Series Of Heterocycles Research Articles

Spots on 1H‐Indazole Incorporation into Thiazole Moiety‐Hybrid Heterocycles, Strong Efficacy as Small Molecules with Antimicrobial, Antineoplastic Activity, and In‐Silico Studies

AbstractAmidst the escalating cancer cases and the relentless spread of multidrug‐resistant microbes, the urgency for effective medication is undeniable. In this context, our lab's continuous efforts have led to a promising discovery. We have conducted an extensive study on a series of new heterocycles with an indazolylthiazole component, which holds great promise as antimicrobial and anticancer drugs. The bioactivity tests, conducted with meticulous methodology, have demonstrated that the synthesized compounds possess remarkable antibacterial activity against various pathogenic strains. In a controlled lab setting, we have observed that derivatives 9, 11, and 12a effectively induce apoptosis in HCT‐166 and Huh‐7 (liver carcinoma) cell lines. Among these, derivative 11 has shown the highest selectivity (SI=14.54±1.2 and 16.51±1.4) and the lowest IC50 value. These compounds also exhibit broad‐spectrum antimicrobial activity. The anticancer activity of the synthesized compounds has been computationally confirmed through molecular modeling using MOE software and pharmacokinetic studies. Most of the tested compounds have shown significant cytotoxic activity against tumor cell lines, with high safety against normal human cells, thereby paving the way for a hopeful and promising future of antimicrobial and anticancer drugs, with potential applications in [specific_application_1] and [specific_application_2].

Synthesis, characterization, and biological activities of substituted pyridine-based azomethine scaffolds

The present research work describes the synthesis of a new series of heterocyclic compounds, namely, pyridine-based azomethine scaffolds. A total of eight derivatives were prepared, purified, and characterized by analytical methods such as 1H NMR, 13C NMR, and IR spectroscopic techniques. All compounds were used to investigate their alpha-amylase inhibition activity. We have also reported antimicrobial activity using a micro broth dilution assay, with microbial strains Pseudomonas aeruginosa (NCIM 5031), Escherichia coli (NCIM 2065), Bacillus subtilis (NCIM 2699), Aspergillus niger (NCIM 620), Aspergillus fumigatus (NCIM 902), and Aspergillus flavus (NCIM 549). Finally, we report the antioxidant activity of the synthesized derivatives using a DPPH free radical assay.

Environmental and Convenient Construction Strategy to Obtained New Supreme Series of Fused 1,2,4-Triazalo System Incorporating N-Acetyl Quanazole

The presentation goal is to develop new procedures for regioselective synthesis of unusual series of heterocyclic compounds (2-8) derived from N-acetyl guanazole (1) which received a great deal of attention due to it's unique properties. N-acetyl guaunazole used as active precursor to obtained two type of fused 1,2,4-triazole system. The first one including grinding for (1 min.) of a mixture consist of N-acetyl guanazole , malononitrile and substituted benzaldehlyde through direct one-pot multicomponent reaction to achieve a new series of 1,2,4-trazolo[1,5-a,4,3-a]bispyrimidine (2-7). Whereas, the second one involved firstly the conversion of N-acetyl gluanazole to the corresponding Schiff base (8-13) accelerated by microwave irradiation (MWI) for few minutes, then they will underwent intercyclization reaction with phenyl isothiocynate and also acceclerated by grinding then by microwave irradiation to afford 1,2,4-triazolo[1,5-a,4,3-a] bistriazine (14-18).

Synthesis of organotin(IV) heterocycles containing a xanthenyl group by a Barbier approach via ultrasound activation: synthesis, crystal structure and Hirshfeld surface analysis.

A series of organotin heterocycles of general formula [{Me2C(C6H3CH2)2O}SnR2] [R= methyl (Me, 4), n-butyl (n-Bu, 5), benzyl (Bn, 6) and phenyl (Ph, 7)] was easily synthesized by a Barbier-type reaction assisted by the sonochemical activation of metallic magnesium. The 119Sn{1H} NMR data for all four compounds confirm the presence of a central Sn atom in a four-coordinated environment in solution. Single-crystal X-ray diffraction studies for 17,17-dimethyl-7,7-diphenyl-15-oxa-7-stannatetracyclo[11.3.1.05,16.09,14]heptadeca-1,3,5(16),9(14),10,12-hexaene, [Sn(C6H5)2(C17H16O)], 7, at 100 and 295 K confirmed the formation of a mononuclear eight-membered heterocycle, with a conformation depicted as boat-chair, resulting in a weak Sn...O interaction. The Sn and O atoms are surrounded by hydrophobic C-H bonds. A Hirshfeld surface analysis of 7 showed that the eight-membered heterocycles are linked by weak C-H...π, π-π and H...H noncovalent interactions. The pairwise interaction energies showed that the cohesion between the heterocycles are mainly due to dispersion forces.

Synthesis and in silico studies of certain benzo[f]quinoline-based heterocycles as antitumor agents

A series of benzoquinoline-employing heterocycles was synthesized by treating 3-chlorobenzo[f]quinoline-2-carbaldehyde with N-phenyl-3-methylpyrazolone, 4-aminoacetophenone, 1,2-diaminoethane, and 2-cyanoethanohydrazide. Also, pyridine, chromene, α,β-unsaturated nitrile, thiosemicarbazone, and 1,2-bis-aryl hydrazine derivatives were prepared from the cyanoethanohydrazone obtained. The DFT calculations and experiment outcomes were consistent. In vitro screening of their antiproliferative efficacy was examined against HCT116 and MCF7 cancer cell lines. The pyrazolone 2 and cyanoethanohydrazone 5 derivatives exhibited the most potency, which was demonstrated by their molecular docking towards the CDK-5 enzyme. The binding energies of compounds 2 and 5 were − 6.6320 kcal/mol (with RMSD of 0.9477 Å) and − 6.5696 kcal/mol (with RMSD of 1.4889 Å), respectively, which were near to that of co-crystallized ligand (EFP). This implies a notably strong binding affinity towards the CDK-5 enzyme. Thus, pyrazolone derivative 2 would be considered a promising candidate for further optimization to develop new chemotherapeutic agents. In addition, the ADME (absorption, distribution, metabolism, and excretion) analyses displayed its desirable drug-likeness and oral bioavailability properties.

Evidence for Dearomatizing Spirocyclization and Dynamic Effects in the Quasi-stereospecific Nitrogen Deletion of Tetrahydroisoquinolines.

Selectivity in organic chemistry is generally presumed to arise from energy differences between competing selectivity-determining transition states. However, in cases where static density functional theory (DFT) fails to reproduce experimental product distributions, dynamic effects can be examined to understand the behavior of more complex reaction systems. Previously, we reported a method for nitrogen deletion of secondary amines which relies on the formation of isodiazene intermediates that subsequently extrude dinitrogen with concomitant C-C bond formation via a caged diradical. Herein, a detailed mechanistic analysis of the nitrogen deletion of 1-aryl-tetrahydroisoquinolines is presented, suggesting that in this system the previously determined diradical mechanism undergoes dynamically controlled partitioning to both the normal 1,5-coupling product and an unexpected spirocyclic dearomatized intermediate, which converges to the expected indane by an unusually facile 1,3-sigmatropic rearrangement. This mechanism is not reproduced by static DFT but is supported by quasi-classical molecular dynamics calculations and unifies several unusual observations in this system, including partial chirality transfer, nonstatistical isotopic scrambling at the ethylene bridge, the isolation of spirocyclic dearomatized species in a related heterocyclic series, and the observation that introduction of an 8-substituent dramatically improves enantiospecificity.

Mono- and Bis-Phosphine Promoted Incorporation of Boron, Nitrogen, and Phosphorus into Heterocycles via Staudinger Reactions of Borafluorene Azides.

We report the synthesis and characterization of a series of BNP-incorporated borafluorenate heterocycles formed via thermolysis reactions of pyridylphosphine and bis(phosphine)-coordinated borafluorene azides. The use of diphenyl-2-pyridylphosphine (PyPh2P), trans-1,2-bis(diphenylphosphino)ethylene (Ph2P(H)C═C(H)PPh2), and bis(diphenylphosphino)methane (Ph2PC(H2)PPh2) as stabilizing ligands resulted in Staudinger reactions to form complex heterocycles with four- (BN2P, BNPC, P2N2) and five-membered (BNP2C and BN2PC) rings, which were successfully isolated and fully characterized by multinuclear NMR and X-ray crystallography. However, when bis(diphenylphosphino)benzene (Ph2P-Ph-PPh2) was used as the ligand in a reaction with 9-bromo-9-borafluorene (BF-Br), due to the close proximity of the donor P atoms, the diphosphine-stabilized borafluoronium ion with an unusual borafluorene dibromide anion was formed. Reaction of the borafluoronium ion with trimethylsilyl azide left the cation intact, and the dibromide anion was substituted by a diazide. Density functional theory calculations were used to provide mechanistic insight into the formation of these new boracyclic compounds. This work highlights a new method in which donor phosphine ligands may be used to promote dimerization, cyclization, and ring contraction reactions to produce boracycles via Staudinger reactions.

Synthesis, Characterization, DFT mechanistic study, Antibacterial Activity, Molecular modeling, and ADMET properties of novel chromone-isoxazole hybrids

A series of novel hybrid heterocycles incorporating isoxazole rings have been successfully synthesized, characterized, and evaluated for their antibacterial responses. The synthesized compounds were obtained by a subsequent N-alkylation and 1,3-dipolar cycloaddition reactions, their structures were identified by spectroscopy techniques (1H NMR, 13C NMR and 2D HSQC), and confirmed by mass spectrometry (HRMS). The spectroscopic data also show that the 1,3-dipolar cycloaddition (1,3-DC) reactions proceed in a regiospecific manner to give only one cycloadduct. The observed regioselectivity and the mechanistic study of the 1,3-DC reaction were further highlighted and explained using Density Functional Theory (DFT) calculations with the B3LYP/6–31G(d,p) basis set and Electron Localization Function (ELF) analysis. Moreover, the antibacterial screening shows that some compounds exhibit good efficacy against the tested bacterial strains. In addition, molecular docking studies were carried out to highlight the modes of interaction between the most active molecule 5d and receptors of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus strains. The results show that the studied compound was effectively docked to the active sites of each responsible protein with high protein-binding energies in kcal/mol. Finally, the prediction of ADMET properties suggests that almost all the hybrid compounds have good pharmacokinetic profiles, with no observed signs of toxicity, except for compounds 5e, 5f and 5g.

Parallel Minisci Reaction of gem-Difluorocycloalkyl Building Blocks.

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

Fluorosulfonyl Arylation of Alkynes via Electron Donor-Acceptor Photoactivation.

A radical fluorosulfonyl arylation of alkynes with sulfuryl chlorofluoride as the FSO2 radical precursor via electron donor-acceptor photoactivation driven by daylight or a blue light-emitting diode is disclosed. A series of valuable benzo-fused carbocycles and heterocycles have been produced with simple operation under mild conditions in the absence of any external catalysts or additives. The synthetic potential of this protocol has further demonstrated excellent scalability, as well as diverse postderivatizations, including SuFEx reactions and other useful cascade reactions.

1,3-Dipolar cyclisation reactions of nitriles with sterically encumbered cyclic triphosphanes: synthesis and electronic structure of phosphorus-rich heterocycles with tunable colour.

We describe the synthesis, solid state and electronic structures of a series of tunable five-membered cationic and charge-neutral inorganic heterocycles featuring a P3CN core. 1-Aza-2,3,4-triphospholenium cations [(PR)3N(H)CR']+, [1R]+ (R' = Me, Ph, 4-MeOC6H4, 4-CF3C6H4) were formed as triflate salts by the formal [3 + 2]-cyclisation reactions of strained cyclic triphosphanes (PR)3 (R = t Bu, 2,4,6-Me3C6H2 (Mes), 2,6- i Pr2C6H3 (Dipp), 2,4,6- i Pr3C6H2 (Tipp)) with nitriles R'CN in the presence of triflic acid. The corresponding neutral free bases (PR)3NCR' (2R) were readily obtained by subsequent deprotonation with NEt3. The P3CN cores in 2R show an envelope conformation typical for cyclopentenes and present as yellow to orange compounds in the solid state as well as in solution depending on both substituents R and R' in (PR)3NCR'. The P3CN cores in [1R]+ show a significant deviation from planarity with increasing steric bulk of the R groups at phosphorus, which results in a decrease in the HOMO-LUMO gap and distinct low-energy UV-Visible absorption bands. This allows access to colours spanning red, blue, indigo, and magenta. TD-DFT calculations provide valuable insight into this phenomenon and indicate an intramolecular charge-transfer from the HOMO located on the P3 framework to the N[double bond, length as m-dash]C-R'-based LUMO in the cationic species. The cations [1R]+ represent rare examples of phosphorus-rich heterocycles with tunable colour, which can be incorporated into polymers by post-polymerization modification to afford coloured polymers, which demonstrate utility as both proton and ammonia sensors.

Recent advances in [4 + 4] annulation of conjugated heterodienes with 1,4-dipolar species for the synthesis of eight-membered heterocycles.

Numerous eight-membered heterocycles are of significance in biological chemistry, the pharmaceutical industry, agrochemistry, and materials science. However, the assembly of eight-membered heterocycles is usually challenging due to the unfavorable enthalpic and entropic barriers of the transition states during the ring formation. Tremendous efforts have been devoted to the development of synthetic routes to eight-membered heterocycles. Despite these developments, the exploration of more strategies for the facile and effective assembly of eight-membered heterocyclic molecules in a single vessel under mild conditions is still highly desirable. The conjugated heterodiene-participating [4 + 4] annulation serves as a convenient and robust strategy for the synthesis of eight-membered heterocycles from easily accessible starting materials. In recent years, great progress has been achieved in this attractive field. In this short review, we highlighted the recent advances in the synthesis of eight-membered heterocycles via cascade reactions based on [4 + 4] annulation of conjugated heterodienes with 1,4-dipolar species. The brief backgrounds, the general reactions, the proposed mechanisms and their features are summarized. The prospects and challenges of this field are also outlined at the end of this review. In addition, to highlight the importance and practicality of these reactions, the properties of several series of eight-membered heterocycles have also been introduced briefly.

Синтез новых S-производных 4-амино-1,3,5-триазин-2-тиона и их исследование методами ЯМР 1Н, 13С и хромато-масс-спектрометрии

4-Amino-1,3,5-triazine-2-thione 1 interacts with allyl bromide, 2-methyl-3-chloro-1-propene, 2,3-dibromopropene-1, prenyl bromide in DMFA/K2CO3 and with cinnamyl chloride, butenyl bromide in DMFA/NaOH to form 4-allylsulfanyl- 2, 4-(2-methylpropene-2-yl)sulfanyl- 3, 4-(2-bromopropene-2-yl)sulfanyl- 4, 4-(2-methylbutene-2-yl)sulfanyl- 5, 4-cinnamylsulfanyl- 6 and 4-(butene-1-yl)sulfanyl-1,3,5-triazine-2-amines 7, respectively. The structure of compounds 2–7 was studied by 1H NMR, as well as of compounds 5 and 7, in their case including 13C NMR; allyl sulfide 2, prenyl sulfide 5 and butenyl sulfide 7 were also studied using chromatography mass spectrometry. In the 1H NMR spectra of compounds 2–7, the weakest field signal in the range of 8.22–8.30 p.p.m. is the signal of the aromatic proton of the triazine cycle, manifested as a singlet. The signals of protons of the S-CH2 group are observed in a strong field – at 3.10–4.19 p.p.m. – depending on the presence of electron donor or electron acceptor groups in the alkenyl fragment. The protons of the =CH2 group are present only in the structure of sulfides 2–4 and 7; they form two signals in the 1H NMR spectra: one signal at 4.85–5.58 p.p.m., the second at 5.03–6.10 p.p.m. In the 13C NMR spectra of prenyl sulfide 5 and butenyl sulfide 7, the carbon atoms of the S-alkenyl groups resonate in the region of strong fields. In the region of weak fields, the signals of aromatic carbon atoms of the 1,3,5-triazine cycle are observed: 182.32–157.95 p.p.m. In the mass spectra of compounds 2, 5 and 7, the characteristic peaks are [M 15]+ and [M-33]+ peaks, the formation of which is associated with the fragmentation of molecular ions undergoing cleavage of the methyl radical and the •SH radical, respectively. The haloalkyl derivative of the heterocyclic series – 2-chloro-1-(2,2,4-trimethyl-4-phenyl-3,4-dihydroquinoline-1(2H)-yl) ethanoate – in reaction with compound 1 has led to the introduction of a new pharmacophore fragment into the simm-triazine molecule, which contributes to the expansion of the spectrum of potential biological activity of its derivatives.

Synthesis of Novel Series of 1,2,3-Triazoles Tethered to Pyrazolo[3,4-d]pyrimidine Scaffold with Methoxyphenoxy Linker

A novel series of hybrid heterocycles having pyrazolopyrimidine based 1,2,3-triazole scaffold with two ether linkages were synthesized by 1,3-dipolar cycloaddition reaction of pyrazolopyrimidines tethered to phenoxy alkynes and differently substituted aromatic azides using CuSO4·5H2O and sodium ascorbate mixture as catalyst in DMSO-H2O solvent mixture. The synthesized triazole hybrids were characterized by using various spectroscopic techniques.

Synthesis, Cytotoxic, and Antioxidant Activity of Some Benzoquinoline-Based Heterocycles

A series of benzoquinoline-based heterocycles was synthesized using 2-((3-chlorobenzo[f]quinolin-2-yl)methylene)hydrazine-1-carbothioamide as a key material via condensation of 3-chlorobenzo[f]quinoline-2-carbaldehyde with thiosemicarbazide. The titled thiosemicarbazone scaffold was conducted with some carbon electrophilic reagents such as acetic anhydride, chloroacetyl chloride, chloroacetic acid, 2-bromo-1-(3-nitrophenyl)ethan-1-one, 2-chloro-N-phenylacetamide, and dimethyl but-2-ynedioate to obtain triazole thione, imidazolone, thiazolidinone, and thiazole derivatives. On the other hand, hydrazinolysis of thiosemicarbazone did not proceed as expected but it gave the azine derivative. The in vitro antitumor and antioxidant activity of the synthesized compounds were screened and revealed that triazole thione and thiazole derivatives were the most potent.

Mixtures of Heterocycles and Iodine as the Catalysts for the Formation of Organic Carbonates from Epoxides and CO2

Combinations of a series of nitrogen-containing heterocycles with iodine were tested as the catalysts for the synthesis of cyclic carbonates from epoxides and CO2. It is shown that the systems containing aliphatic substituents are more efficient, the presence of a free NH group has a beneficial effect on the conversion, and the systems with two or more nitrogen atoms are more active.

Synthesis and Antioxidant Activity of Some Benzoquinoline-Based Heterocycles Derived from 2-((3-Chlorobenzo[f]quinolin-2-yl)methylene)hydrazine-1-carbothioamide

A new series of benzoquinoline-based heterocycles was synthesized utilizing the building block synthon, 2-((3-chlorobenzo[f]quinolin-2-yl)methylene)hydrazine-1-carbothioamide via the condensation of 3-chlorobenzo[f]quinoline-2-carbaldehyde with thiosemicarbazide. The titled thiosemicarbazone scaffold was conducted with some carbon-centered electrophilic reagents such as acetic anhydride, chloroacetyl chloride, chloroacetic acid, 2-bromo-1-(3-nitrophenyl)ethan-1-one, 2-chloro-N-phenylacetamide, and dimethyl but-2-ynedioate to achieve triazolethione, imidazolone, thiazolidinone, and thiazole derivatives. In turn, the hydrazinolysis of this substrate did not proceed as expected but it afforded the azine derivative. The antioxidant activity screening of the produced compounds revealed that thiazole and triazolethione derivatives were the most potent.

Photochemically and Thermally Generated BN-Doped Borafluorenate Heterocycles via Intramolecular Staudinger-Type Reactions.

A series of BN-incorporated borafluorenate heterocycles, bis(borafluorene-phosphinimine)s (11-15), have been formed via intramolecular Staudinger-type reactions. The reactions were promoted by light or heat using monodentate phosphine-stabilized 9-azido-9-borafluorenes (R3P-BF-N3; 6-10) and involve the release of dinitrogen (N2), migration of phosphine from boron to nitrogen, and oxidation of the phosphorus center (PIII to PV). Density functional theory (DFT) calculations provide mechanistic insight into the formation of these compounds. Compounds 11-15 are blue emissive in the solution and solid states with absolute quantum yields (ΦF) ranging from 12 to 68%.

Evaluation of Antimicrobial Activity from a Series of Heterocyclic Compounds Derived from 1,8- Diaminonaphthalene

Evaluation of Antimicrobial Activity from a Series of Heterocyclic Compounds Derived from 1,8- Diaminonaphthalene

Tandem Allylic Amination/oxa-Michael Addition of Vinyl Methylene Cyclic Carbonates via Palladium-Organo Relay Catalysis.

A tandem allylic amination/oxa-Michael addition of vinyl methylene cyclic carbonates (VMCCs) has been developed to construct heterocycles by single palladium catalysis or palladium-organo relay catalysis. In this process, the bisnucleophiles first underwent regioselective allylic amination, and then the second nucleophilic group further completed the hetero-Michael addition reaction to form a series of heterocycles. Among them, the chiral 3,4-dihydro-2H-benzo[b][1,4]oxazines could be produced in medium to high yield with good enantioselectivity under a palladium-organo relay catalysis.