Heterocyclic Groups Research Articles

Innovative Synthesis of 3,5-Disubstituted Pyrazoline with Heterocyclic System for Hybrid Development

The synthesis of 3,5-disubstituted pyrazolines, integrated with heterocyclic systems, represents a crucial area of chemical research due to their pharmacological and biological significance. This article reviews various synthetic methods used to prepare 3,5-disubstituted pyrazolines with different heterocyclic groups. The methodology employed in this study entails a multi-step synthesis, where readily available starting materials are transformed into complex pyrazoline derivatives through strategic reaction sequences. Incorporating heterocyclic systems not only enhances the structural diversity but also imparts unique chemical and biological properties to these compounds. Various heterocyclic groups, such as furans, thiophenes, and pyridines, are introduced at the 3,5-positions of the pyrazoline ring, yielding a versatile library of compounds. This study highlights the potential applications of these novel compounds in medicinal chemistry and drug discovery, emphasizing their bioactivity against specific targets. Preliminary data suggests that certain derivatives possess promising pharmacological activities, making them potential candidates for further development as therapeutic agents. In summary, this review provides a valuable contribution to the field of organic synthesis, offering a novel and efficient route to synthesize 3,5-disubstituted pyrazolines with heterocyclic systems. Furthermore, the structural activity relationship of the compounds is also discussed. The structural diversity and potential pharmacological properties of these compounds make them valuable candidates for further exploration and development in drug discovery and related areas.

Nickel-Catalyzed Reductive Dicarbofunctionalization of 1,3-Dienes with Aziridines and (Het)Aryl Electrophiles.

A three-component reductive 1,4-dicarbofunctionalization of 1,3-dienes with aziridines and (het)aryl electrophiles was realized. The combination of Ni catalysis with Mn powder as a final reductant enables the direct formation of a Csp2-Csp3 and a Csp3-Csp3 bond at one time. This protocol afforded a convenient approach to the synthesis of β-arylethylamines bearing various functionals and heterocyclic groups. The utility of this reaction was also demonstrated by scale-up preparation, late-stage modification of bioactive molecules, and diverse transformations.

Synthesis of functional derivatives of chlorine-substituted isothiazoles.

Optimal procedures have been developed for the synthesis of substituted isothiazoles containing an active chlorine atom in position 5 of the heterocycle and various functional groups in position 3: carboxyl, hydroxymethyl, aldehyde. Based on these methods, previously undescribed compounds were obtained: 5-morpholino-substituted 3-hydroxymethyl-4- chloroisothiazole, 4-chloroisothiazole-3-carboxylic acid and its methyl ester. The resulting substances are reactive building blocks for organic synthesis of compounds with a high potential for biological activity.

Visible light-driven decarboxylative alkylation of azomethine imines with carboxylic acids

The alkylation of cyclic five-membered azomethine imines with carboxylic acids proceeds under irradiation with 400 nm light using a dual catalytic system consisting of 9-arylacridine and tetrabutylammonium decatungstate. Azomethine imines containing aromatic, heterocyclic and aliphatic groups are suitable for the process providing pyrazolidin-3-ones in 42–98% yields.

Thermal Truncation of Heptamethine Cyanine Dyes.

Cyanine dyes are a class of organic, usually cationic molecules containing two nitrogen centers linked through conjugated polymethine chains. The synthesis and reactivity of cyanine derivatives have been extensively investigated for decades. Unlike the recently described phototruncation process, the thermal truncation (chain shortening) reaction is a phenomenon that has rarely been reported for these important fluorophores. Here, we present a systematic investigation of the truncation of heptamethine cyanines (Cy7) to pentamethine (Cy5) and trimethine (Cy3) cyanines via homogeneous, acid-base-catalyzed nucleophilic exchange reactions. We demonstrate how different substituents at the C3' and C4' positions of the chain and different heterocyclic end groups, the presence of bases, nucleophiles, and oxygen, solvent properties, and temperature affect the truncation process. The mechanism of chain shortening, studied by various analytical and spectroscopic techniques, was verified by extensive ab initio calculation, implying the necessity to model catalytic reactions by highly correlated wave function-based methods. In this study, we provide critical insight into the reactivity of cyanine polyene chains and elucidate the truncation mechanism and methods to mitigate side processes that can occur during the synthesis of cyanine derivatives. In addition, we offer alternative routes to the preparation of symmetrical and unsymmetrical meso-substituted Cy5 derivatives.

Vibrational study of mycophenolic acid and its quantification with electrochemically assisted surface-enhanced Raman spectroscopy

Mycophenolic acid (MPA) is an immunosuppressant widely used in transplantations, for which therapeutic drug monitoring (TDM) has proven beneficial. There is furthermore a need to develop affordable, rapid, and benchtop analytical methods to perform TDM of MPA in a point-of-need setting. In this paper, we report for the first time the Raman fingerprint region and surface-enhanced Raman spectroscopy (SERS) vibrations of MPA through density functional theory calculations. The output of these simulations was compared with experimental data from electrochemically assisted SERS, i.e. application of a well-defined potential or sequence of potentials in SERS assays. The systematic electrochemically assisted SERS experimental study was carried out to understand the adsorption behaviour of MPA on gold nanopillars (AuNPs) when different potentials were applied. We found that MPA interacts with the AuNPs through its benzofuran heterocycle and carboxylic acid group. Applying different potentials on the SERS substrate resulted in band shifts, which we hypothesise to originate from molecular reorientation on the metal surface. Moreover, an electrochemically assisted SERS assay was developed and carried out on a portable Raman spectrometer. We show that MPA detection can be performed in less than 5 min in a clinically relevant concentration range (1 – 50 µM), with improved repeatability compared to a SERS assay without any applied potential (overall RSD decrease from 34.6 % to 18.5 %).

Path of Pyrazoles from Synthetic Factors to Anti-inflammatory Potential: A Review

Pyrazoles, a class of heterocyclic compounds, have garnered considerable attention in drug development due to their intriguing properties, particularly those containing a pyrazole moiety. Pyrazole, a pivotal chemical in the creation of potent bioactive agents, encompasses five heterocyclic members. The discovery of certain pyrazole compounds exhibiting robust biological activities has spurred interest in this field of inquiry. Heterocyclic compounds incorporating nitrogen and its derivatives have historically served as crucial sources of medicinal compounds. Given that the heterocyclic group constitutes a vast reservoir of organic molecules, its significance in both theoretical and applied chemistry has grown significantly. Extensive literature indicates that researchers have employed diverse synthetic strategies in recent years to produce substituted pyrazole derivatives with promising biological potential as anti-HIV, anti-inflammatory, antitumor and antimicrobial agents. Inflammation, a multifaceted biological response essential for the body’s defense mechanisms, can also contribute to various pathological conditions when dysregulated. Understanding the underlying molecular mechanisms offers a foundation for targeted interventions against inflammatory disorders. These insights fuel ongoing endeavors to discover effective and innovative anti-inflammatory agents with potential therapeutic applications. This review delves into the synthesis and characterization of various pyrazole derivatives, emphasizing structural modifications influencing their anti-inflammatory efficacy. The insights provided herein are invaluable for the rational design and synthesis of novel anti-inflammatory agents. Furthermore, the review concludes with a discussion on future perspectives, underscoring the imperative for further research to optimize the therapeutic potential of pyrazole derivatives as anti-inflammatory agents.

Integrated Electrochemical Oxidation and Biodegradation for Remediation of a Neonicotinoid Insecticide Pollutant.

A novel integrated electrochemical oxidation (EO) and bacterial degradation (BD) technique was employed for the remediation of the chloropyridinyl and chlorothiazolyl classes of neonicotinoid (NEO) insecticides in the environment. Imidacloprid (IM), clothianidin (CL), acetamiprid (AC), and thiamethoxam (TH) were chosen as the target NEOs. Pseudomonas oleovorans SA2, identified through 16S rRNA gene analysis, exhibited the potential for BD. In EO, for the selected NEOs, the total percentage of chemical oxygen demand (COD) was noted in a range of 58-69%, respectively. Subsequently, in the biodegradation of EO-treated NEOs (BEO) phase, a higher percentage (80%) of total organic carbon removal was achieved. The optimum concentration of NEOs was found to be 200 ppm (62%) for EO, while for BEO, the COD efficiency was increased up to 79%. Fourier-transform infrared spectroscopy confirms that the heterocyclic group and aromatic ring were degraded in the EO and further utilized by SA2. Gas chromatography-mass spectroscopy indicated up to 96% degradation of IM and other NEOs in BD (BEO) compared to that of EO (73%). New intermediate molecules such as silanediamine, 1,1-dimethyl-n,n'-diphenyl produced during the EO process served as carbon sources for bacterial growth and further mineralized. As a result, BEO enhanced the removal of NEOs with a higher efficiency of COD and a lower consumption of energy. The removal efficiency of the NEOs by the integrated approach was achieved in the order of AC > CL > IM > TH. This synergistic EO and BD approach holds promise for the efficient detoxification of NEOs from polluted environments.

Metabolism-dependent mutagenicity of two structurally similar tobacco-specific nitrosamines (N-nitrosonornicotine and N-nitrosoanabasine) in human cells, partially different CYPs being activating enzymes

N-nitrosonornicotine (NNN) and N-nitrosoanabasine (NAB) are both tobacco-specific nitrosamines bearing two heterocyclic amino groups, NAB bearing an extra -CH2- group (conferring a hexa- rather than penta-membered cycle) but with significantly decreased carcinogenicity. However, their activating enzymes and related mutagenicity remain unclear. In this study, the chemical-CYP interaction was analyzed by molecular docking, thus the binding energies and conformations of NNN for human CYP2A6, 2A13, 2B6, 2E1 and 3A4 appeared appropriate as a substrate, so did NAB for human CYP1B1, 2A6, 2A13 and 2E1. The micronucleus test in human hepatoma (HepG2) cells with each compound (62.5–1000 μM) exposing for 48 h (two-cell cycle) was negative, however, pretreatment with bisphenol AF (0.1–100 nM, CYPs inducer) and ethanol (0.2% v:v, CYP2E1 inducer) potentiated micronucleus formation by both compounds, while CITCO (1 μM, CYP2B6 inducer) selectively potentiated that by NNN. In C3A cells (endogenous CYPs enhanced over HepG2) both compounds induced micronucleus, which was abolished by 1-aminobenzotriazole (60 μM, CYPs inhibitor) while unaffected by 8-methoxypsoralen (1 μM, CYP2A inhibitor). Consistently, NNN and NAB induced micronucleus in V79-derived recombinant cell lines expressing human CYP2B6/2E1 and CYP1B1/2E1, respectively, while negative in those expressing other CYPs. By immunofluorescent assay both compounds selectively induced centromere-free micronucleus in C3A cells. In PIG-A assays in HepG2 cells NNN and NAB were weakly positive and simply negative, respectively; however, in C3A cells both compounds significantly induced gene mutations, NNN being slight more potent. Conclusively, both NNN and NAB are mutagenic and clastogenic, depending on metabolic activation by partially different CYP enzymes.

Preparation and Mechanical Properties of Flexible Prepreg Resin with High Strength and Low Creep.

In this study, aiming at the problem of low strength and high creep caused by medium-low modulus flexible resin based on the formulation design idea of high-molecular-weight epoxy resin (E12)-reinforced flexible epoxy-terminated urethane resin (EUR), a flexible epoxy prepreg resin with high strength and low bending creep was prepared to be suitable for hot melt processing technology. Flexible EUR was synthesized by grafting flexible polyurethane segments onto the epoxy side chain by urethane bonding. By adjusting the ratio of E12 and EUR, the effects of different ratios of the two components on the mechanical properties and viscoelasticity of the resin were systematically studied with dicyandiamide as the latent curing system. Research has found that when the E12 content is between 20%wt and 40%wt, the resin system has the best coating viscosity at 65 °C to 85 °C. The molecular weight and the content of aromatic heterocyclic groups of the resin determine the strength and creep behavior of the resin. When the content of E12 in the system is less than 50%wt, modulus and strength increase linearly, but after more than 50%wt E12 content, the modulus is almost unchanged and the strength begins to decrease. By increasing the content of E12 in the resin, the creep behavior of the resin is greatly reduced. When the content of E12 increases to 50%wt, the bending creep is the lowest.

Elemental Sulfur Promoted Cyclization of Aryl Hydrazones and Aryl Isothiocyanates Yielding 2-Imino-1,3,4-thiadiazoles.

We report a method for using elemental sulfur to facilitate the cyclization of aryl hydrazones and aryl isothiocyanates, affording biorelated 2-imino-1,3,4-thiadiazoles. Reactions progressed in the presence of elemental sulfur, N-methylmorpholine base, and DMSO solvent, while were tolerant of a wide range of functionalities including halogen, nitro, cyano, methylsulfonyl, and heterocyclic groups. The method appears to offer a general pathway for using simple, cheap, and stable reagents to afford triaryl-substituted 2-imino-1,3,4-thiadiazoles under relatively mild conditions.

Synthesis and evaluation of nitrogen-containing derivatives of 3,11-dioxo-olean-12-en-30-oic acid against HIV-1 protease

Thirteen nitrogen-containing derivatives of 3,11-dioxo-olean-12-en-30-oic acid were synthesised by introducing various amino acids and nitrogen-containing heterocyclic groups at the 30-carboxyl group, starting from 18β-glycyrrhetinic acid. Among the 13 derivatives, 10 exhibited inhibitory activity against HIV-1 PR, with IC50 values ranging from 0.19 to 0.94 mM. Notably, derivatives 2, 3 and 5 displayed relatively moderate inhibitory activity, with IC50 values below 0.24 mM. Molecular docking studies provided further insights into the interaction between derivatives (2, 3 and 5) and the active sites of HIV-1 PR. The results revealed favourable hydrophobic-hydrophobic and hydrogen bonding interactions, with docking scores ranging from −6.22 to −7.00 and glide emodel values from −62.9 to −48.6 (kcal/mol). These findings underscore the potential of derivatives 2, 3 and 5 as promising candidates for the development of HIV-1 PR inhibitors.

New Dual Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 and 2 Based on Deoxycholic Acid: Design, Synthesis, Cytotoxicity, and Molecular Modeling.

Deoxycholic acid derivatives containing various heterocyclic functional groups at C-3 on the steroid scaffold were designed and synthesized as promising dual tyrosyl-DNA phosphodiesterase 1 and 2 (TDP1 and TDP2) inhibitors, which are potential targets to potentiate topoisomerase poison antitumor therapy. The methyl esters of DCA derivatives with benzothiazole or benzimidazole moieties at C-3 demonstrated promising inhibitory activity in vitro against TDP1 with IC50 values in the submicromolar range. Furthermore, methyl esters 4d-e, as well as their acid counterparts 3d-e, inhibited the phosphodiesterase activity of both TDP1 and TDP2. The combinations of compounds 3d-e and 4d-e with low-toxic concentrations of antitumor drugs topotecan and etoposide showed significantly greater cytotoxicity than the compounds alone. The docking of the derivatives into the binding sites of TDP1 and TDP2 predicted plausible binding modes of the DCA derivatives.

Ni0-Catalyzed Regioselective [2 + 2 + 2] Cyclotrimerization of 1,3-Diynes: An Expeditious Synthesis of Hexasubstituted Alkynyl Benzenes.

In the present work, we demonstrate a regioselective [2 + 2 + 2] cyclotrimerization of 1,3-diynes catalyzed by Ni0 to provide hexasubstituted benzenes (HSBs). HSBs have significant applications as functional materials and pharmaceuticals. The present protocol exhibited remarkable versatility, transforming 1,3-diynes with diverse alkyl, aryl, and heterocyclic groups to the corresponding HSBs. With the help of control experiments and density functional theory (DFT), the mechanism of the reaction and the origin of regioselectivity were elucidated.

Advancing Pyrrole Synthesis through DDQ Catalysis: A Comprehensive Research Incorporating DFT, ADMT, and Molecular Docking Analysis

AbstractThe construction of pyrroles is an important heterocyclic group comprising many compounds with interesting properties that have led to numerous applications in various fields. We delineate a new synthetic method for the rapid construction of tree‐substituted pyrroles from readily available ketoximes as starting materials and also a new mechanism and method has been proposed. It is presented that substituted pyrroles were efficiently synthesized in high yields (up to 81 % yield) through the cyclization reaction of starting ketoximes mediated by 2,3‐dichlor‐5,6‐dicyanobenzoquinone (DDQ). Utilizing this protocol various pyrrole derivatives were synthesized from diethyl acetylene dicarboxylate (DEAD). We then developed the dehydrogenation reaction mechanism of this formation, also studied in detail, also all synthesized compounds were analyzed in detail by spectroscopic techniques (FT‐IR, 1H NMR, 13CNMR) which were compared with the computational data estimated at B3LYP/6‐311G** level. The thermochemical and electronic properties of the pyrroles were evaluated after optimizing and then confirming the equilibrium structures. ADMT scores were also considered to estimate/elucidate the possible bioavailability tendencies as well as the toxicity. In addition, the interactions of the optimized molecules were evaluated by molecular docking methods against BSA “Bovine Serum Albumin” and LIF “Leukemia Inhibitory Factor”. The results obtained from this study will ideally provide a fundamental source in contemporary drug design in terms of both the key electronic properties underlying the possible reactivity features and toxicity.

Molecular docking screening, dynamics simulations, ADMET, and semi-synthesis prediction of flavones and flavonols from the COCONUT database as potent bifunctional neuraminidase inhibitors

Finding new neuraminidase (N) inhibitors to improve anti-influenza treatment is necessary because of the high mutation rates of N protein. Over 3,000 flavones/flavonols and their synthesized products from the COCONUT database were performed in silico docking screening with N1-H274Y-oseltamivir protein (PDB ID: 3CL0). Several derivatives containing nitrogen heterocyclic groups or aromatic rings showed higher anti-neuraminidase potential than that of laninamivir. Especially, the linker groups between the flavone aglycone and nitrogen heterocyclic group created the interactions with the triad of arginine residues Arg118-Arg292-Arg371, which suggested these compounds could become bifunctional inhibitors against the influenza virus strains at the sialic acid binding site and the adjacent 430-cavity position through triad of arginine residues binding. ADMET indicators and the synthesis design strategy of the most suitable compound, ethyl 4-{2-[(5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy]acetyl}piperazine-1-carboxylate, were also successfully predicted and it could be a concerned candidate for further wet-lab synthesis, in vivo and clinical study.

Schizocommunin analogues and derivatives as G-quadruplex ligands and anticancer agents

G-quadruplexes (GQs) have become valid targets for anticancer efforts in the recent couple of decades due to their extremely multifaceted biological functions. Our goal is to quantify interactions within GQs, as well as their interactions with potential ligands (Ls). As secondary nucleic acid (NA) structures, GQs may be understood as a central channel of stacked G-quartets, interlinked into a G-stem (GS) with nucleotide loops. Computational data on full GQ energetics are, however, increasingly noisy. Therefore, we have chosen to simplify our GQ model by stripping it off all nucleotide residues into a “naked” GQ. The GQ-L stacking model allows computing of intrinsic interaction energies, as well as external ligand stacking affinities with “chemical precision”. To relate computed ligand – G4 affinities to their biological activity, we use published inhibitory activities (IC50 values) of several groups of heterocycles. Some of our results provide a good linear relationship between ligand stacking affinities to GQ, calculated by quantum chemical DFT methods, and corresponding log(IC50) values. Herewith we discuss the obtained results in terms of a mechanism of anticancer activity of heterocyclic ligands via complexation with GQs and thereby control of GQ cell regulatory activity.

Synthesis of 2-benzyl benzoxazoles and benzothiazoles via elemental sulfur promoted cyclization of styrenes with 2-nitrophenols and N,N-dialkyl-3-nitroanilines.

Herein we report a method for affording 2-benzyl benzoxazoles from substituted styrenes and 2-nitrophenols. The success of this method relies on the use of simple reagents, namely elemental sulfur and DABCO. A combination of identical reagents was utilized for the annulation of styrenes with N,N-dialkyl-3-nitroanilines to afford 2-benzyl benzothiazoles. Overall, benzoxazoles and benzothiazoles bearing useful functionalities such as halogens, amines, and heterocyclic groups were isolated in moderate to good yields. Our methods are a rare example of divergent transformations of substituted nitroarenes towards 2-benzyl benzoxazoles and benzothiazoles.

Investigation of the titanium-mediated catalytic enantioselective oxidation of aryl benzyl sulfides containing heterocyclic groups.

Our enantioselective oxidation protocol, based upon hydroperoxides in the presence of a titanium/(S,S)-hydrobenzoin catalyst, was tested for the first time with aryl benzyl sulfides containing heterocyclic moieties (2-thienyl, 2-pyridyl and benzimidazolyl), two of them being connected with the blockbuster omeprazole drug. Good yields of enantiopure sulfoxides were obtained in most cases. Two exceptions of unsatisfactory enantioselectivity in the oxidation of benzimidazolyl sulfides are reported. However, one of them was solved by crystallization of an enantio-enriched mixture. The present work was supported also by X-ray diffraction analysis of some synthesized sulfoxides and by energetic calculation of the crystal structures. The unexpected result is that the crystal structures of the racemic mixture of the two problematic benzimidazolyl sulfoxides are composed of separate enantiomers (a conglomerate), an interesting result that could be exploited in the future for the separation of the enantiomers of these sulfoxides.

Structure-activity relationship study of anti-wear additives in rapeseed oil based on machine learning and logistic regression.

Anti-wear performance is a crucial quality of lubricants, and it is important to conduct research into the structure-activity relationship of anti-wear additives in bio-based lubricants. These lubricants are eco-friendly and energy-efficient. A literature review resulted in the construction of a dataset comprising 779 anti-wear properties of 79 anti-wear additives in rapeseed oil, at various loadings and additive levels. The anti-wear additives were classified into six groups, including phosphoric acid, formate esters, borate esters, thiazoles, triazine derivatives, and thiophene. Logistic regression analysis revealed that the quantity and kind of anti-wear agents had significant effects on the anti-wear properties of rapeseed oil, with phosphoric acid being the most effective and thiophene being the least effective. To identify the specific structural data that affect the anti-wear capabilities of additives in bio-based lubricants of rapeseed oil, a random forest classification model was developed. The results showed a 0.964 accuracy (ACC) and a 0.931 Matthews Correlation Coefficient (MCC) on the test set. The ranking of importance and characterization of MACCS descriptors in the model confirms that anti-wear additives with chemical structures containing P, O, N, S and heterocyclic groups, along with more than two methyl groups, improve the anti-wear performance of rapeseed oil. The application of data analysis and machine learning to investigate the classifications and structural characteristics of anti-wear additives in rapeseed oil provides data references and guiding principles for designing anti-wear additives in bio-based lubricants.