Search

AbstractSome novel β-Ala-phthalazine derivatives were synthesized from the parent methyl 3-(2-(4-benzyl-1-oxophthalazin-2(1H)-yl) acetamido)propanoate (1). Then, ester 1 underwent hydrazinolysis to produce the hydrazide 2-(4-benzyl-1-oxophthalazin-2(1H)-yl)-N-(3-hydrazineyl-3-oxo propyl) acetamide (2). Under the azide coupling technique, hydrazide 2 formed azide 3 which was further coupled with some amines and amino acid esters hydrochloride to produce the corresponding novel dipeptides 4a–h and 5a–d, respectively. Finally, hydrazide 2 was condensed and/or cyclized with some ketones and/or active methylene compounds resulting in the formation of various derivatives 6a-e. Compounds 2, 6c, and 6d demonstrated significant cytotoxicity, with IC50 values of 1.33, 0.41, and 0.38 μM compared to Sorafenib (IC50 = 2.93 μM). Compounds 6d exhibited potent VEGFR2 inhibition by 97.6% with an IC50 value of 21.9 μM compared to Sorafenib (94.7% and IC50 value of 30.1 μM). The 6d treatment significantly increased apoptotic activity by 23.6-fold, causing a halt in cell proliferation at the G2/M phase. Ultimately, it exhibited a strong affinity for the VEGFR2 protein, with a binding energy of −26.8 Kcal/mol, and it established binding contacts with the crucial amino acids involved in the interaction. [ABSTRACT FROM AUTHOR]

Phthalazine can behave as a diene in Diels–Alder (DA) cycloadditions, typically at the pyridazine ring, however, its application is somewhat limited because these reactions usually require harsh conditions or sophisticated catalysts. As an unconventional example, phthalazine was reported to undergo cycloaddition with the [PCO]− anion without any catalyst. In this computational study, we scrutinise the mechanism of the DA reactions between phthalazine and the so far known [ECX]− (E: P, As; X: O, S, Se) anions as dienophiles. In principle, the attack of an [ECX]− anion may occur at two different sites of phthalazine, either at the benzene or the pyridazine ring, and both of these possible reaction channels were juxtaposed on the basis of energetic aspects. In all of the investigated cases, the analysis of the energy profiles reveals a clear regioselectivity that favours the attack at the pyridazine ring. As a result, so far unprecedented 2‐pnictanaphth‐3‐olate analogues seem achievable as final products. Comparing the characteristics of these pathways allowed us to clarify the source of this regioselectivity: The pyridazine ring of phthalazine exhibits lower aromaticity than the benzene subring; therefore, in the DA step, the former ring shows a higher affinity toward a dienophile than the latter, leading to lower activation barriers. To further map the electronic and structural features of the cycloaddition steps, the local interactions evolving in the transition states were analysed and compared using global and local descriptors. In most aspects, the characteristics of both pathways were found to be rather similar, in contrast to the markedly differing activation barriers on the two routes. [ABSTRACT FROM AUTHOR]

DDR1 and DDR2 are nonintegrin collagen receptors in the receptor tyrosine kinase family. Both DDRs bind to various collagen types and perform crucial functions in embryo development. DDRs are different from other receptor tyrosine kinases due to their interaction with extracellular matrix components and unusual activation kinetics. DDR regulates cell migration, survival, proliferation, differentiation, and extracellular matrix remodeling. Dysregulated DDR function is linked to the advancement of several human illnesses, including fibrosis, arthritis, neurodegenerative diseases, and cancer. DDRs play a vital role in disease progression and development. Therefore, the use of DDR inhibitors represents a promising therapeutic strategy, particularly for disorders with limited therapy alternatives. In recent years, DDRs have been regarded as attractive targets for drug development, as evidenced by a significant rise in research in this field. The current review illustrates about recent advancement of small molecules, their designing strategies and structure‐activity relationship. The DDR inhibitors can contain various core structures such as pyrimidine, phthalazine, pyrazole, pyrazine, imidazo[1,2‐a]sspyrazine, quinazoline, and thieno[3,2‐b]pyridin‐7‐yl derivatives. Furthermore, based on the constructive analysis of the published derivatives, we found that the majority of the powerful compounds have a similar scaffold (amide linker, hydrophobic tail, hinge binder with or without spacer). Among the different literature, the most potent compounds 4 (imidazo[1,2‐a]pyrazine), 5 (pyridine), 19 (pyridine), and 24 (quinazoline) displayed potent activity against DDR1 with IC50 values ranging from 2.26 – 4.67 nM, while DDR2 IC50 values ranging from 3.2 – 7.29 nM. This approach will help medicinal chemists to refine and develop novel small molecules targeting DDR1 and DDR2. [ABSTRACT FROM AUTHOR]

Organic diradicaloids have lately emerged as potential spintronic materials. We report the unprecedented synthesis of a near-IR absorbing indeno[2,1-a]fluorene derivative that displays remarkably low LUMO (−4.15 eV) and a small HOMO–LUMO gap (0.85 eV). NMR/EPR studies indicated its open-shell diradical property, which was supported by DFT calculations while suggesting a 30% diradical character and a small singlet (S)–triplet (T) gap (−2.52 kcal mol−1). A large bond length alternation of the as-indacene core for its single-crystals indicated a quinoidal contribution with greater antiaromaticity, which is in line with the small diradical character despite showing a small S–T gap. [ABSTRACT FROM AUTHOR]

An Iridium(III)‐catalyzed C−H cyclization of N‐arylphthalazinones with α‐diazotized Meldrum's acid afforded tetracyclic phthalazine derivatives with a carbonyl group in 98% yield in only 30 min. The initial formation of tetracyclic phthalazine derivatives also provided access to a powerful building block. The utility of this method is emphasized by the synthetic transformation into a series of potentially bioactive derivatives. [ABSTRACT FROM AUTHOR]

The article discusses the use of the inverse-electron-demand Diels-Alder (IEDDA) reaction as a synthetic tool for creating complex molecular structures. The authors focus on the use of bidentate Lewis acid catalysts to facilitate the IEDDA reaction between phthalazines and cyclooctynes. They found that the catalyst significantly increased the reaction rate and yield of the desired products. The authors also explored the scope of the reaction by testing different substituted phthalazines and cyclooctynes. The method presented in the article provides a convenient and efficient way to synthesize polycyclic aromatic hydrocarbons fused to eight-membered carbocycles. [Extracted from the article]

This study focuses on the cytotoxic effect properties of 4‐aryl‐functionalized benzo[d,e]benzo[4,5]imidazo[2,1‐a]isoquinolin‐7‐one (4‐X−Ar−BBI). The electron‐withdrawing and electron‐donating substituents located at the para position of the phenyl ring attached to the heterocyclic structure have altered the pi electron density within the structure. This change in electron density has influenced the intercalation ability of the heterocyclic structure and has impacted the intensity of its interaction with DNA. The 4‐aryl‐benzo[d,e]benzo[4,5]imidazo[2,1‐a]isoquinolin‐7‐one derivatives (4‐X−Ar−BBI) were prepared via the Suzuki–Miyaura cross‐coupling reaction. The optimum reaction conditions were determined to be 70 °C for 5 hours using catalyst 1 and K2CO3, resulting in a yield of 96 % of 4‐H−Ar−BBI. Characterization of all compounds (4‐X−Ar−BBI) was performed using Fourier Transform Infrared spectroscopy, mass spectrometry, and 1H‐ and 19F‐NMR spectroscopies. The cytotoxic activities of the compounds (4‐X−Ar−BBI) were investigated against cancer cell lines, specifically HeLa (human cervix adenocarcinoma epithelial), PC3 (human prostate), and MCF‐7 (human breast). The stability of 4‐CN−Ar−BBI and the binding modes between 4‐CN−Ar−BBI and DNA were investigated via 1H‐NMR spectroscopy and UV‐Vis spectroscopy, respectively. 4‐CH3−3‐NO2−Ar−BBI exhibited the most potent cytotoxic activity against MCF‐7, and 4‐F−Ar−BBI showed the highest activity against HeLa, with IC50 values of 3.675 and 7.370 μM, respectively. [ABSTRACT FROM AUTHOR]

A visible‐light‐induced strategy has been explored for the synthesis of naphtho[2,1‐d]thiazol‐2‐amines through ortho‐C−H sulfuration of 2‐isocyanonaphthalenes with elemental sulfur and amines under external photocatalyst‐free conditions. This three‐component reaction, which utilizes elemental sulfur as the odorless sulfur source, molecular oxygen as the clean oxidant, and visible light as the clean energy source, provides a mild and efficient approach to construct a series of naphtho[2,1‐d]thiazol‐2‐amines. Preliminary mechanistic studies indicated that visible‐light‐promoted photoexcitation of reaction intermediates consisting of thioureas and DBU might be involved in this transformation. [ABSTRACT FROM AUTHOR]

A pyrrolo[2,1-a]isoquinoline core structure is prevalent in marine and other natural products. This article describes a tungsten-catalyzed [3+2] cycloaddition aromatization of dihydroisoquinoline ester and maleic anhydride or an acrylate. The photochemical reaction tolerates a range of functional groups such as ester, cyano, ketone, bromide, and alkene. It is shown that the cycloaddition-aromatization of 2-substitued acrylate catalyzed by a tungsten photocatalyst can be used to evaluate the leaving ability of the leaving group. Experiments done to determine the reaction mechanism revealed that the formation of an ion-pair intermediate generated in situ from dihydroisoquinoline ester and (Z)-4-methoxy-4-oxobut-2-enoic acid via the solvolysis of maleic anhydride with methanol is crucial for the cascade process to occur. The key cycloadduct acid intermediate derived from [3+2] cycloaddition was isolated and determined by X-ray crystallography. [ABSTRACT FROM AUTHOR]

A novel inorganic-monosaccharide nanohybrid synthesized through coating the nickel–zinc ferrite (NZF) core by silica and subsequent functionalization with galactose (Ni0.4Zn0.6Fe2O4@SiO2/galactose) and characterized by FT-IR, FESEM, EDAX, XRD, XRF, BET, TGA, and VSM techniques. Its catalytic efficacy examined in some domino four-component reactions to obtain various classes of phthalazine derivatives at 90 °C under solvent-free conditions: (i) the reaction of phthalic anhydride (PA), hydrazine hydrate, dimedone, and different aldehydes to get 3,3-dimethyl-13-(aryl)-3,4-dihydro-1H-indazolo[1,2-b]phthalazine-1,6,11(2H,13H)-triones; (ii) the reaction of phthalic anhydride/phthalimide, hydrazine hydrate, malononitrile, and different aldehydes to obtain 3-amino-5,10-dioxo-1-(aryl)-5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine-2-carbonitriles; and (iii) the reaction of succinic anhydride, hydrazine hydrate, dimedone, and different aldehydes to prepare 3,3-dimethyl-11-(aryl)-3,4,7,8-tetrahydro-1H-pyridazino[1,2-a]indazole-1,6,9(2H,11H)-triones. In addition, the recovery and reusability of the Ni0.4Zn0.6Fe2O4@SiO2/galactose determined successfully, and the reused nanocomposite identified through FESEM and EDAX techniques. [ABSTRACT FROM AUTHOR]

The Re(I) organometallic compounds [(Re(CO)3L1-6)Cl], where ligands L are tryptanthrin derivatives, prepared and characterized by various spectroscopic techniques. To assess the binding capacities and binding manner, tests of calf thymus DNA under the impact of organometallic complexes were conducted using absorption titration and viscosity measuring techniques. Data from the research mentioned above point to an intercalation type of binding, which was verified by the docking study. Swiss ADME tools were used to carry out an ADME study. The work focuses on computing the molecular orbital energies for the synthesized compounds using the density functional theory (DFT). The compounds were tested against the MCF-7 cell line to determine their anticancer effects. It was observed that their IC50 values were equivalent to those of the standard medication, indicating that they had a similar antiproliferative impact. [ABSTRACT FROM AUTHOR]

The reaction 5-(arylmethylidene)-2,4,6-pyrimidine-2,4,6(1H,3H,5H)-triones with isoquinoline and dimethyl but-2-ynedioate gave cycloaddition products, mixtures of diastereoisomeric substituted dimethyl 2-aryl-2′,4′,6′-trioxo-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a]isoquinoline-1,5′-pyrimidine]-3,4-dicarboxylates which were converted to the corresponding dipotassium salts by treatment with excess potassium hydroxide in ethanol. The synthesized compounds are of interest as promising intermediate products with potential antitubercular and fungicidal activities. [ABSTRACT FROM AUTHOR]

8-Aroyl-3,4-dihydro-1Н-pyrrolo[2,1-с][1,4]oxazine-1,6,7-triones reacts with N-ethylaniline with formation of N-phenyl-N-ethylammonium 3′-aroyl-1′-(2-hydroxyethyl)-2,5′-dioxo-1-ethyl-1′,5′-dihydrospiro[indoline-3,2′-pyrrol]-4′-oates, which, at acidification, are converted into 3′-aroyl-4′-hydroxy-1′-(2-hydroxyethyl)-1-ethylspiro[indoline-3,2′-pyrrole]-2,5′(1′H)-diones, the structure of both classes of products was confirmed by X-ray diffraction. [ABSTRACT FROM AUTHOR]

The sonochemical synthesis and biological properties of compounds simultaneously containing several heterocycles, namely phthalazine, 1,3,4-oxadiazole, and 1,2,3-triazole rings, have been studied as part of our ongoing research in the field of organic and medicinal chemistry. In this study, we performed ligand-based pharmacophore modeling as a promising design strategy for substituted 1,2,3-triazole–1,3,4-oxadiazole–phthalazin-1(2H)-one hybrids from 2-[4-ethyl-1-oxophthalazin-2(1H)-yl]acetohydrazide as key intermediate product. The prepared compounds were characterized by 1H and 13C NMR, IR, and mass spectra and elemental analyses. The synthesized scaffolds were screened for their antitubercular activity against Mycobacterium tuberculosis H37Rv strain by the agar microdilution method. The compounds were further evaluated for their ADMET properties by using ADEMTlab 2.0 and SwissADME. Molecular docking study was also performed against M. tuberculosis DNA gyrase using AutoDock 4.2. The o-fluorophenyl 1,3,4-oxadiazolyl–1,2,3-triazole derivative, which showed excellent antitubercular activity against H37Rv strain with MIC = 3.24 μg/mL (compared to streptomycin, MIC = 3.12 μg/mL), was found to exhibit the strongest bondings with the amino acid residues Asp94(A), Tyr93(A), Pro123(A), Lys72(A), Ala124(A), Arg128(A), Ala126(A), Pro124(A), Ala74(A), and Met127(A) with a docking score of –6.992 kcal/mol. [ABSTRACT FROM AUTHOR]

Lipophilicity, a significant physicochemical parameter of bioactive molecules, along with absorption, distribution, metabolism, excretion parameters and toxicity risk, was investigated for 32 thiazolo[3,2-b][1,2,4]triazole and imidazo[2,1-b][1,3,4]thiadiazole derivatives with anti-inflammatory potential. The experimental lipophilicity study was carried out by reversed-phase thin-layer chromatography in a binary isopropanol-water mobile phase, and the obtained results were compared with the theoretical lipophilicity parameters estimated by various computational methods. Strong correlations were found between the experimental retention factors and calculated partition coefficients. A modified Petra/Osiris/Molinspiration analysis was performed on the previously synthesized compounds, using SwissADME, Osiris and Molinspiration web tools. The predicted in silico parameters highlighted the most promising compounds as potential drug candidates. The compounds showed good gastrointestinal absorption, moderate activity according to the bioactivity score (values situated between −1.25 and −0.06), and a safe toxicity profile. The results obtained in this study will contribute to lipophilicity studies and other future studies focused on modulating new drug candidates starting from thiazolo[3,2-b][1,2,4]triazole and imidazo[2,1-b][1,3,4]thiadiazole derivatives, which are important heterocycles in medicinal chemistry. [ABSTRACT FROM AUTHOR]

A metal-free electrochemical oxidative difluoroethylation of 2-arylbenzimidazoles was accomplished, which provided an efficient strategy for the synthesis of MeCF2-containing benzo[4,5]imidazo[2,1-a]-isoquinolin-6(5H)-ones. In addition, the method also enabled the efficient construction of various difluoroethylated indolo[2,1-a]isoquinolin-6(5H)-ones. Notably, this electrochemical synthesis protocol proceeded well under mild conditions without metal catalysts or exogenous additives/oxidants added. [ABSTRACT FROM AUTHOR]

This article discusses the synthesis of novel benzimidazo[2,1-b]thiazoles, which have various biological properties including antitumor, antimicrobial, and antifungal activities. The authors describe a three-component, one-pot synthesis of these compounds and optimized the reaction conditions to obtain good yields. The synthesized compounds were characterized using various analytical techniques. The article also provides a series of chemical analyses for different compounds, including their physical properties and spectroscopic data. The authors express hope that the synthesized compounds will be useful for further investigation in biological applications. The work was supported by Vali-e-Asr University of Rafsanjan. [Extracted from the article]

A Ni(II) complex of 3,3′-(-(pentane-3,3-diylbis(1H-pyrrole-5,2-diyl))bis(diazene-2,1-diyl)) dipyridine, NiL, has been synthesized and characterized. In the crystal, the Ni(II) ion is in square-planar geometry by coordinating to two pyrrole nitrogen atoms and two azo nitrogen atoms. Anagostic C–H···Ni interactions, as well as C–H···N hydrogen bond were found play important role in the self-assembly of the complex molecules. The intermolecular interactions were evaluated by Hirshfeld surface analysis. Frontier molecular orbitals (HOMO and LUMO), their energy gap and associated reactive parameters were calculated to understand the properties of the complex. UV–Vis spectrum of the complex were also performed. Anagostic C–H···Ni interactions were found play important role in the crystal of the Ni(II) complex with 3,3'-(-(pentane-3,3-diylbis(1H-pyrrole-5,2-diyl))bis(diazene-2,1-diyl)) dipyridine. [ABSTRACT FROM AUTHOR]

The current study investigates the adsorption properties of a novel heterocyclic compound, 13-(4-chlorophenyl)-3, 3-dimethyl-3, 4-dihydro-1H-indazolo[1,2-b] phthalazine 1,6,11(2H,13H)-trione (DDIP), as an inhibitor against the oxidation of brass in hydrochloric acid solution. The experimental investigation included several methods, including EIS and PDP. The inhibition efficiency of the compound followed the order of 90.0%. The adsorption process of this inhibitor on the brass substrate followed the Langmuir adsorption model. SEM/EDS and XRD techniques were utilized to analyze surfaces, revealing the presence of a protective film overlaying the brass substrate. In addition, the results of DFT calculations of the DDIP compound revealed the existence of many active sites on the brass surface, facilitating the adsorption of our inhibitor. [ABSTRACT FROM AUTHOR]

This article explores the use of palladium-catalyzed acylation reactions in organic synthesis. The authors emphasize the significance of the carbonyl group in organic chemistry and the limitations of traditional methods for creating ketones. They present their own research on a Pd-catalyzed direct acylation method that allows for the synthesis of various ketones without the need for directing groups. The authors also investigate the synthesis of benzofuranones and indenones using sequential one-pot operations. Overall, this article offers valuable insights into the development of innovative synthetic strategies for producing biologically relevant substances. [Extracted from the article]

The study of the chemical and biological properties of molecules simultaneously comprising various heterocycles, such as fused 1,3,4–oxadiazolyl–1,2,3–triazoles and 1,2,4–triazolyl–1,3,4–thiadiazole have been conducted as part of our ongoing research in the field of medicinal and organic chemistry. In this study, we performed ligand–based pharmacophore modelling as a promising design strategy of substituted phthalazinone derivatives (5 and 7). These were synthesized from key intermediate mercapto‐containing oxadiazo‐phthalazinone derivative 2. The synthesized compounds were characterized by IR, 1H and 13C NMR, elemental analysis and mass spectrometric techniques. In preliminary antibacterial studies, analogues 5 d, 5 f, 7 a and 7 d were found to be most effective against S. epidermidis, whereas 5 d displayed excellent activity against P. aeruginosa microorganism. Later, explored the probable key active site and inhibitors of Cytochrome P450 CYP121A1 interactions from M. tuberculosis H37Rv based antitubercular drug candidate with 5O4K protein and ligand 7 b possesses highest hydrophobic amino acid residues. The physicochemical and medicinal properties were also evaluated using SwissADME and ADMETlab2.0 web to function as effective oral bioavailability medications. [ABSTRACT FROM AUTHOR]

Efficient access to the tetracyclic pyrazolo-fused carbo- and N-heterocyclic systems: naphtho [2',1':3,4]cyclohepta[2,1-c]pyrazolones, naphtho[2',1':5,4]azepino[6,7-c]pyrazolones, naphtho [2',1':5,4]azocino[6,7-c]pyrazolones and naphtho[2',1':6,5]azonino[7,8-c]pyrazolones is described involving intramolecular Friedel--Crafts cycliacylations of synthesized pyrazole-based carboxylic acid or ester derivatives aided by treatment with Lewis and Brønsted acids. The required starting carbaldehyde was obtained by the Vilsmeier--Haack reaction of the corresponding 2-acetylnaphthalene hydrazone. Our developed strategy, involving a three-step route, offers easy access to tetracyclic pyrazole-fused systems in moderate to good yields. [ABSTRACT FROM AUTHOR]

A novel phthalazine‐based phthalonitrile resin was prepared by two different curing procedures. The phthalonitrile monomer, namely, 4,4′‐(((phthalazine‐1,4‐diylbis(oxy))bis(3,1‐phenylene))bis(oxy))diphthalonitrile (PDOP), was synthesized from the reaction of 1, 4‐dichloropthalazine, resorcinol, and 4‐nitrophthalonitrile. Its curing behavior and curing kinetics with 4‐(4‐aminophenoxy)phthalonitrile (APPH) were investigated by Differential Scanning Calorimetric (DSC). Isoconversional method based on Starink was applied to analyze the curing process of PDOP/APPH. The PDOP monomer exhibits a low melting point (89 °C) and a wide processing window (146 °C). The PDOP polymer mainly forms triazine, isoindoline, and phthalocyanine structure, as revealed by Fourier Transform Infrared (FTIR) spectroscopy, and its properties improved with the increase of post‐curing temperature and curing time. After post‐curing at 350 °C, the polymer has high storage modulus (3313 MPa), high glass‐transition temperature (380 °C), and outstanding thermal stability and thermal oxidation stability. [ABSTRACT FROM AUTHOR]

The sulfa-Michael/aldol cascade reaction of (Z)-2-(arylmethylene)-5,6-dihydroimidazo[2,1-b]thiazol-3(2H)-ones and 1,4-dithiane-2,5-diol afforded novel 2'-aryl-4'-hydroxy-4',5,5',6-tetrahydro-2'H,3H-spiro[imidazo[2,1-b]thiazole-2,3'-thiophen]-3-ones in moderate yields. The structures of all the products were characterized thoroughly by IR and NMR spectroscopy and HRMS, as well as XRD analysis. [ABSTRACT FROM AUTHOR]

An efficient, acid‐mediated, intramolecular alkyne iminium ion cyclization of oxoisoindolidene for the diastereoselective synthesis of pyrrolo/pyridoisoindole is described. This protocol features broad substrate scope and easy scalability. An unusual N to C‐1,3‐alkyl shift is observed with substrates bearing strong electron donating group at the phenyl ring attached to alkyne with concomitant hydration of alkyne to the ketone. [ABSTRACT FROM AUTHOR]

The synthesis of pyrazolo[b]phthalazine diones and indazolo[b]phthalazine triones was efficiently achieved using novel magnetically recoverable supported Bronsted acidic ionic liquids. The heterogeneous catalysts were prepared by synthesizing two organosulfonate salts from n-methylimidazole and 1-benzyl-4-phenyl-1H-1,2,3-triazole with 1,4-butanesultone. The organosulfonate zwitterions were non-covalently immobilized onto the previously synthesized nanomagnetic Fe3O4@SiO2–SO3H support to prepare the organometallic hybrid catalysts. Various thermal and spectroscopic techniques, including 1H and 13C NMR, FTIR, SEM, EDX, mapping, XRD, and VSM, were employed to confirm the successful preparation of the novel nanoorganometallic hybrid catalysts. The immobilization of BAILs on the nanoparticles of Fe3O4@SiO2–SO3H facilitated their recycling and improved their thermal stability. This immobilization strategy preserved the flexibility of BAILs, while also allowing for the benefits of both heterogenized and free forms of BAILs. Furthermore, the introduced catalysts demonstrated short reaction times and high yields of products, along with high TON and TOF values, making them superior replacements for previously reported catalysts. [ABSTRACT FROM AUTHOR]

New C3-substituted 5,6-dihydropyrrolo[2,1-a]isoquinolines have been synthesized via three-com-ponent domino reaction of 1-aroyl-3,4-dihydroisoquinolines, dimethyl acetylenedicarboxylate, and CH acids in anhydrous acetonitrile under microwave irradiation at 130°C. [ABSTRACT FROM AUTHOR]

Skin photoaging due to ultraviolet B (UVB) exposure generates reactive oxygen species (ROS) that increase matrix metalloproteinase (MMP). Chlorin e6-photodynamic therapy (Ce6-PDT), in addition to being the first-line treatment for malignancies, has been shown to lessen skin photoaging, while curcumin is well known for reducing the deleterious effects of ROS. In the current study, PDT with three novel Ce6-curcumin derivatives, a combination of Ce6 and curcumin with various linkers, including propane-1,3-diamine for Ce6-propane-curcumin; hexane-1,6-diamine for Ce6-hexane-curcumin; and 3,3′-((oxybis(ethane-2,1-diyl))bis(oxy))bis(propan-1-amine) for Ce6-dipolyethylene glycol (diPEG)-curcumin, were studied for regulation of UVB-induced photoaging on human skin fibroblast (Hs68) and mouse embryonic fibroblast (BALB/c 3T3) cells. We assessed the antiphotoaging effects of Ce6-curcumin derivatives on cell viability, antioxidant activity, the mechanism of matrix metalloproteinase-1 and 2 (MMP-2) expression, and collagen synthesis in UVB-irradiated in vitro models. All three Ce6-curcumin derivatives were found to be non-phototoxic in the neutral red uptake phototoxicity test. We found that Ce6-hexane-curcumin-PDT and Ce6-propane-curcumin-associated PDT exhibited less cytotoxicity in Hs68 and BALB/c 3T3 fibroblast cell lines compared to Ce6-diPEG-curcumin-PDT. Ce6-diPEG-curcumin and Ce6-propane-curcumin-associated PDT showed superior antioxidant activity in Hs68 cell lines. Further, in UVB-irradiated in vitro models, the Ce6-diPEG-curcumin-PDT greatly attenuated the expression levels of MMP-1 and MMP-2 by blocking mitogen-activated protein kinases (MAPKs), activator protein 1 (AP-1), and tumor necrosis factor-α (NF-κB) signaling. Moreover, Ce6-diPEG-curcumin effectively inhibited inflammatory molecules, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, while accelerating collagen synthesis. These results demonstrate that Ce6-diPEG-curcumin may be a potential therapy for treating skin photoaging. [ABSTRACT FROM AUTHOR]

The possibility of expanding a hydrated imidazoline fragment in 2,3-dihydro-9H-dibenzo[b,f]imidazo[2,1-d][1,5]oxazocines was demonstrated for the first time, which granted access to 6,11-dihydro-12H-dibenzo[b,f][1,5]oxazocin-12-one derivatives, previously undescribed compounds with medium-sized rings. In addition, it was shown that imidazooxazocines underwent expansion reactions more readily than their seven-membered analogs. [ABSTRACT FROM AUTHOR]

The resulting solution was evaporated under reduced pressure to give the crude product, which was further purified by column chromatography on silica gel (20% EtOAc/hexane) to furnish B 30 b (49.5 mg, 0.19 mmol, 58%) as a white solid; mp 107.4-107.7 °C. The resulting solution was evaporated under reduced pressure to give the crude product B 29 b , which was further purified by column chromatography on silica gel (20% EtOAc/hexane) to furnish B 29 b (10.5 mg, 0.04 mmol, 75%) as a clear sticky oil. Keywords: epoxidation; cyclization; carbocation; fused-ring systems; stereoselectivity EN epoxidation cyclization carbocation fused-ring systems stereoselectivity 2757 2772 16 08/17/23 20230901 NES 230901 Graph Various oxacycles are privileged scaffolds in pharmaceutical industries, cosmetics, natural products, and drug discovery, among others. TOF-HRMS: I m i / I z i [M + Na] SP + sp calcd for C SB 19 sb H SB 20 sb O SB 4 sb Na: 335.1254; found: 335.1247. tert -Butyldimethyl((3-phenyl-1,3-dihydroisobenzofuran-1-yl)methoxy)silane (26b') By following the General Procedure G, and purification by column chromatography on silica gel (20% EtOAc/hexane), the product (24.0 mg, 0.71 mmol, 44%) was obtained as a yellow sticky gum. [Extracted from the article]

Signal Amplification by Reversible Exchange (SABRE) is an inexpensive and simple hyperpolarization technique that is capable of boosting nuclear magnetic resonance sensitivity by several orders of magnitude. It utilizes the reversible binding of para-hydrogen, as hydride ligands, and a substrate of interest to a metal catalyst to allow for polarization transfer from para-hydrogen into substrate nuclear spins. While the resulting nuclear spin populations can be dramatically larger than those normally created, their lifetime sets a strict upper limit on the experimental timeframe. Consequently, short nuclear spin lifetimes are a challenge for hyperpolarized metabolic imaging. In this report, we demonstrate how both hyperpolarization and long nuclear spin lifetime can be simultaneously achieved in nitrogen-15 containing derivatives of pyridazine and phthalazine by SABRE. These substrates were chosen to reflect two distinct classes of 15N2-coupled species that differ according to their chemical symmetry and thereby achieve different nuclear spin lifetimes. The pyridazine derivative proves to exhibit a signal lifetime of ∼2.5 min and can be produced with a signal enhancement of ∼2700. In contrast, while the phthalazine derivative yields a superior 15 000-fold 15N signal enhancement at 11.7 T, it has a much shorter signal lifetime. [ABSTRACT FROM AUTHOR]

Neuroblastoma represents 8-10 % of all malignant tumors childhood and is responsible for 15 % of cancer deaths in the pediatric population. Aggressive neuroblastomas are often resistant to chemotherapy. Canonically, neuroblastomas can be classified according to the MYCN (N-myc proto-oncogene protein) gene amplification, a common marker of tumor aggressiveness and poor prognosis. It has been found that certain compounds with chelating properties may show anticancer activity, but there is little evidence for the effect of chelators on neuroblastoma. The effect of new chelators characterized by the same functional group, designated as HLZ (1-hydrazino phthalazine), on proliferation (WST-1 and methylene blue assay), cell cycle (flow cytometry), apoptosis (proliferation assay after use of specific pharmacological inhibitors and western blot analysis) and ROS production (fluorometric assay based on dichlorofluorescein diacetate metabolism) was studied in three neuroblastoma cell lines with different levels of MYCN amplification. The molecules were effective only on MYCN-non-amplified cells in which they arrested the cell cycle in the G0/G1 phase. We investigated the mechanism of action and identified the activation of cell signaling that involves protein kinase C. [ABSTRACT FROM AUTHOR]

The pyrazolo conjugated phthalazine derivatives were synthesized with 85–88% yield by the one-pot reaction of diethyl phthalate with hydrazine hydrate, 1H -pyrazole-5-carbaldehydes and malononitrile or ethyl 2-cyanoacetate in [BMIM][OH] as green reaction medium at 70–75°C for 30–45 min. The potential of the synthesized compounds to inhibit cancer growth in HepG2 and MDA-MD-231 cells was evaluated. 3-Amino-1-(1-methyl-1H-pyrazol-5-yl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile demonstrated remarkable cytotoxicity with IC50 values of 8.2 and 8.7 µM against MCF-7 and DU145, respectively. Moreover, in silico studies revealed that this compound had a favorable binding energy of –7.1 kcal/mol in inhibiting the human protein mono-ADP-ribosyltransferase PARP15. [ABSTRACT FROM AUTHOR]

The parent 2-(4-benzyl-1-oxophthalazin-2(1H)-yl)-acetohydrazide (4) has twenty-nine compounds. The starting material for their corresponding mono, dipeptides and reactions with active methylene compounds were produced by chemoselective N-alkylation of 4-Benzyl-2H-phthalazin-1-one (2) with ethyl chloroacetate to afford (4-benzyl-1-oxo-1H-phthalazin-2-yl) methyl acetate (3). The ester 3 was hydrazinolyzed to give hydrazide 4, then azide 5 coupled with amino acid ester hydrochloride and/or amines to produce several monopeptides, then the methyl (2-(4-benzyl-1-oxophthalazin-2(1H)-yl) acetyl) glycinate (7a) was hydrazinolyzed to produce corresponding hydrazide 2-(4-benzyl-1-oxophthalazin-2(1H)-yl)-N-(2-hydrazineyl-2-oxo ethyl) acetamide (8a). The hydrazide 8a under azide coupling method was coupled with amino acid ester hydrochloride and/or amines to produce several dipeptides, and the hydrazide 8a was also condensed and/or cyclized with several carbonyl compounds. The cytotoxicity of the synthesized compounds was tested using MTT assay, as well as apoptosis-induction through EGFR inhibition. Compounds 11d, 12c and 12d exhibited potent cytotoxic activities with IC50 values of 0.92, 1.89 and 0.57 μM against MDA-MB-231 cells compared to Erlotinib (IC50 = 1.02 μM). Interestingly compound 12d exhibited promising potent EGFR inhibition with an IC50 value 21.4 nM compared to Erlotinib (IC50 = 80 nM). For apoptosis, compound 12d induced apoptosis in MDA-MB-231 cells by 64.4-fold (42.5% compared to 0.66 for the control); hence, this compound may serve as a potential target-oriented anti-breast cancer agent. These results agreed with the molecular docking studies that highlighted the binding disposition of compound 12d towards EGFR protein. Hence, compound 12d may serve as a potential and selective anti-breast cancer agent. [ABSTRACT FROM AUTHOR]

An expedient synthesis of hitherto unknown pyrrolo[2,1‐a]isoquinolinium salts from non‐aromatic aryl‐substituted 2H‐ and 3H‐pyrroles and internal alkynes has been developed. The process represents a rare example of N‐nucleophilic reaction of 2H‐ and 3H‐pyrroles and relies on the ortho‐C−H bond activation of non‐aromatic arylpyrroles in the presence of rhodium catalyst followed by alkyne annulation reaction. A broad range of diversely substituted salts was obtained in high yields under mild reaction conditions. The photophysical properties for selected representatives of novel pyrrolo[2,1‐a]isoquinolinium salts have been evaluated to demonstrate their potential as fluorescent materials for light‐emitting devices and bioimaging. [ABSTRACT FROM AUTHOR]

Photoactive Cu(I) complexes are promising luminescent materials owing to their abundant reserves and marvelous biocompatibility. In this work, we report the synthesis and characterization of two binuclear sulfur‐bridged Cu(I) complexes (POP)2Cu2(μ‐HS/Cl)2 ⋅ 0.92MeOH 1 (POP=(oxybis(2,1‐phenylene))bis(diphenylphosphine)) and (POP)2Cu2(μ‐HS)22, which were prepared by one‐pot facile solvothermal method with copper‐4‐tert‐butylbenzenethiol (CuSC6H4tBu) and POP as precursors. Complex 1 exhibits sky‐blue emission while complex 2 displays blue. Complex 1 was systemically investigated by PXRD, UV‐vis spectrum, IR, TGA and steady‐state spectra. Temperature‐dependent steady‐state emission and decay lifetime indicate that complex 1 is a typical phosphorescent emitter. [ABSTRACT FROM AUTHOR]

The microwave-assisted reaction of 2-nitroimidazole with 3-bromophenacyl bromide in the presence of potassium carbonate as a base and dimethylformamide as a solvent afforded 2-(3-bromophenyl)imidazo[2,1-b]oxazole. The formation of this compound was explained via a domino mechanism comprising an initial N-alkylation reaction of the imidazole substrate, followed by the base-promoted deprotonation of the position adjacent to the carbonyl to give an enolate anion that finally cyclizes via an intramolecular SNAr reaction, with the loss of the nitro group as potassium nitrite. Then, the proposed 1-(3-bromophenacyl)-2-nitroimidazole intermediate could be isolated by reducing the reaction time and was shown to be a precursor of the imidazo[2,1-b]oxazole final product. [ABSTRACT FROM AUTHOR]

The present study reports the synthesis and spectroscopic characterization of dinuclear silver(I) complexes, {[Ag(X-O)(phtz-N)]2(µ-phtz-N,N')2} (X = NO3 - (Ag1) and CF3SO3 - (Ag2), and phtz is phthalazine). The interaction of these two complexes with calf thymus DNA (ct-DNA) and bovine serum albumin (BSA) was investigated to assess their binding affinity to these biomolecules. The binding constants of complexes Ag1 and Ag2 to BSA are found to be higher than those for ct-DNA, being in accordance with their higher affinity toward the studied protein. The values of partition coefficient (logP) for the investigated complexes indicate higher cellular uptake efficiency of Ag1 than Ag2. The in vivo toxicity of the complexes Ag1 and Ag2 against the model organism, Caenorhabditis elegans, was studied to check their therapeutic potential.

An efficient and convenient palladium-catalyzed reductive system by employing sodium hydride as the hydrogen donor and acetic anhydride as an activator has been developed for transfer hydrogenation and acetylation of a wide range of N -heteroarenes including quinoline, phthalazine, quinoxaline, phenazine, phenanthridine, and indole. Moreover, acridine substrates could be directly reduced without the use of acetic anhydride. This protocol provides a simple method for the preparation of various saturated N -heterocycles. [ABSTRACT FROM AUTHOR]

The palladium‐catalyzed direct oxidative coupling reaction between 2‐aroylimidazoles with aromatic aldehydes or benzyl alcohols under oxidation conditions has been achieved to furnish a variety of carbonyl functionalized 2‐aroylimidazoles in moderate to good yields. The obtained products could be selectively transformed to the corresponding phthalazines and phthalazin‐1(2H)‐ones with hydrazine hydrate as the cyclization partner under different reaction temperature and construct an array of structurally diverse nitrogen‐containing heterocycles. [ABSTRACT FROM AUTHOR]

A new series of phthalazine−piperazine−pyrazole conjugates were synthesised and evaluated for their in vitro anticancer activity against three human cancer cell lines including MCF‐7 (breast), A549 (lung) and DU‐145 (prostate). The result data showed that compound 2‐((3‐(3,5‐dimethoxyphenyl)‐1H‐pyrazol‐5‐yl)methyl)‐4‐(piperazin‐1‐yl methyl)phthalazin‐1(2H)‐one (5 i) showed comparable activity against all the cell lines with the standard drug Etoposide. As well, compounds 2‐((3‐(3‐methoxyphenyl)‐1H‐pyrazol‐5‐yl) methyl)‐4‐(piperazin‐1‐ylmethyl) phthalazin‐1(2H)‐one (5 j) and 2‐((3‐(3,5‐dimethylphenyl)‐1H‐pyrazol‐5‐yl) methyl)‐4‐(piperazin‐1‐ylmethyl) phthalazin‐1(2H)‐one (5 l) exhibited promising activity against three cancer cell lines as compared to Etoposide. Three potent compounds (5 i, 5 j, and 5 l) were examined against the normal breast cell line in a cell viability assay (MCF‐10A), but none of them showed any apparent cytotoxicity with IC50 values above 78 μM. In addition, compounds 5 i, 5 j, and 5 l were screened for the VEGFR‐2 tyrosine kinase inhibitory activity using sorafenib as the standard drug and found that compound 5 i exhibited more potency in inhibiting the VEGFR‐2 tyrosine kinase as compared to sorafenib. Finally, molecular docking studies of compounds 5 i, 5 j and 5 l were also revealed that these compounds showed more binding interactions with VEGFR‐2 than VEGFR‐1. In accumulation to this, in silico pharmacokinetic profile was carried out for the potent compounds 5 i, 5 j and 5 l by SWISS/ADME and pkCSM. Whereas, 5 i, 5 j and 5 l compounds followed Lipinski, Veber, Egan, and Muegge rules without any deviation. [ABSTRACT FROM AUTHOR]

Recently, we presented a novel enantioselective multicomponent reaction of phthalazines, aldehydes and thiols accessing thioether‐substituted 1,2‐dihydronaphthalenes. Herein, a comprehensive investigation on the mechanism of this domino inverse electron‐demand (IEDDA)/thiol transfer reaction is disclosed. In particular, the origin of the stereochemical outcome has been rationalized, as well as structural requirement of the thiol component for an efficient transfer step. Detailed NMR spectroscopy studies uncover a competing reaction pathway resulting in N,S‐acetals. In addition, DFT computations illuminate the mechanism of the group transfer process and enable an explanation for the formation of the most dominant by‐product. The insights allow a direct prediction of suitable substrates for the reaction and provide the basis for further developments of novel stereoselective domino reactions. [ABSTRACT FROM AUTHOR]

A stereoselective synthesis of isoindolo[2,1‐a]quinolin‐11(5H)‐ones containing three contiguous stereogenic centers is described. This Lewis‐acid mediated reaction of enamides with N‐aryl‐acylimines affords the desired fused heterocyclic isoindolinones in high yields and diastereoselectivities. Scope and limitations of this method are discussed. The stereochemical outcome of this transformation indicates a stepwise reaction pathway. [ABSTRACT FROM AUTHOR]

This work describes the synthesis of 3-hydroxy-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,8-diones, their tautomerism, and reactivity towards binucleophiles. These molecules are novel and convenient building-blocks for the direct construction of biologically important polycyclic pyridones via an oxazinone ring-opening transformation promoted with ammonium acetate or acetic acid. In the case of o-phenylenediamine, partial aromatization of the obtained heterocycles proceeded to form polycyclic benzimidazole-fused pyridones (33–91%). [ABSTRACT FROM AUTHOR]

The racemic title compound, C34H32OS2, comprises an atropisomeric binaphthyl di­thio­acetal substituted at the methyl­ene carbon atom with a chiral benzyl alcohol. The two naphthalene ring systems are additionally substituted at the 3,3′-position with isopropyl groups. The overall stereochemistry is defined as aS,R and aR,S. The hydroxyl group forms an intra­molecular O--H...S hydrogen bond to one of the sulfur atoms. The crystal structure contains weak C--H...π inter­actions that link the mol­ecules into extended arrays. [ABSTRACT FROM AUTHOR]

Synthesis of novel 5‐hydroxyimidazo[2,1‐a]isoquinolin‐6(5H)‐ones have been achieved by Ru(II)‐catalyzed reaction of 2‐arylimidazoles with arylglyoxals. The method provided moderate to good yields of 5‐hydroxyimidazo[2,1‐a]isoquinolin‐6(5H)‐ones and is amenable to gram‐scale synthesis. The reaction involves imidazole‐directed Ru(II)‐catalyzed ortho‐dicarbonylation followed by nucleophilic cyclization of the NH‐group with the carbonyl group. Photophysical properties of the newly synthesized 5‐hydroxyimidazo‐[2,1‐a]isoquinolin‐6(5H)‐ones were investigated. [ABSTRACT FROM AUTHOR]

A highly efficient and versatile synthetic approach for the synthesis of 4-(pyren-1-ylmethyl)-1-(d-glycosyloxy) phthalazine nucleosides 11a,b, 13, β-S-nucleosides 16, 18, 20, and acyclo C-nucleosides 23a,b, 24, 25 and 27a–f was described and fully characterized. Furthermore, a series of desired new nucleoside analogues containing Se of 4-(pyren-1-ylmethyl) phthalazine-1(2H)-selenone 28–33 were synthesized. The structures of all reported compounds were confirmed by IR, 1H-NMR, 13C-NMR, MS and elemental analysis. All compounds have been screened for their antibacterial and antifungal activities. Maximum activity was shown by 20 and 33a comparable to the standard drugs with lower toxicity. The cytotoxicity of the selected compound was measured and evaluated. The energy gap between the highest occupied molecular orbital and lowest unoccupied molecular orbital was calculated using theoretical computations to reflect the chemical reactivity and kinetic stability of the synthesized compounds. Using density functional theory (DFT), electronic parameters such as the highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO) and the molecular electrostatic potential (MEPS) were calculated. On the basis of different studied structures, these properties were computed in order to elucidate the chemical reactivity and the kinetic stability. Obviously, the band gap energy (Eg) of structures studied reveals that the lowest band gap obtained for the structure 16-a indicates that it has the highest chemical reactivity and lowest kinetic stability. [ABSTRACT FROM AUTHOR]

A practical method for the synthesis of hydroxyalkylated indolo[2,1- a ]isoquinoline derivatives through the metal-free cascade cyclization of 2-arylindoles with alcohols in the presence of tert -butyl hydroperoxide (TBHP) is disclosed. The present method features transition-metal-free conditions and exceptional functional group tolerance. A series of valuable hydroxyalkylated indolo[2,1- a ]isoquinoline derivatives bearing various functional groups is synthesized in moderate to excellent yields. [ABSTRACT FROM AUTHOR]

This research presents the design and synthesis of a novel series of phthalazine derivatives as Topo II inhibitors, DNA intercalators, and cytotoxic agents. In vitro testing of the new compounds against HepG-2, MCF-7, and HCT-116 cell lines confirmed their potent cytotoxic activity with low IC50 values. Topo II inhibition and DNA intercalating activities were evaluated for the most cytotoxic members. IC50 values determination demonstrated Topo II inhibitory activities and DNA intercalating affinities of the tested compounds at a micromolar level. Amongst, compound 9d was the most potent member. It inhibited Topo II enzyme at IC50 value of 7.02 ±0.54 µM with DNA intercalating IC50 of 26.19 ±1.14 µM. Compound 9d was then subjected to an in vivo antitumor examination. It inhibited tumour proliferation reducing solid tumour volume and mass. Additionally, it restored liver enzymes, proteins, and CBC parameters near-normal, indicating a remarkable amelioration in their functions along with histopathological examinations. [ABSTRACT FROM AUTHOR]