fungistatic activity). Modification methods were used: the recyclization reaction; acetylation of the amino group; acylation and others. We have synthesized indazole derivatives containing an aryl substituent with a 2-aminoethyl fragment by recyclization of 1-(2-chloroaryl)-3,4-dihydroioquinolines under the influence of hydrazine. The starting structures for the synthesis of indazoles (compounds 5, 6, 7) possess negligible activity toward Colpoda steinii, are practically inactive toward Penicillium italicum but retard the growth of E. coli and Staphylococcus aureus (retard zone 7-9 mm); compounds with dimethoxy groups in the benzene ring (compounds 5 and 6) are active toward E. coli whereas structure 7 has no activity without dimethoxy groups. The recycling reaction leading to indazole structures considerably increases the activity of all compounds (1-4, 8-14). Compounds with a primary amino group (structures 1, 2, and 9) possess marked antiprotozoan activity, the best results in this respect being demonstrated by compound 9 which does not contain dimethoxy groups in the benzene ring (15.6 ?g/ml). Acylation of the amino group in compound 2 allows a 4-fold increase in antiprotozoic activity and a slight fungistatic activity (compound 3). At the same time, acylation with a bulkier and more lipophilic benzoyl group (compound 4) practically suppresses antiprotozoic and fungistatic activities. It should be noted that conversion of the primary amino group of compounds 1 and 9 to the tertiary amino group (compounds 13 and 14) allows a dramatic increase in antiprotozoal activity (31.25 µg/ml for compound 1 and 3.9 µg/ml for compound 13; 15.6 µg/ml for compound 9 and 3.9 µg/ml for compound 14). In addition, these same compounds 13 and 14, unlike compounds 1 and 9, are active against all cultures studied. The best results are shown by compounds 11 and 12 in which the amino group is part of the urea structure.

Molecular Docking Studies and in silico ADMET Screening of Indazole Scaffolds as VEGFR and Enoyl-ACP (CoA) Reductase Inhibitors

Lung cancer is expected to account for 11.4 % of the cancer burden in 2020, with an estimated 2.2 million new cases diagnosed and 1.8 million deaths occurring. Non-small-cell lung cancer accounted for approximately 85% of newly diagnosed lung cancer cases. In non-small cell lung cancer and tuberculosis level of vascular endothelial growth factor was found to be elevated, which induces angiogenesis. In this study molecular docking analysis along with pharmacokinetic/ADMET and drug likeness prediction were carried out to evaluate the newly designed indazole scaffolds as potent VEGFR and Enoyl-ACP (CoA) reductase enzyme inhibitors. Out of 11 screened compounds, two compounds having good scores (-7.72 and -7.54 kcal/mol) emerged as effective and potent VEGFR-2 inhibitors and three compounds showed highest binding affinities (-8.30, -7.76, -7.62 kcal/mol) with Enoyl-ACP. This study reveals that, newly designed indazole compounds could be the potential drug of choice against non-small cell lung cancer and tuberculosis.

Inhibitory Perspective of New Synthesized Compounds against Angiotensin Receptor: Schrodinger-based Induced-Fit Molecular Docking

Angiotensin is a hormone that plays a key role in the development of hypertension. Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) are now the most often prescribed drugs to treat hypertension. The present in silico study involves exploring the antihypertensive potentials of substituted benzimidazoles and indazole compounds ARC 36, ARC 38, ARC 45, ARC 76, and ARC 77 against the most prominent molecular target Angiotensin Receptor (PDB ID: 4YAY, XFEL structure of Human Angiotensin Receptor)using the software Schrodinger Maestro .Based on glide score, ARC 45, ARC 76 and ARC77 were having the docking score of -7.461 Kcal/mol, -7.947 Kcal/mol and -6.683 Kcal/mol which is comparable to the standard drug (Telmisartan) -5.036.The compounds were further screened for Lipinski’s rule for drug-likeliness, and ADME properties. In this study we reported compounds ARC 76 and ARC38had comparable in silico parameters to the standard dug Telmisartan and hence necessitating further in vitro and in vivo studies.

The Anticancer Activity of Indazole Compounds: A Mini Review.

The incidence and mortality of cancer continue to grow since the current medical treatments often fail to produce a complete and durable tumor response and ultimately give rise to therapy resistance and tumor relapse. Heterocycles with potential therapeutic values are of great pharmacological importance, and among them, indazole moiety is a privileged structure in medicinal chemistry. Indazole compounds possess potential anticancer activity, and indazole-based agents such as, axitinib, lonidamine and pazopanib have already been employed for cancer therapy, demonstrating indazole compounds as useful templates for the development of novel anticancer agents. The aim of this review is to present the main aspects of exploring anticancer properties, such as the structural modifications, the structure-activity relationship and mechanisms of action, making an effort to highlight the importance and therapeutic potential of the indazole compounds in the present anticancer agents.

Direct Catalytic Functionalization of Indazole Derivatives

AbstractIndazoles 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.magnified image

Indazole, Pyrrole and 2-Pyrone Compounds as Corrosion Inhibitors for Mild Steel in Acidic Medium: DFT Analysis

Indazole, Pyrrole and 2-Pyrone Compounds as Corrosion Inhibitors for Mild Steel in Acidic Medium: DFT Analysis

Synthesis and evaluation of a novel series of 6-bromo-1-cyclopentyl-1H-indazole-4-carboxylic acid-substituted amide derivatives as anticancer, antiangiogenic, and antioxidant agents

A series of novel indazole derivatives has been synthesized and evaluated for anticancer, antiangiogenic, and antioxidant activities. The capability of the synthesized compounds 11a–x to hinder the viability of three human cancer cells lines, HEP3BPN 11 (liver), MDA 453 (breast), and HL 60 (leukemia), were assessed by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Among the compounds 11a–x screened, 11c and 11d showed the higher inhibitory activity on the viability of HEP3BPN 11 (liver), when compared with the standard methotrexate. These compounds were further tested to evaluate their potential to inhibit the proangiogenic cytokines associated with tumor development. Compound 11c was found to be a potent antiangiogenic agent against TNFα, VEGF, and EGF, whereas 11d showed potent antiangiogenic activity against TNFα, VEGF, IGF1, TGFb, and leptin inhibition. All the compounds 11a–x were screened for their antioxidant activities using 2,2-diphenyl-1-picryl hydrazine (DPPH), hydroxyl (OH), and superoxide radical (SOR) scavenging activity. Compounds 11n, 11p, 11q, and 11v have shown significant OH radical scavenging activities, also compounds 11c, 11h, and 11k were found to have a DPPH radical scavenging activity and compounds 11a and 11m exhibited better SOR scavenging activity when compared with the reference compound ascorbic acid. In silico molecular docking analysis revealed important structural insights behind observed anti TNFα effect by present indazole compounds.

Ultrasound assisted, VOSO4 catalyzed synthesis of 4-thiazolidinones: Antimicrobial evaluation of indazole-4-thiazolidinone derivatives

A simple and expedient multicomponent protocol was developed to synthesize 4-thiazolidinones by employing VOSO4 as a catalyst under ultrasonic irradiation. The significant features of this protocol includes shorter reaction time, high yields, low catalyst loading, and also the catalyst can be recovered and reused up to next four cycles without significant loss in catalytic activity. All the synthesized novel indazole compounds were evaluated for their antibacterial and anti-biofilm activities. Compounds 9n, 9o and 9q showed promising activity (MIC value of 3.9 µg/mL) against K. planticola (MTCC 530). They also exhibited significant bactericidal activity against K. planticola (MTCC 530) (MBC value of 15.6 µg/mL). Additionally, 9n, 9o and 9q inhibited biofilm formation (IC50 values ranging between 20.28–20.79 μg/mL) in this organism.

Discovery of DS28120313 as a potent orally active hepcidin production inhibitor: Design and optimization of novel 4,6-disubstituted indazole derivatives

Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis, and its inhibition could be a favorable strategy for treating anemia of chronic disease (ACD). Here, we report the design, synthesis and structure–activity relationships (SAR) of a series of 4,6-disubstituted indazole compounds as hepcidin production inhibitors. The optimization study of multi-kinase inhibitor 1 led to the design of a potent and bioavailable hepcidin production inhibitor, 32 (DS28120313), which showed serum hepcidin-lowering effects in an interleukin-6-induced acute inflammatory mouse model.

From PIM1 to PI3Kδ via GSK3β: Target Hopping through the Kinome.

Selective inhibitors of phosphoinositide 3-kinase delta are of interest for the treatment of inflammatory diseases. Initial optimization of a 3-substituted indazole hit compound targeting the kinase PIM1 focused on improving selectivity over GSK3β through consideration of differences in the ATP binding pockets. Continued kinase cross-screening showed PI3Kδ activity in a series of 4,6-disubstituted indazole compounds, and subsequent structure-activity relationship exploration led to the discovery of an indole-containing lead compound as a potent PI3Kδ inhibitor with selectivity over the other PI3K isoforms.

Synthesis and SAR studies of 3,6-disubstituted indazole derivatives as potent hepcidin production inhibitors

Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Inhibition of hepcidin could be a strategy favorable to treating anemia of chronic disease (ACD). We report herein the synthesis and structure-activity relationships (SARs) of a series of indazole compounds as hepcidin production inhibitors. The optimization study of compound 1 led to a potent hepcidin production inhibitor 45, which showed serum hepcidin lowering effects in a mouse IL-6 induced acute inflammatory model.

Identyfikacja syntetycznego kannabinoidu 5F-NPB-22 (analog indazolowy 5F-PB-22) metodą chromatografii gazowej sprzężonej ze spektrometrią mas (GC/MS)

This article presents the problem of transesterification of a synthetic cannabinoid 5F-NPB-22 and other structurally related indazole and indole-based compounds, such as NPB-22, 5F-PB-22, BB-22 and PB-22, caused by methanol – a solvent commonly applied in gas chromatography/mass spectrometry (GC/MS) analysis. The above process can result in drawing incorrect conclusions about the composition of analyzed product, due to the formation of ester compounds, which mainly affects the reliability of results. In the present study, in addition to the mixture of methanol and toluene, as well toluene alone was used to evaluate the effect of both these solvents on the results obtained with GC/MS. The quality of analyses was additionally confirmed by quadrupole-time-of-flight (Q-TOF) mass spectrometry with direct injection of sample into the ion source. The final results indicate that in the case of transesterification-sensitive compounds, the selection of an adequate extraction-solvent is of major importance. It is recommended to use toluene and exclude transesterification-supporting solvents such as low molecular weight alcohols (methanol.ethanol). Moreover, a prompt analysis of the extracted substances should be ensured in order to eliminate their potential esterification.