Heterocyclic Systems Research Articles

Phospholanes via Twofold C‐H‐Addition to Phospholes

AbstractA synthetic route towards phospholanes via twofold C−H‐addition of a DMSO molecule to β‐H substituted phospholes is described. The resulting fused phospholane oxothiolane system in case of symmetric α‐substitution possesses four stereogenic centers or rather six in case of asymmetric α‐substitution. The reaction conditions are shown to be applicable for a variety of phospholes with different P‐ or α‐substituents always leading to stereoselective formation of the fused heterocyclic ring system. All phospholane derivatives with one exception are sufficiently air stable for purification with column chromatography and are fully characterized by NMR and elemental analysis and mass spectrometry. With the help of X‐ray crystallography, the different configurations of the isomers could be demonstrated. For one model system derivatization reactions are presented. When oxidizing or reducing the sulfoxide group only a single diastereomer is observed.

Тионирование 4-((4-оксо-4H-хромен-3-ил) метилен)-2-фенилоксазол-5(4H)-она с применением реагента LAWESSON’S

Analysis of periodicals has showed that there is no information on the behavior of hybrid heterocyclic systems containing several pharmacophore fragments based on oxazol-5(4H)-ones and chromen-4(4H)-ones in reactions with thionizing reagents under various conditions. The interaction of 4-((4-oxo-4H-chromen-3-yl)methylene)-2-phenyloxazol-5(4H)-one with Lawesson’s reagent (LR) (2,4-bis-[pmethoxyphenyl]) has been studied for the first time – 1,3- dithiaphosphetane-2,4-disulfide) under conditions of thermal activation of the reaction mixture and the use of a closed reactor in the environment of non-polar solvents. Lawesson’s reagent is used as a mild thioniation agent. The scheme of the interaction has been discussed. Initially, it is assumed that the Lawesson reagent (LR) molecule dissociates into the particles of ylide structure, then the interaction with the carbonyl group of the chromen-4-one fragment of the initial substrate takes place, resulting in the formation of a spirocyclic intermediate, the subsequent decomposition of which produces the final product. It has been established that the use of a closed reactor makes it possible to reduce the transformation time and achieve an increase in the yield of the target product compared to the conventional type of activation of the reaction mixture. It has been shown that under the chosen conditions the transformation proceeds with the preservation of the oxazol-5(4H)-one ring. The composition and structure of the resulting compound have been established on the basis of complex data from elemental analysis, IR and NMR spectroscopy.

One-pot multicomponent reaction: An efficient synthesis of 4-(HET)Aryl-substituted pyrazolo-quinolinones.

Pyrazolo-quinolinones (PQs) are a versatile class of Organic chemistry and it was found that they have very advanced functionally promising as selective compounds due to their scaffold and demonstrated low toxicity and considerable clinical promise. Moreover, these compounds have an important role in different applications such as analytical reagents, technical, pharmaceutical development, and biological markers. So, we aimed to synthesize and characterize new 4-(Het)aryl-substituted Pyrazole-quinolinones. Synthesis of One-Pot Multicomponent Reaction was carried out with the reaction of 5-amino-3-methyl-1H-pyrazole 1a, and 5-amino-3-phenyl-1H-pyrazole 1b and dimedone 2 with some (het)aryl aldehydes 3 using ethanol. Characterizations such as the linear structures and the regiospecificity of the reactions were determined by using NMR, GC-MS, IR, and UV measurements. This research will be very useful for all methods and procedures using multi-one-point reactions which are very popular in the synthesis of heterocyclic systems for pyrazole- quinoline skeleton synthesis.

One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline.

A new method for the synthesis of heterocyclic systems containing tetrazole and tetrahydroisoquinoline is developed via the performance of one-pot Ugi-azide and Heck cyclization reactions. The integration of the multicomponent and post-condensation reactions in one-pot maximizes the pot-, atom-, and step-economy (PASE).

Advances in the Synthesis of Sulfur-Containing Cyclic Architectures via Insertion of SO2

AbstractSulfur-containing heterocycles, where the S(R) moiety is located within the cyclic structure, have found tremendous applications in the fields of chemical, pharmaceutical, and materials sciences due to their unique chemical, biological and pharmaceutical activities. Recent years have witnessed increasing interest in sulfur-containing heterocycles, and new methods for their synthesis have been reported by adopting modern methodologies and technologies through insertion of sulfur dioxide. The main objective of this Account is to overview the latest major developments on the synthesis of sulfur-containing heterocyclic systems, mainly covering thermo-, photo- and electron-induced cyclization through the insertion of sulfur dioxide (SO2). We aim to provide the readership with a comprehensive understanding of this topic and offer a positive outlook on the promising future of this field.1 Introduction2 Thermal-Induced Cyclization3 Photoinduced Radical Cyclization4 Electron-Induced Radical Cyclization5 Conclusion

Asymmetric Tandem Michael Addition/Interrupted Nef Reactions of Nitromethane with Oxindole-Derived Alkenes: Enantioselective Synthesis of Spiro-polycyclic Oxindoles.

Chiral spiro-polycyclic oxindoles are valuable heterocyclic ring systems that are widely distributed in natural alkaloids and biologically active compounds. Herein, we reported an asymmetric tandem Michael addition/interrupted Nef reaction of nitromethane with oxindole-derived alkenes catalyzed by a chiral 2-aminobenzimidazole bifunctional organocatalyst. A series of novel enantiomerically enriched spiro-polycyclic oxindole derivatives bearing an oxime group were synthesized in moderate to excellent isolated yields (up to 99%) with an excellent level of enantioselectivities (up to 99% ee). Furthermore, the antiproliferation activity of the resulting oxindoles derivatives were evaluated, and compound 2d demonstrated promising anticancer properties against HCT116 (IC50 = 14.08 μM) and HT29 (IC50 = 15.46 μM) cell lines.

Butadienyl Ketene: An Unexplored Intermediate in Organic Synthesis

AbstractButadienyl ketene is a useful intermediate because of its role as a 2p-component in cycloaddition reactions with a variety of substrates such as simple or conjugated imines and dienes. This review article summarizes recent reports on the generation of butadienyl ketene in situ and their cycloaddition reactions to afford heterocyclic systems. The chemistry of butadienyl ketene is explored with a focus on its [2+2] and [4+2] cycloaddition reactions with a variety of imines and azadiene derivatives such as 1,3-diazabuta-1,3-dienes, for the synthesis of four- and six-membered heterocycles, respectively.

Synthesis and Biological Activities of Heterocyclic Hybrids Containing Piperidine and Pyridine Moieties: Recent Developments

Abstract: Piperidine and pyridine nuclei are essential heterocyclic systems and act as an essential underpinning for agriculture, medicines, industries, etc. The development of novel methods for the synthesis of these exemplary heterocyclic compounds and their respective hybrids, which show a wide range of biological activities, is a very fascinating theme. The derivatives of these pervasive nuclei are used as antibacterial, antimicrobial, antifungal, antimalarial, anticancer, antiproliferative, antihypertensive, antiparasitic, and many other agents. The hybrids of these nuclei have retained a distinct position in medicinal chemistry and are often incorporated in synthetic drug discovery. In this review, we have compiled relevant literature on different derivatives of piperidine and pyridine moieties and their biological activities.

Elaboration and electrochemical characterization of new fused heterocyclic systems as organic electrodes

Elaboration and electrochemical characterization of new fused heterocyclic systems as organic electrodes

Regioselective Rearrangement of Nitrogen- and Carbon-Centered Radical Intermediates in the Hofmann-Löffler-Freytag Reaction.

The Hofmann-Löffler-Freytag (HLF) reaction serves as a late-stage functionalization technique for generating pyrrolidine heterocyclic ring systems. Contemporary HLF protocols utilize in situ halogenated sulfonamides as precursors in the radical-mediated rearrangement cycle. Despite its well-established reaction mechanism, experiments toward the detection of radical intermediates using EPR techniques have only recently been attempted. However, the obtained spectra lack the distinct features of the N-centered radicals expected for the employed reactants. This paper presents phenylbutylnitrone spin-trapped C-centered and N-centered radicals, generated via light irradiation from N-halogen-tosyl-sulfonamide derivatives and detected using EPR spectroscopy. NMR spectroscopy and DFT calculations are used to explain the observed regioselectivity of the HLF reaction.

Some pyrroles as inhibitors of the pentose phosphate pathways enzymes: An in vitro and molecular docking study.

Glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) are pentose phosphate pathway enzymes. Compounds with a heterocyclic pyrrole ring system containing this atom can be derivatized with various functional groups into highly effective bioactive agents. In this study, pyrrole derivatives on these enzyme's activity were investigated. The IC50 values of different concentrations of pyrrole derivatives for G6PD were found in the range of 0.022-0.221 mM Ki values 0.021 ± 0.003-0.177 ± 0.021 and for 6PGD IC50 values 0.020-0.147, mM Ki values 0.013 ± 0.002-0.113 ± 0.030 mM. The 2-acetyl-1-methylpyrrole (1g) showed the best inhibition value for G6PD and 6PGD enzymes. In addition, in silico molecular docking experiments were performed to elucidate how these pyrrole derivatives (1a-g) interact with the binding sites of the target enzymes. The study's findings on pyrrole derivatives could be used to create innovative therapeutics that could be a treatment for many diseases, especially cancer manifestations.

Imidazo[1,2‐α] azine's esters increase selectivity and anti‐inflammatory activity in microglial cells

AbstractChronic neuroinflammation is crucial in many neurodegenerative diseases, including AD. Neuroinflammation activates microglia, the CNS's central effector cells, and immune cells. Toxins and neuroinflammatory reactions can kill or damage neurons, activating microglial cells. Inflammatory mediators from activated microglia can kill neurons like cytokines, chemokines, reactive oxygen species, and reactive nitrogen species. Imidazo[1,2‐α]azines with different acid groups in position two of the heterocycle system were synthesized and tested as anti‐inflammatory and cell immunomodulators. We measured the ability of human neuroblastoma (SHSY‐5Y) and microglial (HMC3) cell lines to decrease PGE2 production under pro‐inflammatory conditions. All derivatives reduced PGE2 production. Inhibitory profiles indicate that compounds 8a and 8b are more effective and potent than 9a and 9b, indicating a steric effect of carboxyphenyl on imidazo[1,2‐α]azines, reducing their potency. However, imidazo[1,2α]pyrimidines (8b and 9b) with nitrogen at position 8 were less effective than those observed by other groups (8a, 9a, and 10a). imidazo[1,2‐α]pyrimidines are more polar due to nitrogen at position 8. The synthetically derivative imidazo[1,2‐α]pyridines decreased PGE2 formation in vitro on neural cells, microglia (HMC3), and neuroblastoma (SH‐SY5Y) cells, proving that they are more effective than imidazo[1,2‐α]pyrimidines. Two product esters selectively reduced HMC3 microglial cell PGE2 production. This finding may help develop neurodegenerative disease anti‐inflammatories.

Double Mannich reaction with ketones as a route to heterocyclic systems: A mini review

AbstractDouble Mannich reaction with ketones is of continuing interest, particularly, in the synthesis of aza‐ and diaza‐heterocycles, alkaloids, and medicinally relevant compounds. The present review deals with the most important literature on the utility of double Mannich reaction in the synthesis and modification of heterocyclic systems.

Gold-catalyzed synthesis of small-sized carbo- and heterocyclic compounds: A review

Abstract Research on gold catalysis has flourished over the last 20 years, and gold catalysts are now acknowledged as the “best choice” for a range of organic transformations. Gold complexes have emerged as promising candidates for this use in recent years because of their high reactivity, which enables them to induce a broad range of transformations under mild conditions. Extensive demonstrations have showcased the extraordinary efficiency of synthesizing complex organic compounds from the basic starting components. In addition to its traditional applications in catalysis, gold catalysis has expanded to include the total synthesis of natural compounds, which is a complex and demanding undertaking. The class of molecules known as carbo- and heterocycles, which is arguably the most important, has a significant impact on the synthesis of agrochemicals and pharmaceuticals among the numerous additional products made possible by the novel procedures pioneered. The main topic of this review is how to use Au salts in homogeneous catalysis to create cyclization processes for small heterocyclic and carbocyclic systems. This study gives an overview of most of the books and articles written after 2013 that discuss making three- and four-membered carbo- and heterocyclic rings with gold as a catalyst. We have made every effort to include all outstanding reports on this subject; nonetheless, we apologize for any omissions.

Multicomponent reactions of cyanoacetanilide derivatives: Synthesis of coumarin and quinoline derivative and evaluations of their cytotoxicity

In this study, several fused heterocyclic systems involving tetrahydrobenzopyrans 7a-i and tetrahydrobenzopyridines 9a-i were synthesized. The reactions proceed via a multicomponent reaction of different aromatic aldehydes, cyanoacetanilide derivatives, and cyclohexane-1,3-dione. All the produced compounds were tested for their anticancer activity by using six cancer cell lines such as A549, HT-29, MKN-45, U87MG, SMMC-7721 and H460 utilizing foretinib as the positive control and the standard MTT assay in vitro. The results indicated that many synthesized derivatives were the most potent towards all the cancer cell lines used, six compounds 7e, 7f, 9b, 9d, 9e, and 9g showed the highest potency. The results obtained in this work enhance further investigations in the future.
 KEY WORDS: Multi-component reactions, Cyanoacetanilide, Pyran, Pyridine, Cytotoxicity
 Bull. Chem. Soc. Ethiop. 2024, 38(3), 739-750. 
 DOI: https://dx.doi.org/10.4314/bcse.v38i3.15

Crystal structure and properties of new benzimidazopyrido[2,3-b]indole-6-carbonitriles

The structure of representatives of a new heterocyclic system, 12H-benzimidazo[1',2':1,6]pyrido[2,3-b]indole-6-carbonitriles, potential bioactive compounds, is elucidated by X-ray diffraction. The compounds exhibit luminescence in the blue region of the spectrum with quantum yields close to unity, which makes them promising phosphors for application in modern emitting devices.

Thiadiazole and Thiazole Derivatives as Potential Antimicrobial Agents.

This review summarizes data on heterocyclic systems with thiadiazole and thiazole fragments in molecules as promising antimicrobial agents. Thiadiazole and thiazole backbones are the most favored and well-known heterocycles, a common and essential feature of various drugs. These scaffolds occupy a central position and are the main structural components of numerous drugs with a wide spectrum of action. These include antimicrobial, antituberculous, anti-inflammatory, analgesic, antiepileptic, antiviral, and anticancer agents. The research is based on bibliosemantic and analytical methods using bibliographic and abstract databases, as well as databases of chemical compounds. This review reports on thiadiazole and thiazole derivatives, which have important pharmacological properties. We are reviewing the structural modifications of various thiadiazole and thiazole derivatives, more specifically, the antimicrobial activity reported over the last years, as we have taken this as our main research area. 80 compounds were illustrated, and various derivatives containing hydrazone bridged thiazole and pyrrole rings, 2-pyridine and 4-pyridine substituted thiazole derivatives, compounds containing di-, tri- and tetrathiazole moieties, spiro-substituted 4- thiazolidinone-imidazoline-pyridines were analyzed. Derivatives of 5-heteroarylidene-2,4- thiazolidinediones, fluoroquinolone-thiadiazole hybrids, and others. 1,3,4-thiadiazoles and thiazoles are valuable resource for researchers engaged in rational drug design and development in this area.

Synthesis, Molecular Docking, Anti-cholinesterase Activity, Theoretical Investigation, and Catalytic Effect of New Encumbered N-benzyladamantyl Substituted Imidazolidin-2-ylidene Carbene Pd-PEPPSI Complexes

Abstract: This study aimed to describe the preparation of novel PEPPSI type Pd(II)-NHC complexes bearing N-benzyladamantyl substituted imidazolidin-2-ylidene group. All synthesized compounds were characterized by using 1H-NMR and 13C-NMR spectroscopies, FTIR, and elemental analysis techniques. One of the objectives of this study was the synthesis of Pd-NHC complexes with AChE/BChE inhibition activities. Among all the tested compounds, complexes 4b and 4c were found to have the most high potential AChE and BChE inhibitory activities with IC50 values of 21.57 ± 0.23 Mm and 15.78 ± 0.39 Mm, respectively. Conducting molecular docking studies helped us in gathering crucial information about the main binding interactions of inhibitors and enzymes, and the results were in agreement with the biological evaluation. The synthesized Pd-NHC complexes were employed for catalyzing the direct C2- and C5-arylation reaction between aryl (hetero) halide and a variety of heterocyclic systems. In both cases (C2 and C5-arylation), Pd-NHC complexes catalysts provided access to the arylated heterocycles in good to high yields in the presence of 1 mol% catalyst loading at 150°C. The DFT theoretical investigation showed that the Pd-NHC complexes were of ML2X2 type, where the the Pd(II) cation had a square planar geometry. The interaction energies obtained by energy decomposition analysis (EDA) demonstrated that the 4d and 4e complexes were more stable in the presence of more methyl substituents. The chemical indicators demonstrated that the less stable 4c complex was more reactive in regard to the chemical hardness, chemical potential, and electrophilicity values.

Exploring novel pyrazole-nitroimidazole hybrids: Synthesis and antiprotozoal activity against the human pathogen trichomonas vaginalis

Trichomoniasis, a prevalent sexually transmitted infection (STI) caused by the protozoan Trichomonas vaginalis, has gained increased significance globally. Its relevance has grown in recent years due to its association with a heightened risk of acquiring and transmitting the human immunodeficiency virus (HIV) and other STIs. In addition, many publications have revealed a potential link between trichomoniasis and certain cancers. Metronidazole (MTZ), a nitroimidazole compound developed over 50 years ago, remains the first-choice drug for treatment. However, reports of genotoxicity and side effects underscore the necessity for new compounds to address this pressing global health concern. In this study, we synthesized ten pyrazole-nitroimidazoles 1(a-j) and 4-nitro-1-(hydroxyethyl)-1H-imidazole 2, an analog of metronidazole (MTZ), and assessed their trichomonacidal and cytotoxic effects. All compounds 1(a-j) and 2 exhibited IC50 values ≤ 20 μM and ≤ 41 μM, after 24 h and 48 h, respectively. Compounds 1d (IC50 5.3 μM), 1e (IC50 4.8 μM), and 1i (IC50 5.2 μM) exhibited potencies equivalent to MTZ (IC50 4.9 μM), the reference drug, after 24 h. Notably, compound 1i showed high anti-trichomonas activity after 24 h (IC50 5.2 μM) and 48 h (IC50 2.1 μM). Additionally, all compounds demonstrated either non-cytotoxic to HeLa cells (CC50 > 100 μM) or low cytotoxicity (CC50 between 69 and 100 μM). These findings suggest that pyrazole-nitroimidazole derivatives represent a promising heterocyclic system, serving as a potential lead for further optimization in trichomoniasis chemotherapy.

SYNTHESIS OF 6,8-DINITRO-11H-INDENO[1,2-b]QUINOXALIN-11-ONE AND 1,3-DINITRO-6H-INDOLO[2,3-b]QUINOXALINE BASED ON 4,6-DINITRO-o- PHENYLENEDIAMINE

The primary tasks of organic chemistry include the production of new nitrogen-containing heterocyclic systems. Quinoxalin derivatives are fragments of many biologically active and pharmacologically important compounds [1]: agonists and antagonists of various receptors, drugs with high antibacterial or antiviral activity [2]. In addition, they are known to be used as dyes [3], effective electroluminescent materials [4], organic semiconductors [5], "building blocks" in the synthesis of anionic receptors [6] and DNA-binding agents [7]. As part of the study, syntheses of compounds not previously described in the literature - 6,8-dinitro-11H-indeno[1,2-b]quinoxaline-1-one and 1,3-dinitro-6H-indolo[2,3-b]quinoxaline-1-one and 1,3-dinitro-6H-indolo[2,3-b]quinoxaline- were carried out. 6,8-dinitro-11H-indeno[1,2-b]quinoxalin-1-oh was obtained by the reaction of 2-amino-4,6-dinitroaniline, ninhydrin and glacial acetic acid when the mixture was heated in a boiling water bath for 6 hours and the sediment matured overnight. After filtration of the precipitate on the Schott filter, it was washed with cold isopropanol, recrystallized from ethanol, the isolated precipitate was dried at room temperature and at 60°C. 1,3-dinitro-6H-indolo[2,3-b]quinoxalin was synthesized during the reaction of 2-amino-4,6-dinitroaniline, isatin and glacial acetic acid. The mixture was heated in a boiling water bath for 9 hours. After the end of the reaction, the solution was left overnight to mature the precipitate. The next day, the sediment was filtered on a Schott filter, washed with cold isopropanol. Recrystallization was carried out from ethanol, and then the isolated precipitate was dried at room temperature and at 60°C. The structure of the obtained compounds was established using 1H, 13C NMR data and heteronuclear (HMBC, HSQC) correlation NMR spectroscopy, as well as data from elemental analysis, mass and IR spectroscopy. The developed synthesis methods are characterized by relative simplicity of execution, mild conditions, availability of reagents and allow obtaining target products with a yield of 75% (for 6,8-dinitro-11H-indeno[1,2-b]quinoxaline-11-one) and 92% (for 1,3-dinitro-6H-indolo[2,3-b]quinoxaline).