Heterocyclic Core Research Articles

Parallel Minisci Reaction of gem-Difluorocycloalkyl Building Blocks.

Parallel Minisci reactions of nonfluorinated and gem-difluorinated C4-C7 cycloalkyl building blocks (trifluoroborates and carboxylic acids) with a series of electron-deficient heterocycles were studied. A comparison of the reaction's outcome revealed better product yields in the case of carboxylic acids as the radical precursors in most cases, albeit these reagents were used with three-fold excess under optimized conditions. The nature of the heterocyclic core was found to be important for successful incorporation of the cycloalkyl fragment. The impact of the CF2 moiety on the oxidation potential of fluorinated cycloalkyl trifluoroborates and the reaction outcome, in general, was also evaluated.

Heterocyclic-Based Analogues against Sarcine-Ricin Loop RNA from Escherichia coli: In Silico Molecular Docking Study and Machine Learning Classifiers.

Heterocyclic-based drugs have strong bioactivities, are active pharmacophores, and are used to design several antibacterial drugs. Due to the diverse biodynamic properties of well-known heterocyclic cores, such as quinoline, indole, and its derivatives, they have a special place in the chemistry of nitrogen-containing heterocyclic molecules. The objective of this study is to analyze the interaction of several heterocyclic molecules using molecular docking and machine learning approaches to find out the possible antibacterial drugs. The molecular docking analysis of heterocyclic-based analogues against the sarcin-Ricin Loop RNA from E. coli with a C2667-2'-OCF3 modification (PDB ID: 6ZYB) is discussed. Many heterocyclic-based derivatives show several residual interaction, affinity, and hydrogen bonding with sarcin-Ricin Loop RNA from E. coli with a C2667-2'-OCF3 alteration which are identified by the investigation of in silico molecular docking analysis of such heterocyclic derivatives. The dataset from the molecular docking study was used for additional optimum analysis, and the molecular descriptors were classified using a variety of machine learning classifiers, including the GB Classifier, CB Classifier, RF Classifier, SV Classifier, KNN Classifier, and Voting Classifier. The research presented here showed that heterocyclic derivatives may operate as potent antibacterial agents when combined with other compounds to produce highly efficient antibacterial agents.

Water-Soluble Small Organic Fluorophores for Oncological Theragnostic Applications: Progress and Development.

Cancer is one of the major noncommunicable diseases, responsible for millions of deaths every year worldwide. Though various cancer detection and treatment modalities are available today, many deaths occur owing to its late-stage detection and metastatic nature. Noninvasive detection using luminescence-based imaging tools is considered one of the promising techniques owing to its low cost, high sensitivity, and brightness. Moreover, these tools are unique and valuable as they can detect even the slightest changes in the cellular microenvironment. To achieve this, a fluorescent probe with strong tumor uptake and high spatial and temporal resolution, especially with highwatersolubility, is highly demanded. Recently, several water-soluble molecules with emission windows in the visible (400-700nm), first near-infrared (NIR-I, 700-1000nm), and second near-infrared (NIR-II, 1000-1700nm) windows have been reported in literature. This review highlights recently reported water-soluble small organic fluorophores/dyes with applications in cancer diagnosis and therapeutics. We systematically highlight and describe the key concepts, structural classes of fluorophores, strategies for imparting water solubility, and applications in cancer therapy and diagnosis, i.e., theragnostics. We discuss examples of water-soluble fluorescent probes based on coumarin, xanthene, boron-dipyrromethene (BODIPY), and cyanine cores. Some other emerging classes of dyes based on carbocyclic and heterocyclic cores are also discussed. Besides, emerging molecular engineering methods to obtain such fluorophores are discussed. Finally, the opportunities and challenges in this research area are also delineated.

In Silico Design of Potential Small-Molecule Antibiotic Adjuvants against Salmonella typhimurium Ortho Acetyl Sulphydrylase Synthase to Address Antimicrobial Resistance.

The inhibition of O-acetyl sulphydrylase synthase isoforms has been reported to represent a promising approach for the development of antibiotic adjuvants. This occurs via the organism developing an unpaired oxidative stress response, causing a reduction in antibiotic resistance in vegetative and swarm cell populations. This consequently increases the effectiveness of conventional antibiotics at lower doses. This study aimed to predict potential inhibitors of Salmonella typhimurium ortho acetyl sulphydrylase synthase (StOASS), which has lower binding energy than the cocrystalized ligand pyridoxal 5 phosphate (PLP), using a computer-aided drug design approach including pharmacophore modeling, virtual screening, and in silico ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) evaluation. The screening and molecular docking of 4254 compounds obtained from the PubChem database were carried out using AutoDock vina, while a post-screening analysis was carried out using Discovery Studio. The best three hits were compounds with the PubChem IDs 118614633, 135715279, and 155773276, possessing binding affinities of -9.1, -8.9, and -8.8 kcal/mol, respectively. The in silico ADMET prediction showed that the pharmacokinetic properties of the best hits were relatively good. The optimization of the best three hits via scaffold hopping gave rise to 187 compounds, and they were docked against StOASS; this revealed that lead compound 1 had the lowest binding energy (-9.3 kcal/mol) and performed better than its parent compound 155773276. Lead compound 1, with the best binding affinity, has a hydroxyl group in its structure and a change in the core heterocycle of its parent compound to benzimidazole, and pyrimidine introduces a synergistic effect and consequently increases the binding energy. The stability of the best hit and optimized compound at the StOASS active site was determined using RMSD, RMSF, radius of gyration, and SASA plots generated from a molecular dynamics simulation. The MD simulation results were also used to monitor how the introduction of new functional groups of optimized compounds contributes to the stability of ligands at the target active site. The improved binding affinity of these compounds compared to PLP and their toxicity profile, which is predicted to be mild, highlights them as good inhibitors of StOASS, and hence, possible antimicrobial adjuvants.

Construction of Isoquinolone Scaffolds on DNA via Rhodium(III)-Catalyzed C-H Activation.

Isoquinolone is one of the most common heterocyclic core structures in countless natural products and many bioactive compounds. Here, a highly efficient approach to synthesize isoquinolone scaffolds on DNA via rhodium(III)-catalyzed C-H activation has been described. This chemistry transformation is robust and has shown good compatibility with DNA, which is suitable for DNA-encoded library synthesis.

Synthesis and Functional Evaluation of Synthetic Cannabinoid Receptor Agonists Related to ADB-HEXINACA.

ADB-HEXINACA has been recently reported as a synthetic cannabinoid receptor agonist (SCRA), one of the largest classes of new psychoactive substances (NPSs). This compound marks the entry of the n-hexyl tail group into the SCRA landscape, which has continued in the market with recent, newly detected SCRAs. As such, a proactive characterization campaign was undertaken, including the synthesis, characterization, and pharmacological evaluation of ADB-HEXINACA and a library of 41 closely related analogues. Two in vitro functional assays were employed to assess activity at CB1 and CB2 cannabinoid receptors, measuring Gβγ-coupled agonism through a fluorescence-based membrane potential assay (MPA) and β-arrestin 2 (βarr2) recruitment via a live cell-based nanoluciferase complementation reporter assay. ADB-HEXINACA was a potent and efficacious CB1 agonist (CB1 MPA pEC50 = 7.87 ± 0.12 M; Emax = 124 ± 5%; βarr2 pEC50 = 8.27 ± 0.14 M; Emax = 793 ± 42.5), as were most compounds assessed. Isolation of the heterocyclic core and alkyl tails allowed for the comprehensive characterization of structure-activity relationships in this compound class, which were rationalized in silico via induced fit docking experiments. Overall, most compounds assessed are possibly emerging NPSs.

Sterically Crowded Donor-Rich Imidazole Systems as Hole Transport Materials for Solution-Processed OLEDs.

Imidazole, being an interesting dinitrogenic five-membered heterocyclic core, has been widely explored during the last several decades for developing various fascinating materials. Among the different domains where imidazole-based materials find wide applications, the area of optoelectronics has seen an overwhelming growth of functional imidazole derivatives developed through remarkable design and synthesis strategies. The present work reports a design approach for integrating bulky donor units at the four terminals of an imidazole core, leading to the development of sterically populated imidazole-based molecular platforms with interesting structural features. Rationally chosen starting substrates led to the incorporation of a bulky donor at the four terminals of the imidazole core. In addition, homo- and cofunctional molecular systems were synthesized through a suitable combination of initial ingredients. Our approach was extended to develop a series of four molecular systems, i.e., Cz3PhI, Cz4I, Cz3PzI, and TPA3CzI, containing carbazole, phenothiazine, and triphenylamine as known efficient donors at the periphery. Given their interesting structural features, three sterically crowded molecules (Cz4I, Cz3PzI, and TPA3CzI) were screened by using DFT and TD-DFT calculations to investigate their potential as hole transport materials (HTMs) for optoelectronic devices. The theoretical studies on several aspects including hole reorganization and exciton binding energies, ionization potential, etc., revealed their potential as possible candidates for the hole transport layer of OLEDs. Single-crystal analysis of Cz3PhI and Cz3PzI established interesting structural features including twisted geometries, which may help attain high triplet energy. Finally, the importance of theoretical predictions was established by fabricating two solution-process green phosphorescent OLED devices using TPA3CzI and Cz3PzI as HTMs. The fabricated devices exhibited good EQE/PE and CE of ∼15%/56 lm/W/58 cd/A and ∼13%/47 lm/W/50 cd/A, respectively, at 100 cd/m2.

Targeted and Long-Term Fluorescence Imaging of Plant Cytomembranes Using Main-Chain Charged Polyelectrolytes with Aggregation-Induced Emission.

Fluorescent polyelectrolytes have attracted tremendous attention due to their unique properties and wide applications. However, current research objects of fluorescent polyelectrolytes mainly focus on side-chain charged polyelectrolytes, and the applications of polyelectrolytes in plant cytomembrane imaging with long time and high specificity still remain challenging. Herein, long-time and targeted fluorescence imaging of plant cytomembranes was achieved for the first time using main-chain charged polyelectrolytes (MCCPs) with aggregation-induced emission (AIE). A series of MCCPs were designed and synthesized, among which the red-emissive and AIE-active MCCP with a triphenylamine linker and a cyano group around the cationic ring-fused heterocyclic core showed the best fluorescence imaging performance of plant cells. Unlike other MCCPs and its neutral form of polymer, this cyano-substituted conjugated polyelectrolyte can specifically target the cytomembrane of plant cells within a short staining time with many advantages, including wash-free staining, high photostability and imaging integrity, excellent durability (at least 12 h), and low biotoxicity. In addition to onion epidermal cells, this AIE fluorescence probe also shows good imaging capabilities for other kinds of plant cells such as Glycine max and Vigna radiata. Such an AIE-active MCCP-based imaging system provides an effective design strategy to develop fluorescence probes with high specificity and long-term imaging ability toward plant plasma membranes.

METABOLIC PROFILE OF 4F-MDMB-BICA IN HUMAN URINE

The purpose of the study is to study the metabolic profile of the cannabimimetic 4F-MDMB-BICA in the urine of consumers and to identify markers of 4F-MDMB-BICA use using gas chromatography with a mass spectrometric detector (GC-MS) and liquid chromatography with tandem mass spec-trometry (LC-MS/ MS) in the urine of consumers of psychoactive substances, for chemical-toxicological and forensic chemical analysis. Material and methods. The study of urine samples of 4F-MDMB-BICA cannabimimetic users using enzymatic hydrolysis in combination with solid-phase extraction and gas chromatography with mass spectrometric detection showed that the 4F-MDMB-BICA marker and, in some cases, its nor-metabolite are detected in the urine of consumers. The 4F-MDMB-BICA nor-metabolite is a common biotransformation product for the cannabimimetics 4F-MDMB-BICA and 5F-MDMB-PICA, resulting from the hydrolysis of the ester bond and N-dealkylation of the heterocyclic core. Results. 35 compounds were identified by liquid chromatography with tandem mass spectrometry, including the original parent 4F-MDMB-BICA, 31 metabolites of biotransformation phases I and II, and 3 metabolite artifacts; it was found that the latter are the product of intramolecular cyclization of 4F-MDMB-BICA metabolites. 16 previously undescribed compounds, including 15 metabolites and one artifact were identified. The putative structures, mass spectra and some characteristics of the identified compounds are given, including retention time, MRM transitions, and relative peak area of the substance. Conclusion. From the presented data, it can be seen that the main pathways of 4F-MDMB-BICA metabolism in the human body are hydrolysis of the ester group, hydroxylation of alkyl radicals and the heterocyclic core, oxidative defluorination, and N-dealkylation. The hydrolysis products of the ester bond and hydroxyl derivatives are subsequently conjugated with glucuronic acid.

ZNL0325, a Pyrazolopyrimidine-Based Covalent Probe, Demonstrates an Alternative Binding Mode for Kinases.

The pyrazolopyrimidine (PP) heterocycle is a versatile and widely deployed core scaffold for the development of kinase inhibitors. Typically, a 4-amino-substituted pyrazolopyrimidine binds in the ATP-binding pocket in a conformation analogous to the 6-aminopurine of ATP. Here, we report the discovery of ZNL0325 which exhibits a flipped binding mode where the C3 position is oriented toward the ribose binding pocket. ZNL0325 and its analogues feature an acrylamide side chain at the C3 position which is capable of forming a covalent bond with multiple kinases that possess a cysteine at the αD-1 position including BTK, EGFR, BLK, and JAK3. These findings suggest that the ability to form a covalent bond can override the preferred noncovalent binding conformation of the heterocyclic core and provides an opportunity to create structurally distinct covalent kinase inhibitors.

Shaping Chirality via Stereoselective, Organocatalytic [4+2] Cycloadditions involving Heterocyclic ortho-Quinodimethanes.

Polycyclic compounds bearing a complex heterocyclic core such as an aromatic heterocycle "fused" with one or more functionalized rings, are widespread leading molecules in the domain of synthetic organic chemistry and pharmaceuticals. Although many synthetic methodologies have been devised to access achiral, fused heteroaromatic scaffolds, or related chiral variants adorned with out-of-cycle stereogenic elements, equally efficient strategies to afford chiral heterocycles featuring in-cycle stereocenters, exist to a lesser extent and presently represent a growing field of investigation. The mild, organocatalytic generation of elusive ortho-quinodimethane intermediates (oQDMs), derived from suitable heteroaromatic carbonyl- or carbonyl-like pronucleophiles has recently proved successful in the synthesis of such peculiar chiral architectures via stereoselective [4+2] cycloadditions. This review provides an overview of the most important advances attained in this field over the last decade.

Synthesis of new heterocyclic derivatives (benzodioxane-2-yl)methanol and their effect on rat intraocular pressure

Objective: Synthesis of new compounds, melatonin isosters, and study of their ability to reduce intraocular pressure.
 Materials and methods: Based on the previously made forecast and on the similarity with the selected compounds, the synthesis of new compounds was carried out – melatonin isosters having a 2,3-dihydro-1,4-benzodioxin cycle connected by a linker of various chemical structure with a nitrogen-containing heterocyclic core. The structure of the synthesized compounds was proved by 1H- and 13C- NMR spectroscopy, purity and individuality – by chromatographic methods. Intraocular pressure in laboratory animals was measured using a contact veterinary tonometer Tonovet (Finland). Cytotoxicity was assessed using MTT test on normal rat skin fibroblasts.
 Results: Derivatives (benzodioxane-2-yl)methanol reduced the level of IOP in varying degrees of severity. The VMA-22-37 compound showed the greatest activity. With topical application of a 0.4% solution, the compound reduced the intraocular pressure of intact rats by 26.6%, while not affecting the control eye. This compound also has low cytotoxicity.
 Conclusion: Derivatives (benzodioxane-2-yl)methanol is promising for the search for compounds capable of reducing increased intraocular pressure.

A Mechanistic Insight on CuI‐Catalyzed Synthesis of Oxazolidinones through a Four‐Component Reaction

AbstractIn this contribution, we describe a straightforward and efficient synthesis of oxazolidin‐2‐ones through a Cu(I)‐catalyzed four‐component coupling of amines, aldehydes, terminal alkynes, and CO2 via carboxylative cyclization of propargylamine intermediates. This strategy enables the selective synthesis of a variety of (Z)‐5‐alkylidene‐oxazolidin‐2‐ones substituted in positions 3, 4 and 5 of the heterocyclic core with a variety of functional groups, well‐tolerated in terms of scope. A mechanistic study was carried out monitoring the process in solution by different techniques (operando FTIR, multi‐nuclear NMR), with the aim of identifying the intermediates, both organic compounds and Cu(I) coordination complexes, which showed the plausible multi‐metallic nature of the catalytic intermediates (identified by X‐ray diffraction analyses on monocrystal).

Pyridinium‐abgeleitete mesoionische N‐heterocyclische Olefine (py‐mNHOs)

AbstractMesoionische Polarisation ermöglicht den Zugang zu elektronenreichen Olefinen, die als Organokatalysatoren, Liganden oder Nucleophile Anwendung finden. Wir berichten hier über die Synthese und Charakterisierung einer Reihe von 3‐Methylpyridinium‐abgeleiteten mesoionischen Olefinen (py‐mNHOs). Wir verwendeten ein mit DFT‐Rechnungen unterstütztes Designkonzept, das zeigte, dass Arylgruppen an den 1‐, 2‐, 4‐ und 6‐Positionen des heterocyclischen Kerns die kinetische Stabilisierung der neuartigen mesoionischen Verbindungen ermöglicht. Die elektronischen Tolman‐Parameter zeigen, dass py‐mNHOs bemerkenswert starke σ‐Donor‐Liganden für Übergangsmetalle und Hauptgruppen‐Lewis‐Säuren sind. Außerdem gehören sie zu den stärksten Nucleophilen auf der Mayr‐Reaktivitätsskala. Bei Reaktionen von py‐mNHOs mit elektronenarmen π‐Systemen wurde experimentell ein sukzessiver Übergang von der Bildung zwitterionischer Addukte über schrittweise zu konzertierten 1,3‐dipolaren Cycloadditionen beobachtet und durch quantenchemische Rechnungen analysiert.

Pyridinium-Derived Mesoionic N-Heterocyclic Olefins (py-mNHOs).

Mesoionic polarization allows access to electron-rich olefins that have found application as organocatalysts, ligands, or nucleophiles. Herein, we report the synthesis and characterization of a series of 3-methylpyridinium-derived mesoionic olefins (py-mNHOs). We used a DFT-supported design concept, which showed that the introduction of aryl groups in the 1-, 2-, 4-, and 6-positions of the heterocyclic core allowed the kinetic stabilization of the novel mesoionic compounds. Tolman electronic parameters indicate that py-mNHOs are remarkably strong σ-donor ligands toward transition metals and main group Lewis acids. Additionally, they are among the strongest nucleophiles on the Mayr reactivity scale. In reactions of py-mNHOs with electron-poor π-systems, a gradual transition from the formation of zwitterionic adducts via stepwise to concerted 1,3-dipolar cycloadditions was observed experimentally and analyzed by quantum-chemical calculations.

Pseudo Four-Component Synthesis of 5,6-Dihydroindolo[2,1-a]isoquinolines.

An easy synthesis of novel highly functionalized 5,6-dihydroindolo[2,1-a]isoquinolines was developed via a pseudo four-component domino reaction of 1-aroyl-3,4-dihydroisoquinolines, terminal α,β-ynones, and malononitrile. The selective formation of this biologically relevant heterocyclic core was achieved using a one-pot approach under microwave irradiation. The formation of the same skeleton through the reaction of 5,6-dihydropyrrolo[2,1-a]isoquinolines with malonic acid dinitrile supports the proposed mechanism, involving the intermediate product of the three-component reaction. Furthermore, the disproval of an alternative reaction pathway, which involved the dimerization of malononitrile followed by three-component transformation, was demonstrated. Introducing the malononitrile dimer as a CH acid resulted in the formation of a different pyrido[3',4':4,5]pyrrolo[2,1-a]isoquinoline core. Additionally, the synthesized 5,6-dihydroindolo[2,1-a]isoquinolines were examined for their photophysical properties, revealing their attractive luminescent characteristics.

Pyrazolopyridine-based kinase inhibitors for anti-cancer targeted therapy.

The need for effective cancer treatments continues to be a challenge for the biomedical research community. In this case, the advent of targeted therapy has significantly improved therapeutic outcomes. Drug discovery and development efforts targeting kinases have resulted in the approval of several small-molecule anti-cancer drugs based on ATP-mimicking heterocyclic cores. Pyrazolopyridines are a group of privileged heterocyclic cores in kinase drug discovery, which are present in several inhibitors that have been developed against various cancers. Notably, selpercatinib, glumetinib, camonsertib and olverembatinib have either received approval or are in late-phase clinical studies. This review presents the success stories employing pyrazolopyridine scaffolds as hinge-binding cores to address various challenges in kinase-targeted drug discovery research.

An overview on 2-indolinone derivatives as anticancer agents

2-Indolinone nucleus is considered one of a promising heterocyclic core in medicinal chemistry that showed numerous range of activity among which antimicrobial, antioxidant, antiviral, antitubercular and anticancer activities. Cancer targeting is still an issue so there is a need for developing new agents that inhibit cancer growth without or low effect on normal body cells. Some derivatives of indolin-2-one are known to be a critical structure in some inhibitors of receptor tyrosine kinases (RTKs); a cancer target therapy, for example, Sunitinib. Herein in this review we focus on 2-indolinone derivatives as RTKs inhibitors as cancer targeting therapy.

Recent Advances in The Electrochemical Functionalization of N-heterocycles

Nitrogen-containing heterocyclic cores are of immense importance due to their high abundance in naturally occurring or synthetic molecules having wide applications in different fields of basic and applied sciences. The...

Synthesis and biological activity of rhodanine-furan conjugates: A review

Rhodanines are recognized as privileged heterocycles in medicinal chemistry. The main achievements include the development of drug-like molecules with numerous biological activities as well as approved drugs. The Furan nucleus is considered one of the promising heterocyclic cores in medicinal chemistry that showed numerous ranges of activity. The combination of several heterocycles in a one molecule commonly provides much more interest in the enhanced activity profile of its analogs than their parent separate constituents. Such conjugates are promising objects for modern medicinal chemistry. In this review paper recent advances in the synthesis and biological activities rhodanine-furan conjugates which its application in the different field of drug discovery.