Nitrogen Heterocycles Research Articles

Highly Chemoselective Synthesis of α, α-Dideuterio Amines by the Reductive Deuteration of Thioamides Using Mild SmI2-D2O.

An efficient and chemoselective protocol for the single-electron-transfer (SET) reductive deuteration of thioamides using SmI2 and D2O is reported. This method uniquely produces α,α-dideuterio amines via a thio-ketyl radical intermediate without generating alcohol byproducts, distinguishing it from the SET reduction of amides. The inherent high reactivity of thioamides obviates the need for ligands like Et3N to improve the reducing power of SmI2, thereby enabling milder reaction conditions that are compatible with a broad range of sensitive functional groups. This protocol tolerates both primary and secondary aliphatic and aromatic thioamides, leading to the synthesis of 27 α,α-dideuterio amines and valuable deuterated nitrogen heterocycles with >95% deuterium incorporations.

A Review on Recent Synthesis and Diverse Biological Activities of Isoquinolone

Abstract: Isoquinolone scaffolds are among the most important core structures of nitrogen heterocyclic compounds, which possess vital roles in biological and physiological activities such as anti-tumor, anti-microbial, anti-leukemic, anti-malaria, anti-dengue, anti-HIV and anti-bacterial. Over the years, multiple studies have been done to synthesize these isoquinolone derivatives, and several authors have reported on various methods and synthetic routes to produce the target skeletons of isoquinolones. Therefore, many scientific communities have developed these compounds as the intended structure and evaluated their biological activities. Thus, this review confers several information on isoquinolone analogue synthetic strategies and their biological effects on mosquito- borne diseases.

Emergence of a distinct mechanism of C-N bond formation in photoenzymes.

C-N bond formation is integral to modern chemical synthesis due to the ubiquity of nitrogen heterocycles in small-molecule pharmaceuticals and agrochemicals. Alkene hydroamination with unactivated alkenes is an atom economical strategy for constructing these bonds. However, these reactions are challenging to render asymmetric when preparing fully substituted carbon stereocenters. Here, we report a photoenzymatic alkene hydroamination to prepare 2,2-disubstituted pyrrolidines by a Baeyer-Villiger Monooxygenase. Five rounds of protein engineering afforded a mutant, providing excellent product yield and stereoselectivity. Unlike related photochemical hydroaminations, which rely on the oxidation of the amine or alkene for C-N bond formation, this work exploits a through-space interaction of a reductively generated benzylic radical and the nitrogen lone pair. This antibonding interaction lowers the oxidation potential of the radical, enabling electron transfer to the flavin cofactor. Experiments indicate that the enzyme microenvironment is essential in enabling a novel C-N bond formation mechanism with no parallel in small molecule catalysis. Molecular dynamics simulations were performed to investigate the substrate in the enzyme active site which further support this hypothesis. This work is a rare example of an emerging mechanism in non-natural biocatalysis, where an enzyme has access to a mechanism that its individual components do not. Our study showcases the potential of enhancing emergent mechanisms using protein engineering to provide unique mechanistic solutions to unanswered challenges in chemical synthesis.

Supramolecular cyclodextrin complexes of biologically active nitrogen heterocycles

The review is devoted to the rapidly developing field of modern supramolecular chemistry - cyclodextrin complexes of biologically active nitrogen heterocycles, such as piperidines, piperazines, morpholines and pyridines. Interest in cyclodextrin complexes is growing due to the search and construction of supramolecular assemblies for targeted drug delivery. The latter is achieved as a result of supramolecular self-assembly, based on the principles of molecular recognition, and is one of the areas of modern chemistry, leading to the creation of new materials with new properties. This review fully demonstrates the ongoing scientific and practical interest in the problem of encapsulation with cyclodextrins, including nanoencapsulation. Encapsulation with cyclodextrins provides a wide range of advantages: obtaining solid dosage forms from liquid ones, stabilizing and protecting active substances from the adverse effects of external factors, increasing solubility, increasing bioavailability, reducing toxicity, prolonging action, etc. The presented review includes recent advances in the field of supramolecular complexes of biologically active nitrogen heterocycles with cyclodextrins and concludes with a discussion and identification of future promising directions for research. The review presents the results of supramolecular self-assembly of biologically active azaheterocycles with cyclodextrins.

Three-Component Synthesis of 1-Substituted 5-Aminotetrazoles Promoted by Bismuth Nitrate.

A nontoxic bismuth-promoted multicomponent synthesis of 5-aminotetrazoles and bistetrazoles is reported. The reaction of phenyl isothiocyanate, NaN3, and amine (primary aliphatic, aromatic, and aliphatic diamine) promoted by Bi(NO3)3·5H2O under microwave heating affords good yields, short reaction times, simple workup, and purification without column chromatography. A set of diagnostic 1H NMR signals was identified as a guide for quickly elucidating the exclusive (or main) regioisomer formed, with the stronger electron donor group located at heterocyclic nitrogen 1. This regioselectivity is strongly dependent on the electronic density of the amine. It is opposite to that obtained by several thiourea desulfurization methods promoted by thiophilic metals and metal-free protocols.

Bibliometric Analysis of Pyrimidine Compounds with Anti-cancer Activity: Research Trends from 2015 to 2023

Cancer remains one of the most pervasive diseases in the world, globally, leading to millions of fatalities annually. Currently, numerous anti-cancer treatments are available to address the various types of cancer. Pyrimidine, a class of heterocyclic nitrogenous compounds, holds substantial promise in anti-cancer drug development due to its structural similarity to the nucleotide base pairs found in DNA and RNA. This work aimed to conduct a bibliometric analysis of studies on pyrimidine compounds with anti-cancer characteristics. Using the Scopus database, we examined literature published between 2015 and 2023, explicitly concentrating on pyrimidine derivatives as potential anti-cancer agents. Data analysis such as network analysis, co-occurrence, and visualization were conducted utilizing VOSviewer 1.6.13. Nine hundred twenty-two papers altogether, including reviews and original research, discussing the anti-cancer activity of pyrimidine compounds were identified within the specified timeframe up to January 10, 2023. Among these, 922 journal articles were selected for further analysis. Results show that Egypt led in research productivity with 267 articles (28.96%), followed by India with 234 articles (25.38%), and China with 163 articles (17.68%). Cairo University in Egypt ranked first in institutional productivity with 9 articles (0.98%), while the journal Bioorganic Chemistry was the most prolific, publishing 62 articles (6.72%) on pyrimidine compounds with anti-cancer activity. The notable increase in publications on the anti-cancer activity of pyrimidine compounds in recent years underscores the significant interest they have garnered from both pharmaceutical and academic researchers. The data presented in this study will serve as a foundational reference for future comparative studies in this area.

Effects of imidazole derivatives on cellular proliferation and apoptosis in myeloid leukemia.

Acute promyelocytic leukemia (APL) is the sub-type of Acute myeloid leukemia (AML) which is described by differentiation block at promyelocytic stage and t(15; 17) translocation with All trans retinoic acid (ATRA) and arsenic trioxide (ATO) as standard treatments. Chronic myeloid leukemia (CML) translocation t (19; 22) causes a rise in granulocytes and their immature precursors in the blood. Different mutations cause resistance to first-line tyrosine kinase therapies in CML. Beside drug resistance, leukemia stem cells (LSC) are critical resources for relapse and resistance in APL and CML. The drug toxicity and resistant profile associated with LSC and current therapeutics of APL and CML necessitate the development of new therapies. Imidazoles are heterocyclic nitrogen compounds with diverse cellular actions. The purpose of this research was to assess the anti-leukemic properties of four novel imidazole derivatives including L-4, L-7, R-35, and R-NIM04. Pharmacological and biochemical approaches were used which showed that all four imidazole derivatives interfere with the NB4 cells proliferation, an APL cell line, while only L-7 exhibit anti-proliferative activity against K562 cells, a CML cell line. The anti-proliferative effect of imidazole derivatives was linked to apoptosis induction. Further real-time polymerase chain reaction (RT-PCR) analysis revealed downregulation of AXL-Receptor Tyrosine Kinase (AXL-RTK) and target genes of Wnt/beta-catenin pathway like c-Myc, Axin2 and EYA3. An additive effect was observed after combinatorial treatment of L-7 with standard drugs ATRA or Imatinib on the proliferation of NB4 and K562 cells respectively which was related to further downregulation of target genes of Wnt/beta catenin pathway. Imidazole derivatives significantly reduce proliferation of NB4 and K562 cells by inducing apoptosis, down regulating of AXL-RTK and Wnt/β-catenin target genes.

Delivery of N-heterocyclic drugs, acids, phenols, and thiols via Tailor−made Self−immolative linkers

Heterocyclic drugs display diverse pharmacological activities and metabolic stability. However, their poor solubility and pharmacokinetic properties often compromise bioavailability and clinical outcomes. Nevertheless, the prodrug approach provides a viable strategy to overcome unwanted attributes of drug candidates. In this proof-of-concept study, we report the synthesis and biological evaluation of glycol methylene-bridged phosphate (GMBP) prodrugs developed for heterocyclic drug delivery. Through methylene bridging, the heterocyclic nitrogen was directly attached to the phosphate, whereas the glycol moiety enabled drug release via cyclization, as confirmed by 31P NMR spectroscopy. Additional prodrugs of carboxylic acids, phenols, and thiols confirmed the broad application scope of our GMPB approach. Heterocyclic GMBP prodrugs were stable in aqueous buffers and activated by phospholipase CAL-B in vitro. Select prodrugs, including zidovudine prodrug 33, were even more potent (3 nM on HIV-1) than the parent compound. These findings demonstrate that our GMBP approach is not only feasible but also highly versatile.

A Fragment-Based Screen for Inhibitors of Escherichia coli N5-CAIR Mutase.

Although purine biosynthesis is a primary metabolic pathway, there are fundamental differences between how purines are synthesized in microbes versus humans. In humans, the purine intermediate, 4- carboxy-5-aminoimidazole ribonucleotide (CAIR) is directly synthesized from 5-aminoimidazole ribonucleotide (AIR) and carbon dioxide by the enzyme AIR carboxylase. In bacteria, yeast and fungi, CAIR is synthesized from AIR via an intermediate N5-carboxyaminoimidazole ribonucleotide (N5-CAIR) by the enzyme N5-CAIR mutase. The difference in pathways between humans and microbes indicate that N5-CAIR mutase is a potential antimicrobial drug target. To identify inhibitors of E. coli N5-CAIR mutase, a fragment-based screening campaign was conducted using a thermal shift assay and a library of 4,500 fragments. Twenty-eight fragments were initially identified that displayed dose-dependent binding to N5-CAIR mutase with Kd values ranging from 9-309 μM. Of the 28, 14 were obtained from commercial sources for retesting; however, only 5 showed dose-dependent binding to N5-CAIR mutase. The five fragments were assessed for their ability to inhibit enzyme activity. Four out of the 5 showed inhibition with Ki values of 4.8 to 159 μM. All fragments contained nitrogen heterocycles with 3 out of the 4 containing 5-membered heterocycles like those found in the substrate of the enzyme. The identified fragments show similarities to compounds identified from studies on B. anthracis N5-CAIR synthetase and human AIR carboxylase suggesting a common pharmacophore.

Formal [2σ + 2σ]-Cycloaddition of Aziridines with Bicyclo[1.1.0]butanes: Access to Enantiopure 2-Azabicyclo[3.1.1]heptane Derivatives.

Saturated nitrogen heterocycles are among the most significant structural components in small-molecule pharmaceuticals. Herein, a protocol for the construction of enantiopure 2-azabicyclo[3.1.1]heptane derivatives by a stereospecific intermolecular formal cycloaddition of aziridines with bicyclo[1.1.0]butanes is described. The reaction is run by using B(C6F5)3 as a catalytic additive to give access to a library of enantiopure 2-azabicyclo[3.1.1]heptane derivatives (37 examples) under mild and operationally simple conditions. Successful scale-up reactions, mechanistic experiments, density functional theory (DFT) calculations and synthetic applications are presented.

Effect of reactive oxygen species (ROS) produced by pyridine and quinoline on NH4+-N removal under phenol stress: The shift of nitrification pathway and its potential mechanisms

Pyridine and quinoline are typical nitrogenous heterocyclic compounds with different structures that are found in coking wastewater. However, neither the corresponding mechanism nor its effect on the degradation of NH4+-N under phenol stress is known. In this study, the effects of pyridine and quinoline degradation on NH4+-N removal under phenol stress were evaluated using three lab-scale sequencing batch reactors. The average NH4+-N removal efficiencies of the reactors were 99.46 %, 88.86 %, and 98.64 %. With the increased concentration of pyridine and quinoline, NH4+-N and NO3--N accumulated to 58.37 mg/L and 141.37 mg/L, respectively, due to the lack of an electron donor and anaerobic environment. The addition of pyridine and quinoline significantly improved antioxidant response and altered the nitrification pathway. The nitrification process shifted from the mediation of amo and hao to the mediation of Ncd2 due to oxidative stress induced by pyridine and quinoline. Furthermore, oxidative stress interferes with the metabolism of carbon sources, resulting in decreased biomass. These results provide a new perspective for coking wastewater treatment processes.

Tandem diazotization/cyclization approach for the synthesis of a fused 1,2,3-triazinone-furazan/furoxan heterocyclic system.

A straightforward protocol for the synthesis of a previously unknown [1,2,5]oxadiazolo[3,4-d][1,2,3]triazin-7(6H)-one heterocyclic system was developed. The described approach is based on tandem diazotization/azo coupling reactions of (1,2,5-oxadiazolyl)carboxamide derivatives bearing both aromatic and aliphatic substituents. The NO-donor ability of the synthesized furoxano[3,4-d][1,2,3]triazin-7(6H)-ones was additionally evaluated. The elaborated method provides access to novel nitrogen heterocyclic compounds with potential applications as drug candidates or thermostable components of functional organic materials.

Photochemical Decarboxylative Radical Alkylation/Cyclization Reaction to Fused Nitrogen Heterocycles by LiI/PPh3 Catalysis

Comprehensive SummaryA visible‐light‐induced decarboxylative radical cascade cyclization reaction between N‐(2‐cyanoaryl)‐acrylamides and alkyl N‐(acyloxy)phthalimide (NHPI esters) for the construction of phenanthridine derivatives has been developed. This approach utilizes lithium iodide (LiI) and triphenylphosphine (PPh3) as the redox catalysts and the alkyl radical is produced through the photoactivation of the electron donor‐acceptor (EDA) complex. A series of primary, secondary, and tertiary alkyl‐substituted phenanthridines are prepared in up to 82% yield without transition‐metal catalysts, chemical oxidants, or metal‐/organic dye‐based photocatalysts.

Metal‐Supported Heterogeneous Catalysts for the Synthesis of Nitrogen‐Containing Heterocycles: A Comprehensive Review

AbstractThe use of metals in the preparation of heterocycles has become increasingly popular due to several key advantages of metals as catalysts. These include recycling capability, eco‐friendliness, simplicity of catalyst preparation and separation, longer lifespan, abundance, and higher yields. As a result of their novel applications in organic, inorganic, medicinal, industrial, polymer chemistry, material sciences, nanotechnology, and biological processes, the utilization of nitrogen‐containing heterocycles has rapidly increased in recent years. Various nitrogen‐containing organic moieties are used in therapeutic processes to enhance effectiveness against several bacterial and viral diseases. This review covers the preparation of imidazoles, triazoles, tetrazoles, pyridine derivatives, azo compounds, pyrimidines, quinoxalines, and quinolines using metals as heterogeneous catalysts. It provides an overview of current methodologies for metal‐assisted heterogeneous catalytic reactions, including product yield, operating temperature, and solvents, among other factors. Heterogeneous catalyst‐mediated organic synthetic reactions offer several advantages, particularly in medicinal chemistry, pharmaceuticals, and industrial applications, by reducing time and energy consumption. This review emphasizes recent advancements in the fabrication of nitrogen heterocycles utilizing heterogeneous catalysts, taking into account various economic, eco‐friendly, and user‐friendly considerations. Additionally, it discusses the benefits, reaction conditions, and yields reported in the literature over the past six years.

Design, Docking, Synthesis, and In vitro Evaluation of Potent Anti-tubercular Agents Targeting DNA Gyrase

Background: Tuberculosis caused by Mycobacterium tuberculosis has been reported to infect about two-third of the global population and to continuously develop multidrug resistance. DNA gyrase, a type II topoisomerase, is a promising target of the quinolone class of drugs in the treatment of tuberculosis. Objective: The present study is focused on the design and synthesis of newer nitrogen heterocyclics containing indole, n-methyl piperazine, piperidine, and pyrrolidine ring structures. Methods: Initially designed compounds were evaluated for their affinity to the DNA gyrase target. The molecular docking performed using FlexX indicated compounds IIb5 (1-(R)-(4-hydroxyphenyl)(4- methylpiperazin-1-yl)methyl)-3-((S)-(4-hydroxyphenyl)(4-methylpiperazin-1-yl)methyl)urea and IIc5 ((1-(R)-(4-hydroxyphenyl)(4-methylpiperazin-1-yl)methyl)-3-((S)-(4-hydroxyphenyl)(4-methylpiperazin- 1-yl)methyl) thiourea to exhibit promising binding affinity (dock score of -15.01 and -13.77) respectively when compared to the reference MFX moxifloxacin (dock score -4.40) with the target 5BS8 (DNA gyrase). Further, the best 10 compounds were synthesized by one-pot synthesis employing the reaction of indole/N-methyl piperazine/piperidine/pyrrolidine with N-substituted benzaldehydes in the presence of acetamide/urea/thiourea to afford the compounds in 54.60% to 85.47% yield. The synthesized compounds were suitably characterized using chromatographic and spectroscopic tools. Results: In the microplate Alamar Blue assay (MABA), compounds IIb1, IIIc2, IIIb1, and IIb5 exhibited good minimum inhibitory concentrations of 1.6 μg/mL, 3.12 μg/mL, and 12.5 μg/mL, respectively, when compared to the standard rifampicin with 0.8 μg/mL inhibitory concentration. The MTB gyrase supercoiling assay performed using Mycobacterium tuberculosis gyrase supercoiling assay kit demonstrated compound IIb5 at a concentration of 300 μg/mL to show gyrase inhibition in comparison to MFX at 60 μg/mL. In the MTT assay performed using the human breast cancer cell line MCF-7, compounds IIc2, IIb5, and IIb1 showed IC50 values of 2.57 μM, 12.54 μM, and 12.75 μM, respectively, compared to doxorubicin (1.10 μM) at 7-48 hrs and 72 hrs of the study. Conclusion: Based on these observations, N-methyl piperazine class of compounds can serve as a lead/pharmacophore for the rational design of potent molecules against MTB gyrase to combat the growing issue of MDR-TB.

Synthesis, Structure, and Properties of a Copper(II) Binuclear Complex Based on Trifluoromethyl Containing Bis(pyrazolyl)hydrazone.

A new complex of copper(II) with methyl-5-(trifluoromethyl)pyrazol-3-yl-ketazine (H2L) was synthesized with the composition [Cu2L2]∙C2H5OH (1). Recrystallization of the sample from DMSO yielded a single crystal of the composition [Cu2L2((CH3)2SO)] (2). The coordination compounds were studied by single-crystal X-ray diffraction analysis, IR spectroscopy, and static magnetic susceptibility method. The data obtained indicate that the polydentate ligand is coordinated by both acyclic nitrogen and heterocyclic nitrogen atoms. The cytotoxic activity of the ligand and complex 1 was investigated on human cell lines MCF7 (breast adenocarcinoma), Hep2 (laryngeal carcinoma), A549 (lung carcinoma), HepG2 (hepatocellular carcinoma), and MRC5 (non-tumor lung fibroblasts). The complex was shown to have a pronounced dose-dependent cytotoxicity towards these cell lines with LC50 values in the range of 0.18-4.03 μM.

Copper-Catalyzed, Intramolecular Amination of Unactivated C(sp3)-H Bonds through Radical Relay.

Although copper-catalyzed amination of activated C(sp3)-H bonds through radical relay has been developed, amination of unactivated C(sp3)-H bonds is rare. Herein, copper-catalyzed intramolecular amination of remote unactivated C(sp3)-H bonds is reported. The reaction is conducted in a mild and effective manner with moderate to good yields, demonstrating broad tolerance toward various functional groups and exhibiting complete regio- and chemoselectivities. This innovation supplies novel synthetic pathways for the construction of saturated nitrogenated heterocycles.

Optimizing sodium storage mechanisms and electrochemical performance of high Nitrogen-Doped hard carbon anode materials Derived from waste plastics for Sodium-Ion batteries

The development of high-performance hard-carbon (HC) anode materials for sodium-ion batteries was constrained by slow charge-transfer kinetics and sodium-storage mechanisms. In this paper, high nitrogen-doped (12.24 %) HC with an efficient interworking structure was synthesized in situ using waste plastics as precursors by utilizing the strong 2-D self-template effect of guanine. Elucidating the mechanism of sodium storage in heteroatom-doped carbon with coexisting heterocyclic and graphitic nitrogen, which synergistically enhances electrochemical activity, utilizing a range of in-situ and ex-situ characterization methods. Based on density functional theory (DFT), it has been discovered that the doping of pyrrole nitrogen (N5) and pyridinium nitrogen (N6) can effectively expand the interlayer spacing during the Na+ sodiated/de-sodiated process, thereby enhancing electrochemical activity. The optimized HC has increased the Na+ diffusion coefficient by 1.5 orders of magnitude (10-8.2 cm2 s−1 vs 10-9.76 cm2 s−1) and exhibits high reversible capacity (452 mAh/g@20 mA g−1), high rate performance (388mAh/g@500 mA g−1), superior cycling stability (87.6 % @500 mA g−1 after 2,000 cycles). The full cell exhibits good cyclic stability (91.87 %@100 mA g−1 after 2,00 cycles), while the designed pouch cell also demonstrates favorable cycle life (90.78 %@200 mA g−1 after 100 cycles).

Direct C4 and C2 C-H Amination of Heteroarenes Using I(III) Reagents via a Cross Azine Coupling.

Aminated nitrogen heterocycles are valuable motifs across numerous chemical industries, perhaps most notably in small molecule drug discovery. While numerous strategies for installing nitrogen atoms onto azaarenes exist, most require prefunctionalization and methods for direct C-H amination are almost entirely limited to position C2. Herein, we report a method for the direct C2 and C4 C-H amination of fused azaarenes via in situ activation with a bispyridine-ligated I(III) reagent, [(Py)2IPh]2OTf, or Py-HVI. Unlike commonly used N-oxide chemistry, the method requires no preoxidation of the azaarene and provides unprecedented direct access to C4 amination products. The resulting N-heterocyclic pyridinium salts can be isolated via simple trituration. The free amine can be liberated under mild Zincke aminolysis, or the amination and cleavage can be telescoped to a one-pot process. The scope of the method is broad; the conditions are mild and operationally simple, and the aminated products are produced in good to excellent yields. Computational studies provide insights into the mechanism of activation, which involves an unusual direct nucleophilic functionalization of an I(III) ligand, as well as a kinetic basis for the observed C2 and C4 amination products.

Synthesis of N-heterocycles through alcohol dehydrogenative coupling.

Nitrogen heterocycles are found in the structures of many biologically important compounds, as well as materials used in the synthesis of fine chemicals. Notably, ~59% of US Food and Drug Administration-approved small-molecule drugs contain nitrogen heterocycles. It is therefore meaningful to explore greener or more sustainable methods for their synthesis. The use of alcohols as reagents is attractive as they can be readily obtained from biomass derived natural resources. In the last two decades, alcohol dehydrogenative coupling reaction to synthesize various heterocycles were extensively explored which furnished hydrogen (H2) and water (H2O) as the two greener byproducts. In this protocol, we describe several efficient catalytic transformations to synthesize quinolines, 1,8-naphthyridines, quinoxalines, quinazolines, pyrimidines, benzimidazoles, pyrroles and pyridines, using alcohol as starting materials. We also describe the synthesis of several homogeneous iridium/ruthenium catalysts and heterogeneous cobalt/copper catalysts that can be used in these transformations. The reaction setup is simple; in a Schlenk/reaction tube with magnetic stir-bar, alcohol, corresponding coupling reagents (nucleophiles), catalyst, base and solvent (water or organic solvent such as toluene, dioxane or p-xylene) are added. The reaction mixture is refluxed at the specified temperature (110-150 °C)-either in air or under argon-to furnish these heterocycles. Synthesis of the catalysts takes 3-5 h and the coupling reactions take 4-5 h depending on the target product. The cobalt- and copper-based heterogeneous catalytic systems displayed an good catalyst recyclability.