Nitrogen Heterocycles Research Articles

Synthesis and antibacterial activities of quinazolin-4(3h)-one, 2-methyl-4(3h)-quinazolinone and 2–phenyl-4(3h)-quinazolinone

Background: Quinazoline and quinazolinone scaffolds represent an important class of biologically active nitrogen heterocyclic compounds. Many marketed drugs are based on these moieties. A diverse range of molecules with quinazoline/quinazolinone moieties have been reported to exhibit broad spectrum of biological activities Objective: This study is aimed at the synthesis of these quinazolinone derivatives, quinazolin-4(3H)-One, 2-Methyl-4(3H)-quinazolinone and 2–Phenyl-4(3H)-quinazolin-4(3H)–one and evaluate them for their antibacterial activities. Method: The consolidation of 2-amino-methyl-4-methoxybenzoate with acetic anhydride produced the cyclic compound 2-methyl-4, 5-disubstituted-1, 3-benzo-oxazine-4-one which also produce a novel 2,3-disubstituted quinazolin-4 ones via the reaction with hydrazine hydrate. The quinazolinone derivatives quinazolin-4(3H)-One, 2-Methyl-4(3H)-quinazolinone and 2–Phenyl-4(3H)-quinazolin-4(3H)–one were evaluated pharmacologically for their in vivo analgesic activities by acetic acid induced writhing in mice. The compounds synthesized were assuredly validated by means of Infrared, Nuclear Magnetic Resonance (1H and 13C), Gas Chromatography Mass Spectrophotometer and Elemental analysis. The synthesized compounds were tested for their antibacterial activity.Compounds 1,2 and 3 showed significant antibacterial activities. Discussion: Compound 1 was identified by the absence of methyl group and the presence of methyl group for compound 2. The test analysed compounds exhibited significant antibacterial activities. The compounds synthesized exhibited promising antibacterial activities against the tested organisms. Conclusion: The compounds have high antibacterial activities. Compound 2 has a higher activity compared to Compound 1 and 3. Compound 2 has a higher antibacterial against Escherichia coli, Klebsiella pneumonia and Pseudomonas aeuriginosa

Nucleophilic Halogenation of HeterocyclicN‐Oxides: Recent Progress and a Practical Guide

AbstractThe review summarizes recent advances in the synthesis of C2‐halogenated nitrogen heterocycles via nucleophilic halogenation of corresponding N‐oxides as well as application of this methodology in the synthesis of pharmaceuticals. Both scientific and patent literature is reviewed mostly over the period of the last ten years. The review contains a practical guide (typical procedures and infographic based on extensive literature analysis), which can help practitioners in choosing optimal reagents/conditions for nucleophilic halogenation of N‐heterocycles of different types. The bibliography contains 199 references.magnified image

Straightforward Construction and Functionalizations of Nitrogen-Containing Heterocycles Through Migratory Insertion of Metal-Carbenes/Nitrenes.

Nitrogen-containing heterocycles are widely found in various biologically active substrates, pharmaceuticals, natural products and organic materials. Consequently, the continuous effort has been devoted towards the development of straightforward, economical, environmentally acceptable, efficient and ingenious methods for the synthesis of various N-containing heterocycles and their functionalizations. Arguably, one of the most prominent direct strategy is regioselective C-H bond functionalizations which provide the step and atom economical approaches in the presence of suitable coupling partners. In this context, site-selective migratory insertion of metal carbenes/nitrenes to the desired C-H bonds has proven as a useful tool to access various functionalized nitrogen heterocycles. In this personal account, we highlight some of our contemporary development toward constructing N-containing heterocycles and their direct functionalizations via transition metal catalysed C-H bond functionalizations based on migratory insertion of metal-carbenes and nitrenes.

Synthesis, DFT, and eco-friendly insecticidal activity of some N-heterocycles derived from 4-((2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-phenyloxazol-5(4H)-one

A new series of nitrogen heterocycles encompassing a quinoline scaffold such as imidazolone, benzimidazole, triazinone, triazole, and thiazole derivatives was synthesized utilizing the readily obtainable building block synthon, 4-((2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-phenyloxazol-5(4H)-one (3). It was interesting that the fused heterocycle, pyranoquinoline derivative 15 was successfully synthesized by different routes of reactions. The synthesized compounds were evaluated for their insecticidal activity and compounds 6, 17, and 20 were the most potent against both Mythimna separata and Nilaparvata lugens. The DFT study was performed for the most potent compounds.

In vitro antimicrobial evaluation and in silico studies of coumarin derivatives tagged with pyrano-pyridine and pyrano-pyrimidine moieties as DNA gyrase inhibitors.

Several coumarin-containing substitute nitrogen heterocycles have recently received considerable importance due to their diverse pharmacological properties. One-pot and rapid synthesis of coumarin derivatives was achieved via reactions of acetyl-coumarin with p-chloro-benzaldehyde and malononitrile to provide compound 2-containing cyano-amine using conventional heating. Compound 2 was condensed with different carbon electrophiles triethyl orthoformate, phenyl isocyanate, carbon disulfide, benzoyl chloride, and acetyl chloride that afforded the corresponding chromene derivatives 3-17. All the newly synthesized compounds were characterized by elemental and spectroscopic evidences. All of the synthesized compounds were tested for antimicrobial activity against S. Pneumoniae, S. Epidermidis, S. Aureus, and E. coli as Gram + ve Bacteria, K. Pneumoniae, S. Paratyphi as Gram -ve Bacteria, P. Italicum, A. Fumigatus representative for Fungi. The preliminary screening results showed that most of the compounds had moderate to high activity against all tested organisms. The most potent four compounds were subjected to further investigation against E. Coli DNA gyrase and topoisomerase IV inhibitory activity, and the results showed that all of these derivatives inhibit DNA gyrase and thus cell division. Also, in silico studies were done for the most active compounds which showed good results.

Pyridazine Nucleobase in Triplex-Forming PNA Improves Recognition of Cytosine Interruptions of Polypurine Tracts in RNA.

Sequence specific recognition of regulatory noncoding RNAs would open new possibilities for fundamental science and medicine. However, molecular recognition of such complex double-stranded RNA (dsRNA) structures remains a formidable problem. Recently, we discovered that peptide nucleic acids (PNAs) form an unusually stable and sequence-specific triple helix with dsRNA. Triplex-forming PNAs could become universal tools for recognition of noncoding dsRNAs but are limited by the requirement of polypurine tracts in target RNAs as only purines form stable Hoogsteen hydrogen bonded base triplets. Herein, we systematically surveyed simple nitrogen heterocycles PN as modified nucleobases for recognition of cytosine in PN*C-G triplets. We found that a 3-pyridazinyl nucleobase formed significantly more stable PN*C-G triplets than other heterocycles including the pyrimidin-2-one previously used by us and others for recognition of cytosine interruptions in polypurine tracts of PNA-dsRNA triplexes. Our results improve triple helical recognition of dsRNA and provide insights for future development of new nucleobases to expand the sequence scope of noncoding dsRNAs that can be targeted by triplex-forming PNAs.

Marriage of Peroxides and Nitrogen Heterocycles: Selective Three-Component Assembly, Peroxide-Preserving Rearrangement, and Stereoelectronic Source of Unusual Stability of Bridged Azaozonides.

Stable bridged azaozonides can be selectively assembled via a catalyst-free three-component condensation of 1,5-diketones, hydrogen peroxide, and an NH-group source such as aqueous ammonia or ammonium salts. This procedure is scalable and can produce gram quantities of bicyclic stereochemically rich heterocycles. The new azaozonides are thermally stable and can be stored at room temperature for several months without decomposition and for at least 1 year at -10 °C. The chemical stability of azaozonides was explored for their subsequent selective transformations including the first example of an aminoperoxide rearrangement that preserves the peroxide group. The amino group in aminoperoxides has remarkably low nucleophilicity and does not participate in the usual amine alkylation and acylation reactions. These observations and the 15 pKa units decrease in basicity in comparison with a typical dialkyl amine are attributed to the strong hyperconjugative nN→σ*C-O interaction with the two antiperiplanar C-O bonds. Due to the weakness of the complementary nO→σ*C-N donation from the peroxide oxygens (a consequence of "inverse α-effect"), this interaction depletes electron density from the NH moiety, protects it from oxidation, and makes it similar in properties to an amide.

Ruthenium-Catalyzed Intramolecular Double Hydrofunctionalization of Alkynes. Synthesis of Spirocyclic Hemiaminal Ethers and Their Lewis Acid-Mediated Cleavage/Nucleophilic Addition.

[RuCl2(p-cymene)]2/AgNO3-catalyzed intramolecular double hydrofunctionalization of internal alkynes having nitrogen and oxygen nucleophilic groups at appropriate positions provided a series of spirocyclic hemiaminal ether derivatives in good to excellent yields. The product spiro-hemiaminal ethers underwent Lewis acid-mediated chemoselective cleavage, and in situ-generated iminium/oxocarbenium ions could be trapped with nucleophiles to afford a range of nitrogen and oxygen heterocycles.

Novel method for determination of heterocyclic compounds and their impact in brewing technology

A new simultaneous method for determination of 16 heterocyclic compounds using SPE sample preparation and GC-MS determination was developed regarding increasing interest of the role of sensory active compounds in beer. LiChrolut® EN SPE columns proved to be optimal for both, a mixture of analytes with a different polarity and such complicated matrix as beer. Recoveries of individual analytes are about 100% except for three compounds (2-methylpyridine about 30%, maltol and furaneol about 50%); repeatability, uncertainty and LOQ are satisfactory for the method application. The method was used for monitoring of heterocyclic compounds formation during roasting, mashing, hop boiling and fermentation. To summarize, during roasting of malt, the concentration of oxygen heterocycle compounds (OHC) increases more rapidly in comparison with nitrogen heterocycles compounds (NHC) till a critical point where OHC starts to decrease and NHC starts to be formed sharper (with the exception of 2-acetylpyrrole which is similar to OHC). Finally, the total concentration of NHC during fermentation rapidly decreases whilst the OHC concentration is influenced by many factors, e.g., fermentation conditions and yeast strain.

Synthesis of Fluorinated Nitrogen Heterocycles as New Drug Scaffolds

Synthesis of Fluorinated Nitrogen Heterocycles as New Drug Scaffolds

Silver Benzoate Facilitates the Copper-Catalyzed C-N Coupling of Iodoazoles with Aromatic Nitrogen Heterocycles.

In the literature, C–N coupling methods for the reaction of iodo-oxazole with 2-pyridinone were found to be low yielding. C–N coupling using silver benzoate additives with CuI catalysts and 4,7-dimethoxy-1,10-phenanthroline ligands has been developed to afford synthetically useful yields of the desired heterobicycle product. The reaction conditions are applied to the coupling of a range of iodo-heterocycles with 2-pyridinone. The coupling of a variety of NH-containing heterocycles with 4-iodo-oxazole is also demonstrated. The use of 2-, 4-, or 5-iodo-oxazole allows for the coupling of pyridinone to each oxazole position.

Arene Amination Instead of Fluorination: Substitution Pattern Governs the Reactivity of Dialkoxybenzenes with Selectfluor.

Arene substitution patterns are well-known to affect the regioselectivity of a given transformation but not necessarily the type of reactivity. Herein, we report that the substitution pattern of alkoxyarenes dictates whether a putative one-electron or two-electron reaction predominates in reactions with Selectfluor. A series of amination products is presented, resulting from the single-electron oxidation of electron-rich arenes followed by direct C-H to C-N bond formation. We demonstrate the ability of this transformation to synthesize medicinally and biologically relevant nitrogen heterocycles. Lastly, this unusual "mechanistic switch" is probed with computational chemistry and competition experiments.

Route Design to Manufacture: Synthesis of the Heterocyclic Fragment of AZD5718 Using a Non-cryogenic Lithiation-Alkoxycarbonylation Reaction

Route design and process development of the small nitrogen heterocycle 2·HCl, a constituent of AZD5718 (1), is described. The novel synthetic sequence to 2.HCl involves a desymmetrizing alkylation ...

A biocompatible Y-based metal-organic framework based on nitrogen heterocycle as a pH-responsive oral drug carrier

A Y-based metal-organic framework ZJU-16 with outstanding biocompatibility was synthesized by solvothermal method from organic nitrogen heterocycle ligand H3TATB and Y(NO3)3•6H2O. ZJU-16 was selected as an oral drug carrier and encapsulated an anionic anti-inflammatory drug Ibuprofen sodium (IBUNa) resulting in IBUNa@ZJU-16. The maximum capacity of IBUNa was about 53.46 wt% at the mass ratio of 2:1. The drug release behavior was investigated and the result exhibited excellent pH-responsive release. Drug molecules neligible released in the simulated environment of the stomach (pH 2.0). Meanwhile, the IBUNa were released in the simulated intestinal environment (pH 7.4) significantly, indicating its possible application as an oral drug carrier.

QSAR and Pharmacophore Modeling of Nitrogen Heterocycles as Potent Human N-Myristoyltransferase (Hs-NMT) Inhibitors.

N-myristoyltransferase (NMT) is an important eukaryotic monomeric enzyme which has emerged as an attractive target for developing a drug for cancer, leishmaniasis, ischemia-reperfusion injury, malaria, inflammation, etc. In the present work, statistically robust machine leaning models (QSAR (Quantitative Structure–Activity Relationship) approach) for Human NMT (Hs-NMT) inhibitory has been performed for a dataset of 309 Nitrogen heterocycles screened for NMT inhibitory activity. Hundreds of QSAR models were derived. Of these, the model 1 and 2 were chosen as they not only fulfil the recommended values for a good number of validation parameters (e.g., R2 = 0.77–0.79, Q2LMO = 0.75–0.76, CCCex = 0.86–0.87, Q2-F3 = 0.74–0.76, etc.) but also provide useful insights into the structural features that sway the Hs-NMT inhibitory activity of Nitrogen heterocycles. That is, they have an acceptable equipoise of descriptive and predictive qualities as per Organisation for Economic Co-operation and Development (OECD) guidelines. The developed QSAR models identified a good number of molecular descriptors like solvent accessible surface area of all atoms having specific partial charge, absolute surface area of Carbon atoms, etc. as important features to be considered in future optimizations. In addition, pharmacophore modeling has been performed to get additional insight into the pharmacophoric features, which provided additional results.

Gas‐phase OH oxidation kinetics of pyrazine, pyrimidine, and pyridazine

AbstractThe gas‐phase kinetics of the OH‐oxidation of three six‐membered nitrogen heterocycles C4N2H4 isomers, namely pyrazine, pyrimidine, and pyridazine, were determined in a photochemical reactor coupled to a FTIR spectrometer and a SPME‐GC/MS, at atmospheric pressure over the temperature range 298–353 K. Experiments were conducted using the relative rate method where two different references were employed for each studied compound. The obtained Arrhenius expressions are (in cm3 molecule–1 s–1) urn:x-wiley:05388066:media:kin21486:kin21486-math-0001These results were compared with available literature data for other heterocyclic compounds and discussed in terms of structure–reactivity and temperature dependency. Their tropospheric lifetimes with respect to reaction with OH radicals were then calculated and found to be of the order of 29, 34, and 37 days for pyrazine, pyrimidine, and pyridazine, respectively.

Highly Efficient Synthesis and Acaricidal and Insecticidal Activities of Novel Oxazolines with N-Heterocyclic Substituents.

Nitrogen heterocycles are found in numerous natural products, pharmaceuticals, and pesticides. Herein, we report the design and synthesis of a series of novel 2,4-diphenyl-1,3-oxazolines bearing various N-heterocyclic substituents via a 4-(4-(chloromethyl)phenyl)-2-(2,6-difluorophenyl)-4,5-dihydrooxazole intermediate generated by a modified Ritter reaction. Evaluation of the activities of the oxazolines against carmine spider mites (Tetranychus cinnabarinus) by means of a leaf-dipping method showed that most of the compounds exhibited good to excellent larvicidal and ovicidal activities. In particular, five compounds (one with a phthalimidyl group and four with a substituted indolyl group) have lower LC50 values than the commercial acaricide etoxazole (0.088 mg/L against larvae and 0.128 mg/L against eggs). This work lays a foundation for the development of novel acaricides.

Rhodium-Catalyzed C-H Alkenylation/Electrocyclization Cascade Provides Dihydropyridines That Serve as Versatile Intermediates to Diverse Nitrogen Heterocycles.

Nitrogen heterocycles are present in approximately 60% of drugs, with nonplanar heterocycles incorporating stereogenic centers being of considerable interest to the fields of medicinal chemistry, chemical biology, and synthetic methods development. Over the past several years, our laboratory has developed synthetic strategies to access highly functionalized nitrogen heterocycles with multiple stereogenic centers. This approach centers on the efficient preparation of diverse 1,2-dihydropyridines by a Rh-catalyzed C-H bond alkenylation/electrocyclization cascade from readily available α,β-unsaturated imines and alkynes. The often densely substituted 1,2-dihydropyridine products have proven to be extremely versatile intermediates that can be elaborated with high regioselectivity and stereoselectivity, often without purification or even isolation. Protonation or alkylation followed by addition of hydride or carbon nucleophiles affords tetrahydropyridines with divergent regioselectivity and stereoselectivity depending on the reaction conditions. Mechanistic experiments in combination with density functional theory (DFT) calculations provide a rationale for the high level of regiocontrol and stereocontrol that is observed. Further elaboration of the tetrahydropyridines by diastereoselective epoxidation and regioselective ring opening furnishes hydroxy-substituted piperidines. Alternatively, piperidines can be obtained directly from dihydropyridines by catalytic hydrogenation in good yields with high face selectivity.When trimethylsilyl alkynes or N-trimethylsilylmethyl imines are employed as starting inputs, the Rh-catalyzed C-H bond alkenylation/electrocyclization cascade provides silyl-substituted dihydropyridines that enable a host of new and useful transformations to different heterocycle classes. Protonation of these products under acidic conditions triggers the loss of the silyl group and the formation of unstabilized azomethine ylides that would be difficult to access by other means. Depending on the location of the silyl group, [3 + 2] cycloaddition of the azomethine ylides with dipolarophiles provides tropane or indolizidine privileged frameworks, which for intramolecular cycloadditions yield complex polycyclic products with up to five contiguous stereogenic centers. When different types of conditions are employed, loss of the silyl group can result in either rearrangement to cyclopropyl-fused pyrrolidines or to aminocyclopentadienes. Mechanistic experiments supported by DFT calculations provide reaction pathways for these unusual rearrangements.The transformations described in this Account are amenable to natural product synthesis and drug discovery applications because of the biological relevance of the structural motifs that are prepared, short reaction sequences that rely on readily available starting inputs, high regiocontrol and stereocontrol, and excellent functional group compatibility. For example, the methods have been applied to efficient asymmetric syntheses of morphinan drugs, including the opioid antagonist (-)-naltrexone, which is extensively used for the treatment of drug abuse.

Tunable Covalent Organic Frameworks with Different Heterocyclic Nitrogen Locations for Efficient Cr(VI) Reduction, Escherichia coli Disinfection, and Paracetamol Degradation under Visible-Light Irradiation.

Covalent organic frameworks (COFs) have great application potentials in photocatalytic water treatment. By using p-phenylenediamine with different numbers and locations of heterocyclic nitrogen atoms as a precursor, five types of COFs with different nitrogen positions were synthesized. We found that Cr(VI) photoreduction,Escherichia coli inactivation, and paracetamol degradation by COFs were heterocyclic nitrogen location-dependent. Particularly, the photocatalytic performance for all three tested pollutants by five types of COFs followed the order of the best performance for COF-PDZ with two ortho position heterocyclic N atoms, medium for COF-PMD with two meta position heterocyclic N atoms, and COF-PZ with two para position heterocyclic N atoms, and COF-PD with a single heterocyclic N atom, the worst performance for COF-1 without a heterocyclic N atom. Compared to the other COFs, COF-PDZ contained improved quantum efficiency and thus enhanced generation of electrons. The lower energy barriers and larger energy gaps of COF-PDZ contributed to its improved quantum efficiencies. The stronger affinity to Cr(VI) with lower adsorption energy of COF-PDZ also contributed to its excellent Cr(VI) reduction performance. By transferring into a more stable keto form, COF-PDZ showed great stability through five regeneration and reuse cycles. Overall, this study provided an insight into the synthesis of high-performance structure-dependent COF-based photocatalysts.

Anticancer Activity and Mode of Action of Copper(II)‐Bis(thiosemicarbazonato) Complexes with Pendant Nitrogen Heterocycles

AbstractExploring the potential of bis(thiosemicarbazones) (BTSC), a new family of BTSC ligands derived from GTSM (glyoxal‐bis(N4‐methylthiosemicarbazonato) and respective CuIIBTSC complexes were synthesized. These complexes, having pendant nitrogen heterocycles, exhibited increased water‐solubility, lower lipophilicity at physiological pH and more negative Cu(II)/Cu(I) redox potential, when compared with the parental complex. The cytotoxic evaluation performed in a panel of cancer cells lines showed an important effect of the metal complexation, and furthermore correlated well with the cellular uptake of the compounds, which was determined using their 64Cu congeners. The radiolabelling of the complexes also allowed more detailed uptake studies, with the results suggesting an active transport or facilitated diffusion mechanism for the cellular uptake of 64CuGTSMpip and 64CuGTSMmor, with pendant piperidine and morpholine rings, respectively. Additionally, a comparative study with the corresponding Cu(II) complexes derived from ATSM (diacetyl‐bis(N4‐methylthiosemicarbazonato) that we have previously described, demonstrated a clear difference in their lysosomotropic properties in particular for the piperidine derivatives. From this study, CuGTSMpip emerged as the most promising compound to be further evaluated as an anticancer metallodrug.