Heterocyclic Research Articles

A Review on Synthesis of Azoles

Abstract: Heterocyclic compounds form a major class of compounds in chemistry. There has been considerable interest in the development of novel heterocyclic compounds with varied biological activities. Azoles are famous and widespread scaffold in the pharmaceutical industry due to their range of activities. Diazocarbonyl compounds have found numerous applications in many areas of chemistry. Among the most developed fields of diazo compounds. This approach represents a useful alternative to more conventional methods of the synthesis of azoles. The present review discussed the different characteristics of the azoles of interest, to recognize the differences in pharmacolog, safety, toxicity and potential drug interactions of these antifungal agents.

Unusual Cascade Reactions of 8-Acetoxy-6-hydroxymethyllimonene with Salicylic Aldehydes: Diverse Oxygen Heterocycles from Common Precursors.

Chiral oxygen-containing heterocyclic compounds are of great interest for the development of pharmaceuticals. Monoterpenes and their derivatives are naturally abundant precursors of novel synthetic chiral oxygen-containing heterocyclic compounds. In this study, acid catalyzed reactions of salicylic aldehydes with (-)-8-acetoxy-6-hydroxymethyllimonene, readily accessible from α-pinene, leads to the formation of chiral polycyclic products of various structural types. Three of the six isolated chiral heterocyclic products obtained from salicylic aldehyde contain previously unknown polycyclic ring types. Having carried out the reaction in the presence of Brønsted or Lewis acids (Amberlyst 15, trifluoromethanesulfonic acid, trifluoroacetic acid and boron trifluoride etherate) or aluminosilicates (montmorillonite K10, halloysite nanotubes), we found that the nature of products depends on the catalyst as well as the reaction conditions (reaction time, reactant ratio, presence or absence of solvent). Detailed mechanistic insight on the complex cascade reactions for product formation is provided with extensive experimental and quantum mechanical computational studies.

Design, synthesis and anti-oxidant activities of novel 1,2,3,4-tetrazine, 1,2,3-triazoles and coumarin derivatives and their nanoparticular encapsulation

Nitrogen-containing heterocyclic compounds are currently used for a number of pharmaceutical and agricultural applications because they have biological activities such as antimicrobial, antiviral, antituberculosis, anticancer, analgesic, antioxidant, anti-inflammatory and antidepressant. 1,2,3,4-Tetrazines and 1,2,3-triazoles are examples of high-nitrogen heterocyclic compounds. Coumarins, on the other hand, are lactones that form a group of oxygenated heterocyclic compounds found in plants. In this article, two analogs of 1,2,3,4-tetrazine, two analogs of 1,2,3-triazole and five analogs of coumarin were designed and synthesized. Their chemical structures were characterized by detecting their FTIR, 1H-NMR, and 13C-NMR (APT) spectra. The antioxidant activities of all synthesized molecules were compared at a fixed concentration (0.25 mg ml−1) using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) method. Molecules 9c and 9e, which showed the highest antioxidant activity, were loaded into PLGA (poly(lactic-co-glycolic) acid) nanoparticles using the oil in water (o/w) single emulsion solvent evaporation method as a model study. Synthesized nanoparticles characterized for particle size, zeta potential, functional groups, morphology, and release properties. Particle size and zeta potential of 9c/NP were determined as 216.1 ± 8.944 nm and −14.1 ± 2.40 mV, respectively. The particle size and zeta potential for 9e/NP were measured as 222.0 ± 12.490 nm and −12.4 ± 1.42 mV respectively. The study results obtained on model nanoparticle systems with elucidated physicochemical properties may have the potential to provide a promising basis for oxidative stress-related diseases in the future.

Progress on the Synthesis Pathways and Pharmacological Effects of Naturally Occurring Pyrazines.

As one of the most essential types of heterocyclic compounds, pyrazines have a characteristic smell and taste and have a wide range of commercial applications, especially in the food industry. With the development of the food industry, the demand for pyrazines has increased. Therefore, understanding the properties, functions, and synthetic pathways of pyrazines is one of the fundamental methods to produce, control, and apply pyrazines in food or medical systems. In this review, we provide an overview of the synthesis pathways and physiological or pharmacological functions of naturally occurring pyrazines. In particular, we focus on the biosynthesis and pharmacological effects of 2,3,5,6-Tetramethylpyrazine (TTMP), 2,5-Dimethylpyrazine (2,5-DMP), and 2,3,5-trimethylpyrazine (TMP). Furthermore, areas where further research on pyrazines is needed are discussed in this work.

Investigation of 2,4-Dihydroxylaryl-Substituted Heterocycles as Inhibitors of the Growth and Development of Biotrophic Fungal Pathogens Associated with the Most Common Cereal Diseases.

Climate change forces agriculture to face the rapidly growing virulence of biotrophic fungal pathogens, which in turn drives researchers to seek new ways of combatting or limiting the spread of diseases caused by the same. While the use of agrochemicals may be the most efficient strategy in this context, it is important to ensure that such chemicals are safe for the natural environment. Heterocyclic compounds have enormous biological potential. A series of heterocyclic scaffolds (1,3,4-thiadiazole, 1,3-thiazole, 1,2,4-triazole, benzothiazine, benzothiadiazine, and quinazoline) containing 2,4-dihydroxylaryl substituents were investigated for their ability to inhibit the growth and development of biotrophic fungal pathogens associated with several important cereal diseases. Of the 33 analysed compounds, 3 were identified as having high inhibitory potential against Blumeria and Puccinia fungi. The conducted research indicated that the analysed compounds can be used to reduce the incidence of fungal diseases in cereals; however, further thorough research is required to investigate their effects on plant-pathogen systems, including molecular studies to determine the exact mechanism of their activity.

Electrochemical synthesis of heterocyclic compounds via carbon–heteroatom bond formation: direct and indirect electrolysis

Abstract Electrochemical organic synthesis has attracted attention as an environmentally friendly method for constructing heterocyclic compounds via carbon–heteroatom bond formation. Herein, we describe the representative examples of electrochemical reactions to produce heterocycles and discuss them according to whether they involve direct or indirect electrolysis.

Quantum rate electrodynamics and resonant junction electronics of heterocyclic molecules

The quantum rate theory provides a framework to understand electron-transfer reactions by correlating the electron-transfer rate constant (ν) with the quantum capacitance (Cq) and the molecular conductance (G). This theory, which is rooted in relativistic quantum electrodynamics, predicts a fundamental frequency ν=E/h for electron-transfer reactions, where E is the energy associated with the density of states Cq/e2. This work demonstrates the applicability of the quantum rate theory to the intermolecular charge transfer of push-pull heterocyclic compounds assembled over conducting electrodes. Remarkably, the observed differences between molecular junction electronics formed by push-pull molecules and the electrodynamics of electrochemical reactions on redox-active modified electrodes can be attributed solely to the adiabatic setting of the quantum conductance in push-pull molecular junctions. The electrolyte field-effect screening environment plays a crucial role in modulating the resonant quantum conductance dynamics of the molecule-bridge-electrode structure. In this context, the intermolecular electrodynamics within the frontier molecular orbital of push-pull heterocyclic molecules adhere to relativistic quantum mechanics, consistent with the predictions of the quantum rate theory.

Multitarget Pharmacology of Sulfur-Nitrogen Heterocycles: Anticancer and Antioxidant Perspectives.

Cancer and oxidative stress are interrelated, with reactive oxygen species (ROS) playing crucial roles in physiological processes and oncogenesis. Excessive ROS levels can induce DNA damage, leading to cancer, and disrupt antioxidant defenses, contributing to diseases like diabetes and cardiovascular disorders. Antioxidant mechanisms include enzymes and small molecules that mitigate ROS damage. However, cancer cells often exploit oxidative conditions to evade apoptosis and promote tumor growth. Antioxidant therapy has shown mixed results, with timing and cancer-type influencing outcomes. Multifunctional drugs targeting multiple pathways offer a promising approach, reducing side effects and improving efficacy. Recent research focuses on sulfur-nitrogen heterocyclic derivatives for their dual antioxidant and anticancer properties, potentially enhancing therapeutic efficacy in oncology. The newly synthesized compounds often do not demonstrate both antioxidant and anticancer properties simultaneously. Heterocyclic rings are typically combined with phenyl groups, where hydroxy substitutions enhance antioxidant activity. On the other hand, electron-withdrawing substituents, particularly at the p-position on the phenyl ring, tend to enhance anticancer activity.

Visible Light‐Promoted Mono‐Bromination of Aniline Derivatives and Nitrogen‐Containing Heterocyclic Compounds via Electron Donor‐Acceptor Complex

AbstractWe present a successful development of a photo‐induced mono‐bromination method for anilines, which eliminates the requirement for photocatalysts and excess bromine sources. Experimental investigations, complemented by computational analyses, establish that this method operates via the formation of an electron donor‐acceptor (EDA) complex. This innovative approach enables the synthesis of highly regioselective mono‐brominated products across a diverse range of substrates, all achieved under mild reaction conditions.

A quantum mechanistic investigation into the unusual reactions of nitrilimine and nitrile oxide with 2,3,4,5-tetraphenylcyclopentadienone.

The theoretical study investigates the [3 + 2] cycloaddition (32CA) reactions between C, N-diphenyl nitrilimine with 2,3,4,5-tetraphenylcyclopentadienone and benzonitrile oxide with 2,3,4,5-tetraphenylcyclopentadienone. Nitrilimines and nitrile oxides are dipoles used in the synthesis of several heterocyclic compounds, including spiropyrazoline oxindoles and isoxazolines. The derivatives of these compounds are found with different biological activities, such as ion channel blockers, anti-inflammatory and anticancer agents as well as antimalarial. Conceptual density functional theory (CDFT) analysis, along with the activation energies of the 32CA reaction between C, N-diphenyl nitrilimine with 2,3,4,5-tetraphenylcyclopentadienone, demonstrates concordance with the empirical findings. The 32CA reaction is found to proceed through a very polar single-step asynchronous mechanism. While deductions from the activation energies of the 32CA reaction between benzonitrile oxide and 2,3,4,5-tetraphenylcyclopentadienone are found to lead to the experimental product, the parr function analysis could not explain the observed chemo- and regioselectivity. This 32CA reaction is also found to proceed through a one-step asynchronous mechanism, though with a non-polar character. The modulation of substituents positioned at the reactive sites of the reactants is found to influence the kinetics, thermodynamics, and CDFT parameters of the two 32CA reactions, consequently impacting the observed selectivities. The 32CA reactions between C, N-diphenyl nitrilimine with 2,3,4,5-tetraphenylcyclopentadienone and benzonitrile oxide with 2,3,4,5-tetraphenylcyclopentadienone have been explored theoretically using the density functional theory method at the hybrid ωB97X-D coupled with the split valence triple-ξ (TZ) basis set as implemented in the Gaussian 09. Solvent effects were taken into account by full optimization of the gas phase geometries through the polarizable continuum model developed within the self-consistent reaction field.

Study on Removal of Nitrogen-Containing Heterocyclic Compounds Contained in Crude Methylnaphthalene Oil by Formamide Extraction

Study on Removal of Nitrogen-Containing Heterocyclic Compounds Contained in Crude Methylnaphthalene Oil by Formamide Extraction

Antimicrobial effects of new tetrahydrofurans

The increasing challenge of antimicrobial resistance (AMR) necessitates abrupt attention to discovering a new class of antimicrobials. In this study, we made efforts to prepare some fluoro-phenyl tetrahydrofurans-based DNA gyrase inhibitors as anti-microbial agents. To obtain the title compounds difluoro phenyl tetrahydrofurans (1-12), we used fluorophenyl-tetrahydrofuran and methyl benzenesulfonate to react with isoxazole derivatives and heterocyclic compounds bearing secondary amines in the presence of dimethylformamide (DMF) and sodium hydride (NaH) or potassium carbonate (K2CO3). The compounds were obtained in moderate to excellent yields and were characterized with FTIR, HRMS, NMR, etc. Among all compounds (1-12), compounds 1, 2, 11, and 12 were active against various Gram-positive and Gram-negative bacteria at a low concentration (MIC ranged between 1.25 and 9.75 μg/mL) and displayed low toxicity towards mammalian cells. We testified the in vitro DNA gyrase inhibitory potential for these compounds. A molecular docking study and an ADMET assessment study were carried out to understand the mode of interaction of ligand-DNA gyrase. In conclusion, we screened the compounds 1, 2, 11, and 12 for further clinical and pre-clinical studies.

Pyrolysis characteristics of different types of tobacco and its correlation with the released aroma components under heating condition

An in-depth insight into the pyrolysis characteristics of tobacco is of great significance for the utilization of tobacco wastes. The effects of glycerol addition on the pyrolysis characteristics and distribution of aroma components of four types of tobacco was investigated in this study by using thermogravimetry and self-built rapid heating furnace capture and GC-MS analysis. Further, correlation network analysis was used to study the correlation between pyrolysis characteristics and released aroma components. It was found that the thermal weight loss behavior of different samples exhibited both commonalities and differences, the thermal weight loss process could be divided into four stages. After the application of glycerol, the overall performance of all types of tobacco leaves at stage II showed that DTGmax2 and WL2 increased, and glycerol had a relatively obvious effect on the pyrolysis characteristic parameters of flue-cured tobacco. Pyrolysis kinetic analysis based on Coats-Redfern method showed that the activation energy and pre-exponential factor of tobacco samples were decreased after the addition of glycerol. Under the heating condition, the total amount of released aroma components from each type of tobacco followed the order of burley tobacco > flue-cured tobacco >oriental tobacco > yellow sun-cured tobacco. The release amount of heterocyclic and olefins compounds from burley tobacco were higher, while flue-cured tobacco released higher contents of esters, ketones and furans compounds. The addition of glycerol promoted the release of aroma components. In terms of correlation, Tmax2 was negatively correlated with esters, aldehydes, and furans compounds, and positively correlated with DTGmax3. Tmax3 was significantly correlated with a lot of indicators, positively with acids, aldehydes, and furans compounds, but negatively with olefins and heterocyclic compounds.

Evaluating some new benzimidazole derivative: Insilico docking studies for anthelmintic drug development

The Heterocyclic compounds used as medicinal agents in the field of study since long time. Benzo-fused heterocyclic nucleus benzimidazole founds significant class for new drug development. Molecular docking study is a technique in Computer Aided Drug Designing for studying ligand and protein interaction. The main motto of this work is to perform Preliminary screening using SAR studies, OSIRIS molecular property explorer, PASS Prediction Activity spectra and Rule of Five and to check the proposed benzimidazole compounds are potentially active as Anthelminthic agent by Docking studies with beta tubulin protein (PDB ID 1OJ0) using Auto dock 1.5.6 and VINA. Among all proposed benzimidazole derivatives, 4-((1H-benzimidazol-1-ylimino) methyl) phenol (5d) is the most effective and showed maximum binding energy (−7.4 K/Cal) when compared with standard drug albendazole (−7.1 K/Cal).

Recent synthetic strategies for N-arylation of pyrrolidines: a potential template for biologically active molecules.

The chemistry of nitrogen-containing heterocyclic compounds has been a multifaceted area of research for an extended period due to their varied therapeutic and biological significance. N-Aryl pyrrolidine formed by condensation of aryl group with nitrogen atom of pyrrolidine is present in a wide array of compounds. Various significant activities shown by N-arylated pyrrolidine include anti-Alzheimer, antihypoxic, anticancer, plant activator, analgesic effect, and hepatitis C inhibitor. This review summarizes different synthetic approaches, e.g., transition-metal catalyzed and transition-metal-free synthesis, decarboxylation reaction, reductive amination, nucleophilic cyclization, Ullmann-Goldberg amidation, Buchwald-Hartwig reaction, Chan-Evans-Lam coupling, addition to benzyne, multistep reaction, green synthesis, rearrangement reaction, and multicomponent reaction, to afford the derivatives of N-aryl pyrrolidine. It encompasses synthetic strategies documented from 2015 to 2023.

C3-Alkylation of Imidazo[1,2-a]pyridines via Three-Component Aza-Friedel-Crafts Reaction Catalyzed by Y(OTf)3.

As an important class of nitrogen-containing fused heterocyclic compounds, imidazo[1,2-a]pyridines often exhibit significant biological activities, such as analgesic, anticancer, antiosteoporosis, anxiolytic, etc. Using Y(OTf)3 as a Lewis acid catalyst, a simple and efficient method has been developed for the synthesis of C3-alkylated imidazo[1,2-a]pyridines through the three-component aza-Friedel-Crafts reaction of imidazo[1,2-a]pyridines, aldehydes, and amines in the normal air atmosphere without the protection of inert gas and special requirements for anhydrous and anaerobic conditions. A series of imidazo[1,2-a]pyridine derivatives were obtained with moderate to good yields, and their structures were confirmed by 1H NMR, 13C NMR, and HRMS. Furthermore, this conversion has the advantages of simple operation, excellent functional group tolerance, high atomic economy, broad substrate scope, and can achieve gram-level reactions. Notably, this methodology may be conveniently applied to the further design and rapid synthesis of potential biologically active imidazo[1,2-a]pyridines with multifunctional groups.

Targeting inflammation through inhibition of COX-2 by substituted 4-thiazolidinone analogues: in-vitro, in-vivo and in-silico studies

The prolonged or chronic use of anti-inflammatory agents that are being used clinically is highly unsafe. This flaw or disadvantage has motivated scientists to create new heterocyclic compounds with minimal toxicity and possible anti-inflammatory effects. The design and synthesis of ten 4-thiazolidinone containing pyridine derivatives are reported in the current study article. After conducting an in vitro study, it was discovered that they had anti-inflammatory potential. The compounds were analysed for the COX-2 inhibitory activity. VSA6 found to be most potent candidate, screened further. Also. VSA6 emerged as most potent inhibitor against COX-2 with IC50 of 17.32±1.06µM. Further the antioxidant potential of the candidates was analysed in-vitro data suggested that, synthesized compounds showed the anti-oxidant activity with VSA6, and VSA10 being remarkably potent compounds with IC50 values of 34.39 and 37.32 µM respectively. In RAW 264.7 cells, VSA6 demonstrated dose-dependent suppression of mitochondrial superoxide generation at concentrations of 10 and 20 µM. It decreased intracellular expression of the LPS induced reactive oxygen species; mitochondria induced superoxide, MAPK7 and NF-κβ. The molecule also diminished the expression of extracellular of TNF-α, IL-6, MAPK7, NF-κβ and COX-2 and enhanced the expression of anti-oxidant enzymes i.e. GSH and SOD2. To further validate the COX-2 inhibitory activity of VSA6, gene and protein level expression study was conducted; VSA6 decreased the LPS induced COX-2 expression analysed by flow cytometer, immunofluorescence assay and RT-qPCR. The most efficient compound showed encouraging anti-inflammatory action when tested for in vivo anti-inflammatory potential in carrageenan induced model. To find out how this developed compound interacted with COX-2, an anti-inflammatory target, molecular docking analysis was used. According to the findings, the majority of the compounds could make good candidates for the creation of brand-new anti-inflammatory drugs.

Bringing back Galium aparine L. from forgotten corners of traditional wound treatment procedures: an antimicrobial, antioxidant, and in-vitro wound healing assay along with HPTLC fingerprinting study

BackgroundThe wound healing process, restoring the functionality of the damaged tissue, can be accelerated by various compounds. The recent experimental analysis highlights the beneficial effects of phytochemicals in improving skin regeneration and wound healing. In traditional medicine, one of the widespread plants used for treating different injuries or skin afflictions is Galium aparine L. (GA). Besides, previously reported chemical compounds of GA suggested its therapeutic effects for the wound healing process, yet its regulatory effects on the cellular and molecular stages of the wound healing process have not been investigated.MethodsIn the present study, the phytochemical profile of the GA extract was analyzed using HPTLC fingerprinting, and further scientific evaluation of its phytochemicals was done. The wound-healing effects of GA extract were explored at the cellular and molecular levels while accounting for cell toxicity. The wound closure enhancing effect, antibacterial activity, and antioxidant activity were assessed.ResultsThe HPTLC fingerprinting of the GA extract proved its previously reported phytochemical profile including phenols, flavonoids, tannins, plant acids, ergot alkaloids, flavonoids, anthraquinones, terpenoids, sterols, salicin, lipophilic compounds, saponins, iridoids, and heterocyclic nitrogen compounds. Antimicrobial assessment, of the extract, indicated the more susceptibility of S. aureus to the inhibitory effects of GA rather than E. coli and S. epidermidis. DPPH test results revealed the antioxidant property of GA extract, which was comparable to ascorbic acid. The results of the viability assay showed no cytotoxicity effects on human umbilical endothelial cell (HUVEC) and normal human dermal fibroblast (NHDF) cell lines treated with different concentrations of whole plant extract and cell viability increased in a dose-dependent manner. The results of the scratch assay showed improved cell migration and wound closure.ConclusionsThis study shows the anti-oxidant, anti-microbial, and in vitro wound healing wound-healing effects of GA hydroalcoholic extract, which aligns with its use in traditional medicine. No cytotoxicity effects were shown. The results from this study can be the basis for further investigations such as animal models and phytochemical studies. Further evaluation of its effects on mechanisms and signaling pathways involved in the wound healing processes such as angiogenesis and cell proliferation can provide novel insights into the potential therapeutic effects of the GA extract.

Discerning the Relevance of Singlet Oxygen in Pollutant Degradation in Peroxymonosulfate Activation Processes.

Significant efforts have recently been exerted toward construction of singlet oxygen (1O2)-dominated catalytic oxidation systems for selective removal of organic contaminants from wastewater, with peroxides serving as the chemical source. However, the relevance of 1O2 in the removal of pollutants remains ambiguous and requires elucidation. In this study, we scrupulously exclude the significant role of 1O2 in contaminant degradation in various peroxymonosulfate (PMS) activation systems. Multiple experimental results indicate that the activation of PMS catalyzed by CuO, MnO2, Fe-doped g-C3N4 (Fe-CN), or N-doped graphite does not predominantly follow the 1O2 pathway. More importantly, the reactivity of 1O2 is remarkably overestimated in the literature, given its inferior capacity in degradation of a range of heterocyclic contaminants and aromatic compounds possessing electron-withdrawing groups. In addition, the strong physical quenching effect of water, coupled with the low oxidizing ability of 1O2, would notably reduce the utilization efficiency of peroxide, which is particularly apparent in the degradation of micropollutants. We reckon that this study is expected to end the long-running dispute associated with the relevance of 1O2 in pollutant removal.

Capturing the Effects of Single Atom Substitutions on the Inhibition Efficiency of Glycogen Synthase Kinase-3β Inhibitors via Markov State Modeling and Experiments.

Small modifications in the chemical structure of ligands are known to dramatically change their ability to inhibit the activity of a protein. Unraveling the mechanisms that govern these dramatic changes requires scrutinizing the dynamics of protein-ligand binding and unbinding at the atomic level. As an exemplary case, we have studied Glycogen Synthase Kinase-3β (GSK-3β), a multifunctional kinase that has been implicated in a host of pathological processes. As such, there is a keen interest in identifying ligands that inhibit GSK-3β activity. One family of compounds that are highly selective and potent inhibitors of GSK-3β is exemplified by a molecule termed COB-187. COB-187 consists of a five-member heterocyclic ring with a thione at C2, a pyridine substituted methyl at N3, and a hydroxyl and phenyl at C4. We have studied the inhibition of GSK-3β by COB-187-related ligands that differ in a single heavy atom from each other (either in the location of nitrogen in their pyridine ring, or with the pyridine ring replaced by a phenyl ring), or in the length of the alkyl group joining the pyridine and the N3. The inhibition experiments show a large range of half-maximal inhibitory concentration (IC50) values from 10 nM to 10 μM, implying that these ligands exhibit vastly different propensities to inhibit GSK-3β. To explain these differences, we perform Markov State Modeling (MSM) using fully atomistic simulations. Our MSM results are in excellent agreement with the experiments in that they accurately capture differences in the binding propensities of the ligands. The simulations show that the binding propensities are related to the ligands' ability to attain a compact conformation where their two aromatic rings are spatially close. We rationalize this result by sampling numerous binding and unbinding events via funnel metadynamics simulations, which show that indeed while approaching the bound state, the ligands prefer to be in their compact conformation. We find that the presence of nitrogen in the aromatic ring increases the probability of attaining the compact conformation. Protein-ligand binding is understood to be dictated by the energetics of interactions and entropic factors, like the release of bound water from the binding pockets. This work shows that changes in the conformational distribution of ligands due to atom-level modifications in the structure play an important role in protein-ligand binding.