Aryl Hydrazines Research Articles

Enzymatic synthesis of azide by a promiscuous N-nitrosylase.

Azides are energy-rich compounds with diverse representation in a broad range of scientific disciplines, including material science, synthetic chemistry, pharmaceutical science and chemical biology. Despite ubiquitous usage of the azido group, the underlying biosynthetic pathways for its formation remain largely unknown. Here we report the characterization of an enzymatic route for de novo azide construction. We demonstrate that Tri17, a promiscuous ATP- and nitrite-dependent enzyme, catalyses organic azide synthesis through sequential N-nitrosation and dehydration of aryl hydrazines. Through biochemical, structural and computational analyses, we further propose a plausible molecular mechanism for azide synthesis that sets the stage for future biocatalytic applications and biosynthetic pathway engineering.

Ultrasound-assisted synthesis of 1,5-disubstituted pyrazoles via HFIP-mediated cascade cyclization of enaminones with aryl hydrazine

A simple and efficient metal-free strategy has been developed for the synthesis of 1,5-disubstituted pyrazole derivatives by using 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) medium and ultrasound irradiation. The condensation reactions of β-enaminone and aromatic hydrazine have taken place at room temperature with the assistance of sonication. The protocol provides rapid access to various N-aryl substituted pyrazole compounds with excellent functional group tolerance and yields. Notably, the eco-friendly and cost-effective method allows the conversion within a short time and under mild conditions.

An aerobic copper-catalyzed multi-component reaction strategy for N′,N′-diaryl acylhydrazine synthesis: reactions and mechanism

A sequential multi-component reaction of aldehydes and aryl hydrazines for the synthesis of N',N'-diaryl acylhydrazines with high regioselectivity has been achieved via an aerobic copper-catalyzed process.

Pyrimidine Tethered Pyrazoles: Synthesis, Biological, and Molecular Docking Studies

A series of pyrimidine integrated pyrazoles (5a?5g) has been synthesized in good yields from aryl hydrazines and aralkyl ketones through a protocol of multi-steps such as condensation/imine formation, cyclization/Vilsmeier-Haackreaction, and Knoevenagelcondensation and characterized through physical and spectral techniques. 2,2-diphenylpicrylhydrazyl radical scavenging evaluation revealed that the chemical entity possessing para-fluoro substituent on the aromatic unit tethered at the carbon of pyrazole scaffold 5g exerted the highest activity among the investigated ones. Of the results of cytotoxicity evaluation utilizing AsPC1, BxPC3, SW1990 (pancreatic cancer cells), the chemical entity possessing ortho-chlorosubstitient on the aryl unit integrated at carbon of pyrazole scaffold 5b exhibited superior activity. Besides, the molecular docking studies of the ortho-chloroaryl group possessing chemical entity 5b with BCL-2 (B-cell lymphoma 2) displayed significant binding affinity (-9.1 kcal mol-1). In addition, pharmacokinetic as well as prediction of drug-likeness for all the molecular hybrids 5a?5g have been evaluated using SwissADME tool and all the chemical entities are in good agreement of Lipinski rule with no violation.. KEYWORDS :Cytotoxicity, Molecular docking, Pyrazoles, Pyrimidines, Radical scavenging, SwissADME.

Spectroscopic, DFT, molecular docking and anti-cancer studies of regioselectively designed 1-aryl-indenopyrazoles

L-Proline catalyzed condensation of 1-indanones with DMF-DMA (N,N-dimethylformamide dimethyl acetal) resulted in (Z)-2-((dimethylamino)methylene-2,3-dihydro-1H-inden-1-ones 2 instead of their E-isomers 3, which is further regioselectively transformed into 1-aryl-2,4-dihydroindeno[1,2-c]pyrazole 4 rather than 2-aryl-2,4-dihydroindeno[1,2-c]pyrazoles 5 by condensing with aryl hydrazines. Spectrochemical characterizations and single crystal X-ray diffraction studies were used to resolve syntactic ambiguity between the possible geometric isomers of enaminones (E & Z) and regioisomers 1H-indenopyrazole and 2H-indenopyrazoles. The experimental findings were correlated with computed values and have shown good correlation with the proposed structures. The synthesized indenopyrazoles 4a–f were tested for their ability to inhibit the proliferation of A549 human lung cancer cell lines, and the compound 4b have showed IC50 value 13.77 µM comparable to the reference medication erlotinib (10.26 µM). The complete cell cycle analysis have revealed the accumulation of mitotic cells in G1/S phase. The flow cytometric analysis also revealed the increase in apoptotic cells indicating tumor suppression by the derivative 4b. To get insight into the interactions of the compound and EGFR tyrosine kinase protein molecular docking was performed. Also, pharmacokinetic profiling revealed about the oral compatibility of the synthesized compounds.

Conventional Versus Microwave Induced Synthesis and Biological Evolution of Coumarin Substituted Thioaryl Pyrazolyl Pyrazoline

Aim: This is a comparative study of some new coumarin substituted thioaryl pyrazolyl pyrazoline. Methods: The target compounds were synthesized using both conventional as well as microwave irradiation by reaction of coumarin chalcones with different substituted hydrazine hydrates and aryl hydrazines to give the resultant pyrazoline derivatives. Microwave reaction, enhanced or-ganic reactions, and reduced reaction time led to better yields and selectivity than conventional methods. Results: The obtained compounds were characterized by different spectroscopic analysis includ-ing IR, 1H-NMR, 13C-NMR, mass spectroscopy and elemental-analysis and evaluated for their antimicrobial screening against a representative panel of bacteria (Bacillus subtilis, Staphylococ-cus aureus, Escherichia coli, Salmonella typhi) and fungi (Aspergillus niger, Candida albicans). Conclusion: In the present study, we have synthesized coumarin pyrazoline derivatives clubbed with benzofuran pyrazole via both conventional and microwave irradiation and also subjected to antibacterial and antifungal studies. Synthesis of target compounds by the microwave irradiation enhanced reaction rate and reduced reaction time led to better yields and selectivity than conven-tional methods. The study of antibacterial and antifungal activities revealed that all the com-pounds exhibited reasonable to excellent activities against the pathogenic strains.

Iodine‐Mediated One‐Pot Synthesis of 1,4,5‐Substituted Pyrazoles from MBH Acetates via Allyl Hydrazone Intermediate

AbstractHerein, we report the regioselective one‐pot synthesis of 1,4,5‐trisubstituted pyrazoles by reacting Morita‐Baylis‐Hillman (MBH) acetates derived from aryl aldehydes with alkyl or aryl hydrazines in the presence of iodine under aerobic conditions. The reaction proceeds through sequential SN2′ nucleophilic substitution of substituted hydrazine onto the MBH acetate, I2‐catalyzed oxidation of the allylic hydrazine to allylic hydrazone, heating‐induced intramolecular aza‐Michael reaction and cyclization, and oxidative aromatization. The key intermediate, thes‐transallyl hydrazones were isolated in good yields by performing the reactions at room temperature. However, the allyl hydrazones prepared from the MBH acetates of aliphatic aldehydes did not furnish the pyrazole owing to the absence of an activated methylene group in the substrate. The synthetic applications of the pyrazoles in Ugi reactions, decarboxylative halogenation, Pd‐catalyzed benzoylation of the N‐aryl ring, and metal‐free tetrazole synthesis has been demonstrated.

Modular Synthesis of Phosphino Hydrazones and Their Use as Ligands in a Palladium-Catalysed Cu-Free Sonogashira Cross-Coupling Reaction.

Phosphino hydrazones represent a versatile class of nitrogen-containing phosphine ligands. Herein, we report a modular synthesis of phosphino hydrazone ligands by hydrazone condensation reaction of three different aryl hydrazines with 3-(diphenylphosphino)propanal (PCHO). Complexation reactions of these phosphino hydrazone ligands with palladium(II) and platinum(II) were investigated and the catalytic activity of the palladium(II) complexes was explored in a Cu-free Sonogashira cross-coupling reaction achieving yields up to 96 %. Additionally it was shown that the catalytically active species is homogeneous.

Three-Component Chemo-Selective Synthesis of N-(o-Alkenylaryl) Pyrazoles by Pyrazole Annulation and Rh-Catalyzed Chemo-Selective Aryl C-H Addition Cascade.

By using readily available enaminones, aryl hydrazine hydrochlorides, and alkynes as starting materials, the chemo-selective three-component synthesis of atropisomeric N-(o-alkenylaryl) pyrazoles has been efficiently accessed with rhodium catalysis. Unlike Satoh-Miura reaction leading to the alkyne-based C-H benzannulation by using prior prepared N-phenyl pyrazoles and alkynes as substrates, this three-component protocol displays unprecedented selectivity of C-H alkenylation by blocking the second round metal alkenylation with the key protonation step in the presence of acids.

Design, synthesis and anticancer activity of amide derivatives of substituted 3-methyl-benzofuran-2-carboxylic acid

We have designed and synthesized amide derivatives of substituted 3-methyl-benzofuran-2-carboxylic acid with aryl sulfonamide piperazines, aryl hydrazides and aryl hydrazines. All the synthesized compounds were screened for their anticancer activity against lungs cancer cell line (A549) and breast cancer cell line (MCF7) using MTT assay. Compound 12b showed excellent activity against lungs cancer cell line (A549) with IC50 value of 0.858 µM and compound 10d showed good activity against breast cancer cell line (MCF7) with IC50 value of 2.07 µM. Hence, compounds 10d and 12b were studied further for their mechanism of cytotoxicity by using EtBr/AO and LDH assay in respective cell lines. The cytostatic potential of compound 10d and 12b was uncurtail by Trypan blue exclusion assay and active involvement of ROS was quantified using DCFH-DA dye. The drug-likeliness and toxicity predictions were done using in-silico-based SwissADME and ProTox-II webserver, which confirmed negligible toxicity (Class IV).

FeO(OH)@C-Catalyzed Selective Hydrazine Substitution of p-Nitro-Aryl Fluorides and their Application for the Synthesis of Phthalazinones.

An efficient hydrazine substitution of p‐nitro‐aryl fluorides with hydrazine hydrates catalyzed by FeO(OH)@C nanoparticles is described. This hydrazine substitutions of p‐nitro‐aryl fluorides bearing electron‐withdrawing groups proceeded efficiently with high yield and selectivity. Similarly, hydrogenations of p‐nitro‐aryl fluorides containing electron‐donating groups also smoothly proceeded under mild conditions. Furthermore, with these prepared aryl hydrazines, some phthalazinones, interesting as potential structures for pharmaceuticals, have successfully been synthesized in high yields.

Microwave-assisted Synthesis of Novel Triazolyl Pyrazolyl Pyrazoline Substituted Coumarins and Their Antimicrobial Activity

Background: The 1,2,3-triazole, pyrazole, and coumarin-based derivatives have received much attention due to their wide coverage of biological properties. The present work describes the microwave synthesis of novel triazolyl pyrazolyl pyrazoline substituted coumarins. The structures of all the newly synthesized compounds are characterized by spectral analysis and screened for their in vitro antimicrobial activity by the Broth dilution method. Methods: Using the synthetic method, the targets were prepared by reacting various 3-{3-[3-(5- methyl-1-aryl-1H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-4-yl]acryloyl} coumarins (coumarin chalcones) (3a-d) with hydrazine hydrate or aryl hydrazine (5a-c) in the presence of acetic/propionic acid under microwave irradiation. Results: The structures of all the synthesized compounds were established by IR, 1H-NMR, 13CAPT, and selected mass spectral data. The target compounds were also screened for their in vitro antimicrobial efficiency against a representative panel of pathogenic strains, specifically Gram-positive bacteria (Staphylococcus aureus,italic> Bacillus subtilis), Gram-negative bacteria (Escherichia coli, Salmonella typhi), and Fungi (Candida albicans, Aspergillusniger). Conclusion: In conclusion, the target compounds were obtained by Microwave Irradiation (MWI) technique in good yield with a short reaction time. Among all the synthesized compounds, 4c, 4h, 6a, 6h, and 6l were found to have significant activity against bacterial and fungal strains.

One‐Pot Manganese (IV)‐Mediated Synthesis of Sulfonyl Fluorides from Arylhydrazines

AbstractSulfonyl fluorides, a useful structure in various organic syntheses, are found in several biologically active molecules and have been used in sulfur (VI) fluoride exchange‐based “click chemistry”. In the present study, a novel MnO2‐mediated synthetic method to prepare sulfonyl fluorides from aryl hydrazines employing DABSO and NFSI as effective reagents affording a variety of sulfonyl fluoride products in good to excellent yields is described. Our results suggest the generality of this MnO2 mediated transformation of various aryl hydrazines into sulfonyl fluorides under mild reaction conditions.

AgF-Mediated Electrophilic Amination of Alkoxyarylsilanes with Azodicarboxylates.

A facile and efficient AgF-mediated electrophilic amination of alkoxyarylsilanes with azodicarboxylates was developed. The reaction proceeds in green solvent under simple and mild conditions to generate the corresponding aryl hydrazines. AgF acts both as a stoichiometric fluoride source and a reagent for transmetalation to the arylsilver intermediate that eventually reacts with azodicarboxylates to provide aryl hydrazines.

One-step synthesis of picolinohydrazides from fusaric acid: DFT, structural characterization and molecular inhibitory studies on metastatic tumor-derived exosomal and non-exosomal proteins

A new class of picolinohydrazide analogs (5–7) was synthesized via the one-pot reaction between fusaric acid (1) and aryl hydrazines (2–4) using amide coupling reagents. The synthesized compounds (5–7) were characterized using density-functional theory (DFT) computational spectroscopy, and instrumental methods. Global and local reactivity descriptors of these compounds were calculated at the B3LYP/6–311++g(d) level of theory to predict the reactivity and the reactive sites. The evaluated electronic properties (HOMO and LUMO) gave an insight into the molecular properties of the molecule. The charge distribution and molecular electrostatic potential facilitated the prediction of either the electrophilic or nucleophilic reactivity of these compounds. Extracellular heat shock protein-90 (HSP90) plays an essential role in tumor invasion while epidermal growth factor receptor (EGFR) is found at high levels on the surface of metastatic tumors. Blocking EGFR and HSP90 may predict metastatic spread. Molecular docking and molecular dynamics showed that picolinohydrazide analogs (5–7) act as inhibitors to the active-site cavity of the target proteins, i.e., EGFR and HSP90. The fluorine scaffold (6) has a potential binding free energy of -31.01 kcal mol−1 and -30.54 kcal mol−1 for EGFR and HSP90, respectively. The binding complex of fluorine scaffold (6) with EGFR and HSP90, respectively has also shown substantial stability in the post-dynamics analysis. Our results implicate the potential efficacy of novel adjunct therapeutic insights in treating advanced cancer.

Growth vector elaboration of fragments: regioselective functionalization of 5-hydroxy-6-azaindazole and 3-hydroxy-2,6-naphthyridine.

This article discusses the reactivity of 6-azaindazole (1) and 2,6-naphthyridine (2), proposed to be "heteroaromatic rings of the future," which would be useful for fragment-based drug discovery (FBDD) campaigns, developing growth vectors for fragment elaboration by selectively functionalizing different positions on the rings. The pyridone oxygens and pyrazole nitrogen can be functionalized selectively. Arylation at the α-carbon of the pyridone moiety was achieved by a transition metal-free radical cross-coupling using aryl hydrazines. This method proceeded under mild conditions without the need for protection of the hydroxypyridine. Additionally, we developed a method for the regioselective C-3 functionalization of heterocycle 1via N-sulfonamide rearrangement. This method involved a novel regioselective base-mediated N-C migration of the N-1 sulfonamide to yield the C-3 sulfone. This procedure is also applicable for indazole C-3 functionalization and mechanistic studies of the rearrangement suggest that an intermolecular process is involved. These reactions enable the fragment elaboration of heterocycles 1 and 2 in several growth vectors to facilitate their use in FBDD.

Tunable Pd/C-catalyzed oxidative alkoxycarbonylation/aminocarbonylation of aryl hydrazines with alcohols/inert tertiary amines through C–N bond activation

We report Pd/C-catalyzed oxidative amino- and alkoxycarbonylation of unactivated aryl hydrazines, employing inert tertiary amines as an aminal source and arylhydrazines via oxidative sp3 and sp2 C–N bond activation using molecular oxygen as an oxidant.

SYNTHESIS, ANTIMICROBIAL, AND ANTITUBERCULAR ACTIVITIES OF NOVEL N-PYRAZOLYLBENZAMIDE DERIVATIVES

The current study investigated the antimicrobial and antitubercular activities of novel N-Pyrazolyl Benzamide derivatives. The study includes the synthesis, characterization, and ligand-based molecular docking of the designed molecules. Synthesis of N-Pyrazolyl Benzamide derivatives involves a two-step process in which 5-amino pyrazole (3) intermediate is produced by the condensation reaction of aryl hydrazine (1) and β-keto nitrile (2) in acidic conditions. The final N-Pyrazolyl Benzamide derivatives (5a-n) were synthesized by the reaction involving amide coupling between 5-amino pyrazole (3) and various substituted benzoyl halides (4a-n). The compounds (5a-n) were tested for antimicrobial activity against two gram-negative strains (E. coli and S. Typhi), two gram-positive strains (S. aureus and B. subtilis) and M. tuberculosis MTB H37Rv (ATCC 27294) strains were used for evaluating antitubercular activity. Molecular docking studies of designed derivatives were performed with the Schrodinger glide package against mycobacterial pantothenate synthetase (PDB ID: 4MQ6). All the tested compounds displayed moderate to good antimicrobial and antitubercular activity against the selected strains of bacteria. All the docked molecules were found occupying the active site and established a minimum of two hydrogen bond interactions in molecular docking studies

Expanding 1,2,4-triketone toolbox for use as fluorinated building blocks in the synthesis of pyrazoles, pyridazinones and β-diketohydrazones

Fluorinated lithium β-diketonates bearing a methyl acetal group behave in the condensation reactions with hydrazines as trielectrophilic building blocks for the preparation of pyrazoles, pyridazinones and β-diketohydrazones. For the first time, solvent-induced regioisomeric and heterocyclic ring size-controlled formation was observed for 1,2,4-triketone analogues. Fluoroalkylated acetyl NH-pyrazoles or substituted 5-RF-pyrazoles were obtained from the acid-catalyzed cyclocondensation of lithium β-diketonates with (aryl)hydrazines in ethanol. In methanol solvent acetyl-containing 3-CF3-pyrazoles were isolated because of inverse nucleophilic attack of arylhydrazines. The use of aprotic acetonitrile in the condensation resulted in regioselective trifluorinated pyridazinones and fluorinated β-diketohydrazones formation via initial acetal fragment interaction with N,N-dinucleophile.

Cobalt Ferrite MNPs: An Efficient and Robust Catalyst for Synthesis of 1,3,5‐Trisubstituted Pyrazolines

AbstractNovel synthesis of 1,3,5‐trisubstituted‐2‐pyrazoline and its derivatives, showing broad spectrum of biological activities in wide range of scientific disciplines is designed via condensation of substituted chalcones and aryl hydrazine in presence of the magnetically separable cobalt ferrite nanoparticles (CoFe2O4 MNPs) to get aimed product with excellent yield in possibly shorter reaction time. Divers structural, morphological, and spectral analytical studies as X‐ray diffraction (XRD), scanning electron microscopy (SEM), and FTIR confirm the formation of CoFe2O4 nanoparticles. The synthesized compounds are characterized and confirmed by spectral analysis. The ambient reaction conditions, ease of purification of the products, and reusability of the catalyst up to five catalytic cycles with almost negligible decrement of catalytic activity making the current protocol benign and promising for its synthetic applications.