Heteroaromatic Derivatives Research Articles

A Review on Functionalization of Benzo-5,6-Fused Bicyclic Heteroaromatic Compounds.

Over the decades, functionalized heteroaromatic compounds and their scaffolds have drawn significant attention in synthetic organic chemistry as well as in interdisciplinary sciences due to their prevalence in natural products, hormones, vitamins, and their applications in pharmaceuticals, agrochemicals, veterinary products, dyes and pigments, bio-imaging, semiconductors, and optoelectronics, etc. This review explores various synthetic strategies for functionalization of numerous 5,6 benzo-fused heteroaromatic derivatives such as indole, benzofuran, benzothiophene, benzimidazole, benzoxazole, benzothiazole and benzotriazole through various methods including C-H activation, cross-coupling, metal catalysis, photo-catalysis, electrocatalysis and organocatalysis in recent years (2019-2023). Highly functionalized heterocyclic scaffolds are the important precursors for synthesizing many bioactive drugs like fenbendazole, viozan, griseofulvin, zileuton, flunoxaprofen, natural products, and optoelectronic materials, etc.

Imidazo[4,5-b]Pyridines: From Kinase Inhibitors to more Diversified Biological Properties.

Imidazo[4,5-b</i>]pyridines are amongst the oldest known heteroaromatic derivatives. Their structural similarity with purine basis has however aroused the curiosity of biologists and resulted in the developments of innovative bioactive compounds. This review thus firstly describes the main synthetic ways currently used to produce imidazo[ 4,5-b</i>]pyridine derivatives, and secondly gives examples of their potential, especially focusing on protein inhibition abilities, thus opening the way to applications as anti-cancer or antimicrobial agents.

Synthesis and Antidepressant Evaluation of Heteroaromatic derivatives of Gallic Acid

Oxidative stress is a causative factor of depression and several studies have reported that gallic acid or the derivatives thereof had proven to be effective in displaying antidepressant like action in animal models. Owing to the antioxidant property of GA and the study of structural features it was hypothesized to design new small molecule antidepressant drugs based on GA containing piperazine/piperidine. The two step reaction involved the formation of acid chloride of GA and its conversion to the target compounds in presence of acetone. All the compounds were subjected to evaluation of antidepressant effect using the widely used TST and FST models in mice at dose of 40mg/kg intraperitoneally. The synthesized compounds 2b, 2c and 2e were able to reduce the immobility time in both the models as comparable to the reference compound fluoxetine (10mg/kg) while compounds 2a and 2d were not very significant in reducing the immobility of mice.

Reactions of 5-(Trialkyl)silylpent-1-en-4-yn-3-ones with Hydrazines: Original Synthetic Routes to Luminescent Substances Containing Azole Motifs

AbstractOn the basis of the selective reactions of hydrazines with trialkylsilyl-substituted cross-conjugated enynones (pent-1-en-4-yn-3-ones) as fundamental building blocks, this work presents the developed common methodology for the synthesis of polysubstituted luminescent derivatives of acetylenic pyrazolines, pyrazoles, and combined polyheterocycles containing structural fragments from pyrazolines, isoxazoles, thiophenes, thiazoles, benzo[d]thiazoles, and benzo[d]imidazoles. In reactions with hydrazine and its monosubstituted aromatic and heteroaromatic derivatives, the mentioned pent-1-en-4-yn-3-ones, containing Me3Si, Et3Si, and t-BuMe2Si groups at the triple bond, give 3-(trialkylsilyl)ethynylpyrazolines. Following stages of desilylation and 1,3-dipolar cycloaddition with nitrile oxides, the 3-(trialkylsilyl)ethynylpyrazolines provide the formation of combined polyheterocyclic derivatives. Thus, a one-pot synthetic route to pyrazoline-containing isoxazoles from cross-conjugated enynones, arylhydrazines, and α-chlorobenzaldoximes has been developed. Some aspects of cyclocondensation mechanism and luminescent properties of synthesized azoles derivatives were examined.

Heteroaromatic Diazirines Are Essential Building Blocks for Material and Medicinal Chemistry.

In materials (polymer) science and medicinal chemistry, heteroaromatic derivatives play the role of the central skeleton in development of novel devices and discovery of new drugs. On the other hand, (3-trifluoromethyl)phenyldiazirine (TPD) is a crucial chemical method for understanding biological processes such as ligand-receptor, nucleic acid-protein, lipid-protein, and protein-protein interactions. In particular, use of TPD has increased in recent materials science to create novel electric and polymer devices with comparative ease and reduced costs. Therefore, a combination of heteroaromatics and (3-trifluoromethyl)diazirine is a promising option for creating better materials and elucidating the unknown mechanisms of action of bioactive heteroaromatic compounds. In this review, a comprehensive synthesis of (3-trifluoromethyl)diazirine-substituted heteroaromatics is described.

Iron-Catalyzed Cross-Electrophile Coupling of Inert C–O Bonds with Alkyl Bromides

Iron-Catalyzed Cross-Electrophile Coupling of Inert C–O Bonds with Alkyl Bromides

Design, synthesis, and biological evaluation of trizole-based heteroaromatic derivatives as Bcr-Abl kinase inhibitors

Bcr-Abl is a key driver in the pathophysiology of CML. Broadening the chemical diversity of Bcr-Abl kinase inhibitors to overcome drug resistance is a current medical demand for CML treatment. As a continuation to our research, a series of compounds with heteroaromatics-trizole scaffold as hinge binding moiety (HBM) were developed as Bcr-Abl inhibitors based on in silico modeling analysis. Biological results indicated that these compounds exhibited a significantly enhanced inhibition against Bcr-AblWT and Bcr-AblT315I in kinases assays, along with improved anti-proliferative activities in leukemia cell assays, compared with previous disclosed compounds. In particular, compounds 9f, 28c, 31, and 44c displayed comparable even better potency with that of Imatinib in enzymatic assay and cell assays including K562 cells and adriamycin-resistant K562/A cells. Moreover, compounds 9f, 28c, and 44c exhibited potent inhibition activities against K562R cells bearing T315I mutant with IC50 of 13.35 μM, 40.14 μM, and 1.91 μM, respectively, outperforming that of Imatinib. Meanwhile, the inhibition of Bcr-Abl activity in Ba/F3 cells demonstrated that these compounds exerted effects mainly by acting on Bcr-Abl. Additionally, compounds 9f, 28c, and 44c effectively induced apoptosis, arrest the cell cycle at S or G2/M phase, and inhibited phosphorylation of Bcr-Abl and STAT5 in a dose-dependent manner. Docking studies indicated that trizole indeed retained the hydrophobic interaction of aromatic heterocycles with hinge region, and ADME prediction suggested that tested compounds had a favorable safety profile. Therefore, aromatic heterocycles incorporated with trizole could serve as a promising HBM for Bcr-Abl inhibitors with proline as fexibile linker, and compounds 9f, 28c, especially 44c could be served as a starting point for further optimization.

Synthesis and Opto-electronic features of 5,5′-bis(3,4-(ethylenedioxy)thien-2-yl)-2,2′-bipyridine

Fluorescent compounds are fascinating appreciable attention in various display devices such as solid state lighting, flat panel displays. 2,2′-Bipyridine (bpy), a non-fluorescent compound is frequently used as ancillary unit in the metal complexes. This paper reflects the synthesis of fluorescent derivatives of 2,2′-bipyridine. These organic heteroaromatic derivatives have found numerous applications in electroluminescent devices. The main intention of this paper is to synthesize and characterize the neutral chelating ligands. The compounds were analyzed by various spectroscopic techniques. Photophysical properties of the compounds were identified with the help of photoluminescence spectra. Electrochemical behavior of the compounds was studied by recording I-V curves from cyclic voltammetry. Computational quantum calculations using Avogadro interface were also done in order to attain the molecular mechanics and their electronic energy. Optical band gap data clearly indicated the good kinetic stability and chemical inertness of the compounds.

Heteroaryl-Ethylenes as New Lead Compounds in the Fight against High Priority Bacterial Strains.

The widespread use of antibiotics has led to a gradual increase in drug-resistant bacterial infections, which severely weakens the clinical efficacy of antibacterial therapies. In recent decades, stilbenes aroused great interest because of their high bioavailability, as well as their manifold biological activity. Our research efforts are focused on synthetic heteroaromatic stilbene derivatives as they represent a potentially new type of antibiotic with a wide antibacterial spectrum. Herein, a preliminary molecular modeling study and a versatile synthetic scheme allowed us to define eight heteroaromatic stilbene derivatives with potential antimicrobial activity. In order to evaluate our compound’s activity spectrum and antibacterial ability, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) tests have been performed on Gram-positive and Gram-negative ATCC strains. Compounds PB4, PB5, PB7, and PB8 showed the best values in terms of MIC and were also evaluated for MBC, which was found to be greater than MIC, confirming a bacteriostatic activity. For all compounds, we evaluated toxicity on colon-rectal adenocarcinoma cells tumor cells (CaCo2), once it was established that the whole selected set was more active than 5-Fluorouracil in reducing CaCo-2 cells viability. To the best of our knowledge, the biological assays have shown for these derivatives an excellent bacteriostatic activity, compared to similar molecular structures previously reported, thus paving the way for a new class of antibiotic compounds.

Vinylogous hydrazone strategy for the organocatalytic alkylation of heteroaromatic derivatives.

A new umpolung approach for the asymmetric Friedel-Crafts-type alkylation of electron-poor heteroaromatic systems has been developed. It is based on the vinylogous reactivity of hydrazones derived from heteroaromatic aldehydes. The donating effect of the hydrazone moiety can be efficiently transferred over the heteroaromatic system activating it towards an asymmetric Friedel-Crafts reaction with α,β-unsaturated aldehydes realized under aminocatalytic conditions. Excellent enantioselectivities have been obtained owing to the application of a MacMillan imidazolidinone catalyst. Unmasking of the hydrazone moiety has also been realized resulting in the development of a unique strategy for the asymmetric functionalization of electron-poor heteroaromatic systems.

Richard Dickinson Chambers. 16 March 1935—18 April 2019

Richard (Dick) Chambers was one of the most creative and distinguished organofluorine chemists of his generation. He synthesized a range of perfluorinated heteroaromatic systems, including pentafluoropyridine and tetrafluoropyrimidine, by halogen exchange processes, and established their chemistry and associated reaction mechanisms. Notably, ‘mirror image’ negative Friedel–Crafts reactions led to perfluoroalkyl heteroaromatic derivatives that could be transformed into unusual valence bond isomers by irradiation. New ranges of stable, observable perfluorinated carbanions, alkenes and dienes were synthesized and their fundamental chemistry established. Dick was an excellent experimental scientist whose career was marked by his unique skill-set in being able to perform reactions at high pressure under vacuum, using γ-ray irradiation, photochemistry, continuous flow processes and a variety of fluorinating reagents. His research into the use of elemental fluorine gas, which established the key role of solvent in reaction control, established fluorine as a viable reagent for organic synthesis. Several of his new synthetic processes, including syntheses of perfluorocarbon iodides, highly fluorinated heteroaromatic derivatives and α-fluoro-β-ketoester systems, were adopted for scale-up by industry. But Dick was more than a talented and innovative scientist. He was also an outgoing and fun-loving man, who always made time to offer support, guidance and advice to all his colleagues, research group members and scores of scientific friends within the fluorine science community around the world. As a result, he forged strong personal bonds throughout his life and a legacy that has lasted through generations of chemists.

Golden Age of Fluorenylidene Phosphaalkenes-Synthesis, Structures, and Optical Properties of Heteroaromatic Derivatives and Their Gold Complexes.

The substitution of 2,7-dibromo-9-fluorenyl phosphaalkenes with heteroaromatic substituents (bithiophene, benzothiophene, pyridine) offers access to interesting push–pull dye molecules. Steric shielding due to the bulky P-substituent gives marked different reactivities at the 2- and 7-positions, allowing the synthesis of mixed/asymmetric derivatives. Further functionalization via gold(I) coordination was demonstrated and increased the acceptor character, concomitant with a red-shifted absorption.

3D Coumarin Systems Based on [2.2]Paracyclophane: Synthesis, Spectroscopic Characterization, and Chiroptical Properties.

In this article, we report the preparation of a series of [2.2]paracyclophane-fused coumarin systems through a simple and general procedure involving a transition-metal-catalyzed cyclization of aryl alkynoates as the key step. We also highlight the influence of the [2.2]paracyclophane (pCp) motif and its "phane" interactions on the spectroscopic properties of the newly synthesized fluorophores, which emit in the blue-green region of the visible spectrum (λem up to 560 nm) and show extremely large Stokes shifts (up to 230 nm). Finally, we demonstrate that our straightforward approach can easily be used to access optically active planar chiral 3D coumarins. Compared to previously described fluorescent paracyclophanes and other organic dyes, our compact heteroaromatic derivatives show promising chiroptical properties, both in term of circular dichroism ( gabs ∼ 8 × 10 -3) and circularly polarized luminescence ( glum ∼ 5 × 10 -3), thus demonstrating a practical application of our synthetic method.

Влияние новых производных гетероциклических соединений на физическую работоспособность в экстремальных температурных условиях

The experiments on mice revealed that 2 of 4 new heteroaromatic derivatives and organic acid tested- LHT-4-97 and LHT-1-13 - were capable to improve the physical efficiency of animals in swimming test in a pool under conditions of hyper- and hypothermia. LHT-4-97 in a dosage of 10 mg / kg and LHT-1-13 in a dosage of 1 mg / kg increased the duration of swimming by 25% and 23%, respectively under conditions of immersion hyperthermia, and under conditions of immersion cooling - 25% and 16 %, respectively. At the same time they do not yeald in actoprotective action to the compared drug- Ladasten, which manifests its activity in dosage of 50 and 100 mg/kg.

Synthesis and anticancer activity of benzoselenophene and heteroaromatic derivatives of 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI).

The current study reports the synthesis of different derivatives of benzoselenophene analogs as well as a diverse series of compounds (14a-p, 15 and 16) from 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI) and benzoselenophene or heteroaromatic acids. The overall yield of scaffold 12 was improved by an one-pot reaction, which helps in large-scale synthesis of CBI, a duocarmycin alkylation subunit analog. The series of compounds were evaluated for their cytotoxicity against SK-OV3 ovarian cancer cell lines, which revealed that benzoselenophene can enhance or maintain the anticancer activity of the duocarmycin analog upon replacing the indole moiety. CBI-benzoselenophenes with N-amido substituents at the C-5 position, 14g, 14f and 16 (IC50 = 0.5, 1.2 and 1.6 nM, respectively), were found to be more potent than the CBI-TMI and other benzoselenophene analogs. The CBI-benzoselenophene analogs, 14f and 14g (containing N-acetamido and N-butyramido substituents, respectively), were found to be 8 and 120 times more potent than the corresponding indole analogs of CBI, 14q and 14r, respectively.

Heteroaromatic Pim Kinase Inhibitors Containing a Pyrazole Moiety.

This review, of the literature published between 2010 and 2015 reports that molecules containing a non-fused and/or fused pyrazole moiety could exhibit very potent activity toward Pim kinases, including the inhibition of cellular Bad phosphorylation as well as antiproliferative activity against various cancer cells. Even if Pim kinase inhibitors currently in clinical trial do not exhibit a pyrazole moiety, heteroaromatic kinase inhibitors containing an indazole part such as Axitinib and Pazopanib already reached the market. Therefore, one can imagine that in the future, heteroaromatic derivatives inhibiting Pim kinases including pyrazoles could be identified and used for their diagnostic and/or therapeutic potential alone or in combination with other drugs for the diseases in which Pim kinases are involved.

Synthetic studies of five-membered heteroaromatic derivatives as potassium-competitive acid blockers (P-CABs).

On the basis of a series of novel and potent potassium-competitive acid blockers represented by 1-sulfonylpyrrole derivative 7, we prepared several five-membered heterocyclic analogues (8) and evaluated their H(+),K(+)-ATPase activities in vitro. We also assessed the role of the methylaminomethyl side chain by comparison with methylamino and ethylamino derivatives. We observed that the five-membered core ring and its orientation affect inhibitory activity and that the methylaminomethyl moiety is the best side chain. On the basis of potency and ligand-lipophilicity efficiency, compound 7 remains the most drug-like of the compounds studied to date. This study revealed the factors necessary for potent H(+),K(+)-ATPase inhibition, such as differences in electron density, the properties of the lone pair at each apical position of the heteroaromatic ring, and the geometry of the substituents.

ChemInform Abstract: A General Synthesis of Diversely Substituted Indazoles and Hetero‐Aromatic Derivatives from O‐Halo‐(het)arylaldehydes or ‐phenones.

Abstract A set of variously substituted indazoles and hetero-aromatic derivatives were synthesized from o -halo-(het)arylaldehydes using a palladium catalyzed amination followed by cyclization. Starting from phenones, this process was extended to give 3-substituted indazoles. Moreover, N -1-substituted-indazoles can be reached by this strategy using an optional selective N-1-alkylation step during the process. This methodology offers a general and easy route for the synthesis of regioselectively substituted indazoles.

Iron-catalyzed C-H borylation of arenes.

Well-defined iron bis(diphosphine) complexes are active catalysts for the dehydrogenative C-H borylation of aromatic and heteroaromatic derivatives with pinacolborane. The corresponding borylated compounds were isolated in moderate to good yields (25-73%) with a 5 mol% catalyst loading under UV irradiation (350 nm) at room temperature. Stoichiometric reactivity studies and isolation of an original trans-hydrido(boryl)iron complex, Fe(H)(Bpin)(dmpe)2, allowed us to propose a mechanism showing the role of some key catalytic species.

A general synthesis of diversely substituted indazoles and hetero-aromatic derivatives from o-halo-(het)arylaldehydes or -phenones

A set of variously substituted indazoles and hetero-aromatic derivatives were synthesized from o-halo-(het)arylaldehydes using a palladium catalyzed amination followed by cyclization. Starting from phenones, this process was extended to give 3-substituted indazoles. Moreover, N-1-substituted-indazoles can be reached by this strategy using an optional selective N-1-alkylation step during the process. This methodology offers a general and easy route for the synthesis of regioselectively substituted indazoles.