N-heterocyclic Moieties Research Articles

Multigram Synthesis of 4,4-Disubstituted 3-Oxopyrrolidones: Efficient Starting Materials for Diverse 3-Functionalized Pyrrolidones

AbstractThe practical, rapid development of chemical leads for drug discovery depends strongly on scalable building block synthesis procedures. N-Heterocyclic moieties, especially unsaturated ones, remain essential tools in the hands of screening and medicinal chemists. Here, we report four novel chemical block families and the interconversions between them. The synthesis of 4,4-disubstituted 3-oxopyrrolidones was an essential milestone in the diversity-oriented production of 3-aminopyrrolidones, 3-hydroxypyrrolidones, and 3,3′-difluoropyrrolidines. These compounds can be functionalized with conformationally flexible spirocyclic substituents. We developed a multigram procedure to access 4,4-disubstituted 3-oxopyrrolidones from commercially accessible and cost-saving reagents via a short three-step procedure. Here, we report the robust conversion of 3-oxopyrrolidones into 3-aminopyrrolidones, 3,3′-difluoropyrrolidones, and 3-hydroxypyrrolidones, involving a minimal number of steps. We demonstrate the scope and limitations and further perspectives for such synthetic approaches.

A Review on Hetero Cyclic Compounds & Schiff Base

The Azetidinone is well known as the (Beta-lactams) rings of a four-membered cyclic amine it is named due to N atom which is linked to Beta-carbonyl with carbonyl. Pyrazine ring plays an important role as a basic scaffold in drug designing. These compounds containing N-heterocyclic moieties are a class of privileged compounds that have found numerous application as pharmaceuticals. Schiff bases are condensation products of primary amines with carbonyl compounds and they were first reported by Schiff in 1864. Pyrazines is used to treat anti-diabetic, anti-tubercular and anti-cancer activities.These compounds containing N-heterocyclic moieties are a class of privileged compounds that have found numerous application as pharmaceuticals. All these above heterocyclic compounds have so many pharmacological activities such as anti microbial, anti bacterial, anti-cancer activities.

Boron Lewis Acid Catalyzed Hydrophosphorylation of N-Heteroaryl-Substituted Alkenes

AbstractThe hydrophosphorylation of N-heteroaryl-substituted alkenes catalyzed by a boron Lewis acid catalyst is reported. This reaction occurs with a range of alkenes bearing N-heterocycles, including pyridines, a quinoline, a pyrrole, and a benzothiazole, resulting in the production of β-N-heteroaryl alkylphosphonates in good yields under additive-free, operationally simple conditions. The mechanistic insights suggest that this hydrophosphorylation involves the deprotonation of the P–H bond of dialkyl phosphites, enabled by the cooperative effects of a boron acid and the basic N-heterocyclic moiety of the alkenes. The resulting phosphonate anion serves as an effective phosphorus nucleophile for the conjugate addition to the concurrently formed N-protonated alkenes. These β-N-heteroaryl alkylphosphonates can be further converted into other valuable organophosphorus compounds through the introduction of an alcohol group or the reduction of the phosphine oxide moiety.

Ruthenium complexes with triazenide ligands bearing an N-heterocyclic moiety, and their catalytic properties in the reduction of nitroarenes.

A series of ruthenium complexes of formulae [RuCl(triazenide)(p-cymene)] have been synthesized using as ligand a triazenide monofunctionalized with an N-heterocyclic moiety. Nuclear magnetic resonance, high resolution mass spectrometry and X-ray diffraction were used to characterize the triazenide ligands and their complexes. In addition, these ruthenium complexes catalyzed the reduction of nitrobenzene to aniline in the presence of sodium borohydride and ethanol as solvent at room temperature. Notably, complex 5 was especially active in the reduction of nitroarenes substituted at the aromatic ring with electron-withdrawing or electron-donating fuctional groups affording the desired arylamines in good to excellent yields (80-100%). The role of the N-heterocyclic moiety on catalysis was explored.

Design, synthesis and neuroprotective evaluation of nitrogen heterocyclic and triazole derivatives of sarracinic acid

Novel sarracinic acid derivatives bearing triazole or N-heterocyclic moiety were prepared via two separate reaction schemes. The triazoles and the N-heterocyclic derivatives were synthesised using standard click chemistry approach and amination of 2-bromoethyl ester of sarracinic acid respectively. All the synthesised derivatives were screened for in vitro neuroprotective activity against corticosterone induced impairment in neuroblastoma cell line SH-SY5Y. Two analogs SA-2 and SA-12 exhibited strong neuroprotective activity. The cell viability, after high dose corticosterone induced cell death, increased remarkably with the pre treatment of SA-2 and SA-12. The in vitro biological activity of SA-2 and SA-12 was verified through docking studies. The docking studies were in good agreement with the biological results. SA-2 and SA-12 showed strong binding affinities with the target protein having ΔGb = −8.88 and −7.52; inhibition constant (ki) = 3.08 nM and 30.9 nM respectively.

Synthesis and Pharmacological Activities of Chalcone and Its Derivatives Bearing N-Heterocyclic Scaffolds: A Review.

The incorporation of heterocyclic moieties into the standard chemical structure with a biologically active scaffold has become of crucial practice for the construction of pharmacologically potent candidates in the drug arena. Currently, numerous kinds of chalcones and their derivatives have been synthesized using the incorporation of heterocyclic scaffolds, especially chalcones bearing heterocyclic moieties that display improved efficiency and potential for drug production in pharmaceutical sectors. The current Review focuses on recent advances in the synthetic approaches and pharmacological activities such as antibacterial, antifungal, antitubercular, antioxidant, antimalarial, anticancer, anti-inflammatory, antigiardial, and antifilarial activities of chalcone derivatives incorporating N-heterocyclic moieties at either the A-ring or B-ring.

DeepAR: a novel deep learning-based hybrid framework for the interpretable prediction of androgen receptor antagonists

Drug resistance represents a major obstacle to therapeutic innovations and is a prevalent feature in prostate cancer (PCa). Androgen receptors (ARs) are the hallmark therapeutic target for prostate cancer modulation and AR antagonists have achieved great success. However, rapid emergence of resistance contributing to PCa progression is the ultimate burden of their long-term usage. Hence, the discovery and development of AR antagonists with capability to combat the resistance, remains an avenue for further exploration. Therefore, this study proposes a novel deep learning (DL)-based hybrid framework, named DeepAR, to accurately and rapidly identify AR antagonists by using only the SMILES notation. Specifically, DeepAR is capable of extracting and learning the key information embedded in AR antagonists. Firstly, we established a benchmark dataset by collecting active and inactive compounds against AR from the ChEMBL database. Based on this dataset, we developed and optimized a collection of baseline models by using a comprehensive set of well-known molecular descriptors and machine learning algorithms. Then, these baseline models were utilized for creating probabilistic features. Finally, these probabilistic features were combined and used for the construction of a meta-model based on a one-dimensional convolutional neural network. Experimental results indicated that DeepAR is a more accurate and stable approach for identifying AR antagonists in terms of the independent test dataset, by achieving an accuracy of 0.911 and MCC of 0.823. In addition, our proposed framework is able to provide feature importance information by leveraging a popular computational approach, named SHapley Additive exPlanations (SHAP). In the meanwhile, the characterization and analysis of potential AR antagonist candidates were achieved through the SHAP waterfall plot and molecular docking. The analysis inferred that N-heterocyclic moieties, halogenated substituents, and a cyano functional group were significant determinants of potential AR antagonists. Lastly, we implemented an online web server by using DeepAR (at http://pmlabstack.pythonanywhere.com/DeepAR). We anticipate that DeepAR could be a useful computational tool for community-wide facilitation of AR candidates from a large number of uncharacterized compounds.

N-Heterocycles as Privileged Scaffolds in FDA Approved Different NMEs of 2021: A Review

Abstract: Presence of N-heterocyclic ring systems as promising features in the molecular skeleton of FDA approved drugs, underlie the remarkable contributions of these heterocyclic nuclei in the field of medicine. Despite instability risks associated with COVID pandemic, the US FDA approved 50 drugs (36 NMEs and 14 biological products) in the year 2021. The active ingredients of 32 drugs out of these 36 NMEs (almost 89%) contain saturated, partially unsaturated and/or aromatic N-heterocyclic moieties in their molecular assemblies, hence dominating the medicinal approvals. While 27 molecules (75% of these NMEs drugs) are prominent small NMEs. Herein, we have considered profiling of those FDA approved 27 small-molecule drugs which are decorated with N-heterocycles as privileged scaffolds. These drugs are grouped on the basis of a number of N-heterocycles present in their structural framework. The spectrum of these drugs in terms of their structural features and medicinal importance is summarized in this review. Also, the pertinent analyses of their drug-likeliness conferring some general pharmacokinetic principles is highlighted.

Theoretical investigation of the influence of heterocycles on the radiative and non-radiative decay processes of iridium(iii) complexes

By means of density functional theory and time-dependent density functional theory, the radiative and non-radiative decay processes of iridium(iii) complexes are investigated to explore the role of N-heterocyclic moieties in chelating ligands.

Novel 1,3,4-oxadiazole thioether and sulfone derivatives bearing a flexible N-heterocyclic moiety: Synthesis, characterization, and anti-microorganism activity

In the search for more efficient and versatile anti-phytopathogen agents, a series of new 1,3,4-oxadiazole thioether/sulfone analogues bearing a flexible N-containing heterocyclic pattern were elaborately prepared, and their bioactivities against plant pathogenic microorganisms were systematically evaluated. Bioassay screening results demonstrated that compounds 32 and 33 significantly inhibited the growth of Xanthomonas oryzae pv. oryzae (Xoo) in vitro (32, EC50 = 5.17 mg L−1; 33, EC50 = 1.19 mg L−1), which were significantly surpass commercial bismerthiazol (BT) and thiodiazole copper (TC). Meanwhile, pot experiments confirmed the prospective applications of compound 33 in managing rice bacterial leaf blight and its good safety toward rice plants. Further studies showed that compound 33 interfered with the formation of bacterial biofilms and inhibited bacterial virulence factors. Furthermore, an in vitro antifungal bioassay showed that compound 32 possessed remarkable growth inhibitory activity against Sclerotinia sclerotiorum (S.s., EC50 = 22.16 mg L−1) and Verticillium dahlia (V.d. EC50 = 32.78 mg L−1). These results all confirmed that the designed 1,3,4-oxadiazole compounds displayed potential for managing plant microbial diseases through targeting dihydrolipoamide S-succinyltransferase (DLST).

Recent advances in the tandem copper-catalyzed Ullmann-Goldberg N-arylation-cyclization strategies.

N-Aryl bond formation under copper catalysis has played a pivotal role and has been extensively used as a key step in the total syntheses of several therapeutic molecules. The construction of fused N-heterocycles remains a flourishing area of research because of their potential importance in drug discovery research and functional materials. On the other hand, tandem reactions provide facile ways to access complex organic molecules by reducing the synthetic steps. This review article provides a detailed overview of the tandem reactions developed in the past two decades, comprising N-arylation-cyclization strategies, including mechanistic aspects, driven by copper catalysts to furnish biologically significant fused N-heterocyclic moieties. The protocols described enlighten the prominence of the copper-catalyzed N-arylation-cyclization tandem strategies; exploration in this direction may open new avenues, inspire the design of new and creative tandem reaction strategies, and may unveil novel transformations with unprecedented reaction mechanisms.

A Review on Six Membered Nitrogen Containing Heterocyclic Compounds with Various Biological Activities

The heterocycles are currently considered as promising compounds for the development of novel therapeutic agents. The analogs of nitrogen-based heterocycles occupy an exclusive position as a valuable source of therapeutic agents in medicinal chemistry. More than 75% of drugs approved by the FDA and currently available in the market are nitrogen-containing heterocyclic moieties. In the forthcoming decade, a much greater share of new nitrogen-based pharmaceuticals is anticipated. Many new nitrogen-based heterocycles have been designed. The number of novel N-heterocyclic moieties with significant physiological properties and promising applications in medicinal chemistry is ever-growing. This paper aims to review on the pharmacological activities of six membered nitrogen contains heterocyclic compounds.

Biochemistry of plants N-heterocyclic non-protein amino acids.

Plants catalyze the biosynthesis of a large number of non-protein amino acids, which are usually toxic for other organisms. In this review, the chemistry and metabolism of N-heterocyclic non-protein amino acids from plants are described. These N-heterocyclic non-protein amino acids are composed of β-substituted alanines and include mimosine, β-pyrazol-1-yl-L-alanine, willardiine, isowillardiine, and lathyrine. These β-substituted alanines consisted of an N-heterocyclic moiety and an alanyl side chain. This review explains how these individual moieties are derived from their precursors and how they are used as the substrate for biosynthesizing the respective N-heterocyclic non-protein amino acids. In addition, known catabolism and possible role of these non-protein amino acids in the actual host is explained.

Photoinduced Enhanced Decomposition of TBHP: A Convenient and Greener Pathway for Aqueous Domino Synthesis of Quinazolinones and Quinoxalines

Catalyst-free photoinduced processes in aqueous medium represent significant advancement toward development of green and sustainable pathways in organic synthesis. tert-Butyl hydroperoxide (TBHP) is a widely used oxidant in organic reactions, where the decomposition of TBHP into its radicals by metal catalysts or other reagents is a key factor for efficient catalytic outcome. Herein, we report a simple and environmentally friendly visible light-promoted synthetic pathway for the synthesis of N-heterocyclic moieties, such as quinazolinones and quinoxalines, in the presence of TBHP as an oxidizing agent in aqueous medium that requires no catalysts/photocatalysts. The enhanced rate of decomposition to generate free radicals from TBHP upon visible light irradiation is the driving force for the domino reaction.

Amine Catalysis with Substrates Bearing N-Heterocyclic Moieties Enabled by Control over the Enamine Pyramidalization Direction.

Stereoselective organocatalytic C-C bond formations that tolerate N-heterocycles are valuable since these moieties are common motifs in numerous chiral bioactive compounds. Such transformations are, however, challenging since N-heterocyclic moieties can interfere with the catalytic reaction. Here, we present a peptide that catalyzes conjugate addition reactions between aldehydes and nitroolefins bearing a broad range of different N-heterocyclic moieties with basic and/or H-bonding sites in excellent yields and stereoselectivities. Tuning of the pyramidalization direction of the enamine intermediate enabled the high stereoselectivity.

Design, synthesis and anti-inflammatory study of novel N-heterocyclic substituted Aloe-emodin derivatives.

A novel series of Aloe-emodin derivatives containing N-heterocyclic moieties was designed and synthesized. The structure-activity relationship studies (SARs) indicated that the replacement of hydroxyethyl and benzhydryl piperazine groups could improve efficacy. Compounds 12r and 14a-14c exhibited a higher inhibitory effect on LPS-induced nitric oxide (NO) production in RAW264.7 macrophages than Aloe-emodin did. Among them, 12r showed the most potent inhibition with an IC50 value of 5.66±0.47μM. Further toxicity and pharmacokinetic studies were carried out and 12r was found to be the most active structure with low toxicity risk and good metabolic properties. It could also decrease the levels of IL-1β, TNF-α, PGE2 and inhibit the activation of nuclear factor-κB signalling pathway. Importantly, 12r showed oral bioavailability of up to 55.16% and attenuated the inflammatory symptoms in an ulcerative colitis mouse model in vivo. These results indicate that 12r is suitable for development as an anti-inflammatory agent.

Iron-Catalyzed Direct Cross-Coupling of Ethers and Thioether with Alcohols for the Synthesis of Mixed Acetals

An iron-catalyzed direct O-alkylation of alcohols via α-C(sp3)–H activation of ethers and a thioether has been established that tolerates cyclic and acyclic ethers and alcohols containing aromatic N-heterocyclic moieties, providing an efficient and green method for the synthesis of mixed acetals with good to excellent yields. The robustness of this protocol is demonstrated by the late-stage oxidation of a structurally complex natural product.

A Review on Recent Advances in Nitrogen-Containing Molecules and Their Biological Applications.

The analogs of nitrogen-based heterocycles occupy an exclusive position as a valuable source of therapeutic agents in medicinal chemistry. More than 75% of drugs approved by the FDA and currently available in the market are nitrogen-containing heterocyclic moieties. In the forthcoming decade, a much greater share of new nitrogen-based pharmaceuticals is anticipated. Many new nitrogen-based heterocycles have been designed. The number of novel N-heterocyclic moieties with significant physiological properties and promising applications in medicinal chemistry is ever-growing. In this review, we consolidate the recent advances on novel nitrogen-containing heterocycles and their distinct biological activities, reported over the past one year (2019 to early 2020). This review highlights the trends in the use of nitrogen-based moieties in drug design and the development of different potent and competent candidates against various diseases.

Eco-friendly and sustainable synthetic approaches to biologically significant fused N-heterocycles

This review summarizes environmentally benign approaches for the synthesis of fused N-heterocycles since 2011. It is mainly focused on one-pot, multicomponent protocols for generating fused N-heterocyclic moieties with biological significance in atom-efficient manner. Several attractive and cost-effective approaches such as metal-, catalyst-, and solvent-free methods are discussed in this review. Electrochemical concept as green and environmentally optional strategy to produce fused N-heterocycles is also discussed. Synthesis of natural bioactive compounds like clausine V, glycoborine, and popular commercial drug alprazolam (Xanax) by utilizing such strategy is described.

Fluorescent chemosensors based on conjugated polymers with N-heterocyclic moieties: two decades of progress

A brief summary of representative fluorescent chemosensors based on conjugated polymers with N-heterocyclic moieties, followed by a discussion on the limitations and challenges of current systems, as well as possible future research directions.