Five-membered Heteroaromatic Rings Research Articles

Review on Pyrazole Hybrids as Anti-microbial Agents

Abstract: A five-membered heteroaromatic ring with two nitrogen atoms, pyrazole, is of immense significance. Pyrazole and its derivatives are well-known nitrogen-containing heterocyclic compounds that are significant in medicinal chemistry and have a variety of biological properties, according to a thorough analysis of this class of heterocyclic lead. This article summarises some biologically active, potent pyrazole hybrids and their structure-activity relationship for antimicrobial activity published by various researchers across the world. It is divided into two sections. The first part summarizes recent developments in pyrazole derivatives for various biological activities, such as anti-Alzheimer’s, antioxidant, anticancer, anti-inflammatory, and antiviral, while the second section focuses on a detailed substitution analysis of pyrazole with its hybrid, which is the structure-activity relationship needed for antimicrobial activity. The presence of pharmacological potential of pyrazole moiety has been demonstrated by the role of a nucleus in pharmacological agents from different therapeutic groups, such as the potent anti-inflammatory agent celecoxib, anti-obesity drug rimonabant, analgesic diphenamizole, H2-receptor agonist betazole, and antidepressant agent fezolamide. The design of new pyrazole derivatives has become an interesting research area due to their versatile nature and biological significance. Moreover, it has been observed that pyrazole in combination with another moiety has a strong potent antimicrobial effect.

Simple π-Conjugated Polymers Based on Bithiazole for Nonfullerene Organic Photovoltaics.

Thiazole, as a family of five-membered heteroaromatic rings, is an interesting building unit that can play a role in coplanarizing the backbone as well as deepening the HOMO energy level, which is beneficial for the design of π-conjugated polymers for the photoactive materials in organic photovoltaics (OPVs). Here, we designed and synthesized π-conjugated polymers with simple chemical structures, which consist of 2,2'-bithiazole or 5,5'-bithiazole and alkylthiophenes as the polymer backbone. In fact, the polymers can be easily synthesized in much fewer steps compared to the typical high-performance polymers based on fused heteroaromatic rings. Interestingly, PTN5 exhibited a markedly higher ordered structure than PTN2. This was likely ascribed to the more coplanar and rigid backbone of PTN5 than that of PTN2 originating in the effectively arranged S···N interaction. As a result, the nonfullerene photovoltaic cell based on PTN5 showed a PCE of 12.2%, which was much higher than the cell based on PTN2 (4.3%) and was high for the polymers consisting of only nonfused rings. These results demonstrate that thiazole-based polymers are promising photoactive materials for OPVs and emphasize the importance of careful molecular design utilizing noncovalent interactions.

Significance of Five-Membered Heterocycles in Human Histone Deacetylase Inhibitors.

Five-membered heteroaromatic rings, in particular, have gained prominence in medicinal chemistry as they offer enhanced metabolic stability, solubility and bioavailability, crucial factors in developing effective drugs. The unique physicochemical properties and biological effects of five-membered heterocycles have positioned them as key structural motifs in numerous clinically effective drugs. Hence, the exploration of five-ring heterocycles remains an important research area in medicinal chemistry, with the aim of discovering new therapeutic agents for various diseases. This review addresses the incorporation of heteroatoms such as nitrogen, oxygen and sulfur into the aromatic ring of these heterocyclic compounds, enhancing their polarity and facilitating both aromatic stacking interactions and the formation of hydrogen bonds. Histone deacetylases are present in numerous multiprotein complexes within the epigenetic machinery and play a central role in various cellular processes. They have emerged as important targets for cancer, neurodegenerative diseases and other therapeutic indications. In histone deacetylase inhibitors (HDACi's), five-ring heterocycles perform various functions as a zinc-binding group, a linker or head group, contributing to binding activity and selective recognition. This review focuses on providing an up-to-date overview of the different five-membered heterocycles utilized in HDACi motifs, highlighting their biological properties. It summarizes relevant publications from the past decade, offering insights into the recent advancements in this field of research.

Molecular transformation of heavy oil during slurry phase hydrocracking process: A comparison between thermal cracking and hydrocracking

To systematically investigate the reaction mechanism of heavy oil in the slurry phase hydrocracking process, comparative experiments of thermal cracking and slurry phase hydrocracking of a residual oil were carried out. The molecular composition of sulfur and nitrogen compounds in the feedstock and their products was comprehensively characterized by gas chromatography and electrospray ionization Orbitrap mass spectrometry. The participation of hydrogen makes the apparent cracking rate in hydrocracking process significantly lower than that in the thermal cracking process, leading to a more controllable cracking degree and higher liquid yield. Nitrogen- and sulfur-containing aromatics with high molecular condensation degree are the key refractory heteroatoms because of large steric hindrance. Aromatics with ring number over 4 have high saturation reactivity, as well as the exposed five-membered heteroaromatic rings. The mutual influence of cracking, aromatic saturation, and hydrodeheteroatom during hydrocracking were also discussed according to bulk properties and molecular composition. The results deepen the understanding of the complex reaction network and mechanism of heavy oil hydrocracking process from both thermal reaction and hydrogenation perspectives, which will be instructive for the catalyst design and the process optimization.

Development of Novel Methodologies for Functionalization of Isoxazoles

Isoxazole is a five-membered heteroaromatic ring that is a highly important framework with widespread applications in pharmaceuticals and agrochemicals. Indeed, the isoxazole ring has desirable pharmacological activity because its two contiguous electronegative heteroatoms (nitrogen and oxygen atoms) contribute to hydrogen bonding with various target enzymes and receptors inaccessible by other ring systems. This unique and significant utility has led to great interest in the synthesis of functionalized isoxazoles, and various synthetic approaches have been developed for this class of compounds. Current synthetic approaches are classified into following four groups: (a) 1,3-dipolar cycloaddition, (b) condensation, (c) cycloisomerization, and (d) direct functionalization. Despite the recent much effort on synthetic researches, however, direct functionalization of isoxazoles (approach d) has still been immature to produce a variety of multifunctionalized isoxazoles. We herein describe our recent studies on direct functionalization of isoxazoles based on the generation of 4-isoxazolyl anion species and the subsequent gold (I)-catalyzed electrophilic aromatic substitution type reactions and rhodium (III)-catalyzed carboxylate-directed C-H activation. These developed functionalization methodologies enabled access to novel isoxazole derivatives that are not readily synthesized by other means. In addition, our interest in photolysis of isoxazoles led us to find photochemical conversion of isoxazoles into 5-hydroxyimidazolines.

Tetrahydroazepines with an annulated five-membered heteroaromatic ring

Tetrahydroazepines with an annulated five-membered heteroaromatic ring

Reactivity of Cross-Conjugated Enynones in Cyclocondensations with Hydrazines: Synthesis of Pyrazoles and Pyrazolines.

The cyclocondensation of cross-conjugated enynones, dienynones, and trienynones (easily available due to low-cost starting compounds) with arylhydrazines leads to the regioselective synthesis of pyrazole derivatives (dihetaryl-substituted ethens, buta-1,3-diens, and hexa-1,3,5-triens) or results in 4,5-dihydro-1H-pyrazoles in good yield. The reaction path is controlled by the character of the substituent in enynone: the pyrazoles are obtained from the reaction of substrates that contain five-membered heteroaromatic substituents with arylhydrazines, and the 4,5-dihydro-1H-pyrazoles are obtained from the reaction of 1,5-diphenylpent-1-en-4-yn-3-one with arylhydrazines consistently. Despite the presence of a substituent, cyclocondensation of 2-hydrazinylpyridine with all of examined cross-conjugated enynones leads to the formation of pyrazoles. The reaction does not require special conditions (temperature, catalyst, inert atmosphere). The cyclocondensation pathways are determined by the electronic effect of an electron-rich five-membered heteroaromatic ring in the substrate. The synthesis allows use of various substituents and functional groups in enynone and hydrazine. The present method features high yields and simplicity of the product purification. The obtained pyrazoles possess fluorescent properties with a quantum yield up to 31%.

Pyrazole (1, 2-diazole) induce apoptosis in lymphoma cells by targeting BCL-2 and BCL-XL genes and mitigate murine solid tumour development by regulating cyclin-D1 and Ki-67 expression

Pyrazole or 1,2-Diazole is a five-membered heteroaromatic ring with two nitrogen atoms which is widely used in pharmacological research and organic synthesis. Several natural and synthetic pyrazole derivatives possess anti-cancer potential and some of them have underwent clinical trials. In this aspect, an investigation into the efficiency of the pyrazole nucleus to inhibit the growth and progression of various cancer cell lines/ experimental tumours would help in giving a better clarity to the anti-cancer behaviour of pyrazole containing drugs. This paper investigates the efficiency of pyrazole against Dalton's Lymphoma Ascites (DLA) cell line. Pyrazole inhibited the growth of DLA cells in vitro by committing them towards apoptosis. In vitro results were consistent in DLA induced murine solid tumour in vivo systems. Drug-treatment improved survival, reduced tumour loads, stabilized body weights and improved the haematological and serum biochemical parameters of DLA solid tumour bearing mice, thereby improving their overall survivability. Drug administration contained the aggravation of solid tumour by targeted downregulation of Cyclin-D1 and Ki-67. In addition, the mRNA expression levels of anti-apoptotic genes, BCL-2 and BCL-XL were downregulated in solid tumours, corroborating the in vitro results that pyrazole encourage apoptotic cell death in DLA cells. The new findings establish pyrazole as a potential anti-cancer drug candidate. The results must encourage future investigations into the efficacy of the drug against various cancer types.

An Overview of the Synthesis and Antimicrobial, Antiprotozoal, and Antitumor Activity of Thiazole and Bisthiazole Derivatives.

Thiazole, a five-membered heteroaromatic ring, is an important scaffold of a large number of synthetic compounds. Its diverse pharmacological activity is reflected in many clinically approved thiazole-containing molecules, with an extensive range of biological activities, such as antibacterial, antifungal, antiviral, antihelmintic, antitumor, and anti-inflammatory effects. Due to its significance in the field of medicinal chemistry, numerous biologically active thiazole and bisthiazole derivatives have been reported in the scientific literature. The current review provides an overview of different methods for the synthesis of thiazole and bisthiazole derivatives and describes various compounds bearing a thiazole and bisthiazole moiety possessing antibacterial, antifungal, antiprotozoal, and antitumor activity, encouraging further research on the discovery of thiazole-containing drugs.

Pyrrole-Containing Semiconducting Materials: Synthesis and Applications in Organic Photovoltaics and Organic Field-Effect Transistors.

Organic semiconducting materials derived from π-electron-rich pyrroles have garnered attention in recent years for the development of organic semiconductors. Although pyrrole is the most electron-rich five-membered heteroaromatic ring, it has found few applications in organic photovoltaics and organic field-effect transistors due to synthetic challenges and instability. However, computational modeling assisted screening processes have indicated that relatively stable materials containing pyrrolic units can be synthesized without compromising their inherent electron-donating properties. In this work, we provide a complete, up-to-date review of pyrrole-containing semiconducting materials used for organic photovoltaics and organic field-effect transistors and highlight recent advances in the synthesis of these materials.

Identification of Novel Resorcinol Amide Derivatives as Potent and Specific Pyruvate Dehydrogenase Kinase (PDHK) Inhibitors.

Pyruvate dehydrogenase kinases (PDHKs) promote abnormal respiration in cancer cells. Studies with novel resorcinol amide derivatives based on VER-246608 (6) led to the identification of 19n and 19t containing five-membered heteroaromatic rings as unique structural features. These substances possess single-digit nanomolar activities against PDHKs. 19t exhibits higher potencies against PDHK1/2/4 than does 6 and inhibits only PDHKs among 366 kinases. Moreover, 19g, 19l, and 19s were found to be isotype-selective PDHK inhibitors. Molecular dynamics simulations provide a better understanding of how the heteroaromatic rings affect the activities of 19n and 19t on PDHK1/2/3/4. Moreover, 19n possesses a much higher antiproliferative activity against cancer cells than does 6. We demonstrated that the results of PDH assays better correlate with cellular activities than do those of PDHK kinase assays. Furthermore, 19n induces apoptosis of cancer cells via mitochondrial dysfunction, suppresses tumorigenesis, and displays a synergistic effect on satraplatin suppression of cancer cell proliferation.

Association of Nucleobases in Hydrated Ionic Liquid from Biased Molecular Dynamics Simulations.

We employed metadynamics-based classical molecular dynamics simulations to methylated adenine-thymine (mA-mT) and guanine-cytosine (mG-mC) base pairs to see favorable conformations in various concentrations of hydrated 1-ethyl, 3-methyl imidazolium acetate. We investigated various stacked and hydrogen-bonded conformations of association of base pairs through appropriately chosen collective variables. Stacked conformations more favored in water for both base pairs, whereas Watson-Crick (WC) hydrogen-bonding conformations are favored in pure and hydrated ionic liquids (ILs) except for 0.75 mol fraction IL. We observe that EMIm cations surround the base pairs in WC conformations creating a kind of hydrophobic cavity and protect the hydrogen bonds between base pairs. However, the five-membered heteroaromatic rings of cations stack with the nucleobases in the cation-base-cation (π-π-π) model, which resembles the base-base-base stacking in a DNA duplex. Interestingly, from additional simulations of 0.5 mol fraction hydrated choline dihydrogen phosphate IL, we observe that the stacked conformations become more favored than the WC conformation due to the absence of π-bonds in cations. The calculated values of relative solubility of base pairs in pure and hydrated ionic liquids compared to those in pure water correlate well with the free energy values of WC and stacked conformations.

Pyrazole: A potent drug candidate with various Pharmacological activities

Aromatic organic heterocycle containing pyrimidine scaffolds. Pyrazole possess, a five-membered hetero aromatic ring with two nitrogen atoms. Presence of this nucleus in these Pyrazole skeletons comprise various ranges of pharmacological activities viz. analgesic, antipyretic, anticancer, antiviral, anti-Inflammatory, antioxidants, antimicrobial, anti-diabetic, anticonvulsant &antiarrhythmic. Pyrazole is a multipurpose lead compound which is developed by chemical architecture for effective molecules which are mostly biologically active. Several synthetic routes are accorded for the development of pyrazole containing reactions to afford a novel molecule.

Heteroatom and solvent effects on molecular properties of formaldehyde and thioformaldehyde symmetrically disubstituted with heterocyclic groups C4H3Y (where Y\xa0=\xa0O\u2013Po)

In this work several molecular properties of symmetrically disubstituted formaldehyde and thioformaldehyde have been studied using a quantum chemistry approach based on density functional theory. Five-membered heteroaromatic rings containing a single group 16 heteroatom were taken into account as the substituents (i.e., furan-2-yl, thiophen-2-yl, selenophen-2-yl, tellurophen-2-yl, and the experimentally as yet unknown polonophen-2-yl). For the resulting ten formaldehyde and thioformaldehyde derivatives, the geometry, energetics, frontier molecular orbitals, dipole moment and polarizability of their molecules were examined in order to establish the effect of ring heteroatom on these properties. Furthermore, these properties were also determined for the molecules in three solvents of low polarity (benzene, chloroform, and dichloromethane) in order to expand our study to include solvent effects. The dipole moment and polarizability of the investigated molecules show regular variations when the ring heteroatom descends through group 16 and the solvent polarity grows. The heteroatom and/or solvent effects on the part of the studied properties are, however, more complex. An attempt is made to rationalize the observed variations in the molecular properties. The conformational behavior of the investigated molecules was also explored and the conformationally weighted values of dipole moment and polarizability are presented.Graphical abstractSome molecular properties of symmetrically disubstituted formaldehyde and thioformaldehyde

D2BIA-flexible, not (explicitly) arbitrary and reference/structurally invariant-a very effective and improved version of the D3BIA aromaticity index.

Although there are a multitude of aromaticity indexes, only a few have a widespread usage. All famous aromaticity indexes are limited: HOMA and FLU are reference-dependent; ELF is π-bond-dependent; PDI is structurally dependent and NICS is ring size dependent. These limitations stimulate the continuous search for better (i.e., having no dependency), more flexible (i.e., applied to any aromatic system) and more effective (i.e., with excellent correlations with other indexes) aromaticity indexes. The D3BIA was our first topological aromaticity index. It is flexible, reference-independent and effective for planar and caged aromatic molecules. However, one of its terms, the degree of degeneracy (δ), is arbitrary and difficult to carry out for new users. Thus, in this work, we show that D2BIA-an improved version of D3BIA-is a good candidate to be used widely, since it retains the strong points of D3BIA while avoiding its weak point. In particular cases where all studied systems have δ=1 (e.g., for acenes), then D2BIA equals D3BIA. For our recent study with acenes, D3BIA (and, as a consequence, D2BIA) has (have) an excellent correlation with FLU according to the MP3 method. In this work, by using DFT calculations for a series involving several six-membered and five-membered heteroaromatic rings, only D2BIA and NICS have very good correlation. All other well known aromaticity indexes used in this work (FLU, HOMA and ELF) gave poor correlations. As to homoaromatic systems, only D2BIA vs NICS and D2BIA vs FLU plots have excellent correlations. HOMA has the worst results in this series. Thus, D2BIA proved to be flexible and effective for the analysis of heteroaromatic rings of different sizes and for caged homoaromatic systems. Moreover, D2BIA has better correlations than D3BIA for planar aromatic systems, and same correlations for caged-homoaromatic systems. Graphical abstract D2BIA-an effective and improved version of the D3BIA aromaticity index.

Tuning Azoheteroarene Photoswitch Performance through Heteroaryl Design.

Photoswitchable compounds, which can be reversibly switched between two isomers by light, continue to attract significant attention for a wide array of applications. Azoheteroarenes represent a relatively new but understudied type of photoswitch, where one of the aryl rings from the conventional azobenzene class has been replaced with a five-membered heteroaromatic ring. Initial studies have suggested the azoheteroarenes-the arylazopyrazoles in particular-to have excellent photoswitching properties (quantitative switching and long Z isomer half-life). Here we present a systematic computational and experimental study to elucidate the origin of the long thermal half-lives and excellent addressability of the arylazopyrazoles, and apply this understanding to determine important structure-property relationships for a wide array of comparable azoheteroaryl photoswitches. We identify compounds with Z isomer half-lives ranging from seconds to hours, to days and to years, and variable absorption characteristics, all through tuning of the heteraromatic ring. Conformation perhaps plays the largest role in determining such properties: the compounds with the longest isomerization half-lives adopt a T-shaped ground state Z isomer conformation and proceed through a T-shaped isomerization pathway, whereas the most complete photoswitching is achieved for compounds that have a twisted (rather than T-shaped) Z isomer conformation. By balancing these factors, we report a new azopyrazole 3pzH, which can be quantitatively switched to its Z isomer (>98%) with 355 nm irradiation, near-quantitatively (97%) switched back to the E isomer with 532 nm irradiation, and has a very long half-life for thermal isomerization (t1/2 = 74 d at 25 °C). Given the large tunability of their properties, the predictive nature of their performance, and the other functional opportunities afforded by usage of a heteroaromatic system, we believe the azoheteroaryl photoswitches to have huge potential in a wide range of optically addressable applications.

Molecular Gyrotops with a Five-Membered Heteroaromatic Ring: Synthesis, Temperature-Dependent Orientation of Dipolar Rotors inside the Crystal, and its Birefringence Change

Three-dimensional arrays of dipolar rotors were constructed as single crystals of molecular gyrotops, which are macrocage molecules with a bridged dipolar rotor. In this study, we synthesized novel molecular gyrotops with a five-membered heteroring, i.e., furan-diyl (1), thiophene-diyl (2), and selenophene-diyl (3), and investigated the temperature-dependent orientation and rotation of the dipolar rotors inside the crystal. Unfortunately, furan derivative 1 did not crystallize; however, crystal structures of the other molecular gyrotops, i.e., 2 and 3, showed three-dimensional arrays of dipolar rotors. Thermal order–disorder transitions of the dipolar rotor orientation inside the crystal were observed in 2 and 3 with the transition temperature in selenophene derivative 3 being lower than that of thiophene derivative 2. This may be ascribed to subtle differences in the molecular structure, e.g., the intersection angle between two Si–C(aryl) bonds corresponding to the rotation axis. In accordance with the t...

Tuning lipase-catalysed kinetic resolution of 2-substituted thiophenes and furans: A scalable chemoenzymatic route to masked γ-bis-oxo-alcohols

The demand for greener and applicable approaches aiming at the synthesis of optically active compounds as single enantiomers has seen a significant growth worldwide. Since most of the chemically synthesized compounds are produced as racemates their kinetic resolution has been of great interest. For this purpose a number of chemo-enzymatic approaches were proposed. One of such approaches, the use of isolated lipases, is a well-established alternative. Herein we report the kinetic resolutions of 2-Substituted five-membered heteroaromatic rings. By optimizing the reaction conditions it was possible to produce (2-hydroxy)-2-substituted furans and thiophenes in high enantiomeric ratio (E>200). Thus, racemic mixtures of compounds with slight structural differences were resolved. The current chemo-enzymatic strategy has been applied to a scalable approach leading to the formation of the enantiopure (S)-2i a well-known building block used for the synthesis of bioactive natural compounds.

ChemInform Abstract: C—H Bond Transformations Leading to the Synthesis of Organic Functional Materials

AbstractReview: [118 refs.

The supramolecular effect of aromaticity on the crystal packing of furan/thiophene carboxamide compounds

N-2-pyrazinyl-2-furancarboxamide (I) and N-2-pyrazinyl-2-thiophenecarboxamide (II) are compounds containing different five-membered heteroaromatic rings, furan and thiophene, respectively. They were designed and synthesized to examine the effect of an increase in aromaticity from furan to thiophene on the crystal packing. In order to explore the various features of the crystal packing motifs in more detail, single crystal X-ray diffraction, Hirshfeld surface analysis and theoretical calculations were carried out on the two compounds. The results clearly show that the heteroatom substitution of O to S in five-membered rings led to an increase in the effectiveness of π-based interactions in II, whereas hydrogen bond interactions play a more important role in the stabilization of the supramolecular architecture of I.