- Phthalazine-1,4-dione derivatives as non-competitive AMPA receptor antagonists: design, synthesis, anticonvulsant evaluation, ADMET profile and molecular docking
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In view of the anticonvulsant activity reported for phthalazine derivatives as non-competitive AMPA receptor antagonists, a new series of phthalazine-1,4-diones (2–12) were designed and synthesized. The neurotoxicity was assessed using rotarod test. The molecular docking was performed for the synthesized compounds to assess their binding affinities toward AMPA receptor as non-competitive antagonists. The molecular modeling data were strongly interrelated to biological screening data. Compounds 8, 7b, 7a, 10 and 3a exhibited the highest binding affinities as non-competitive AMPA receptor antagonists and also showed the highest relative potencies of 1.78, 1.66, 1.60, 1.59 and 1.29, respectively, as anticonvulsants in comparison with diazepam. The most active compounds 8, 7b, 7a, 10 and 3a were further tested against maximal electroshock seizure (MES). Compounds 8 and 7b and 3a showed 100% protection at a dose level of 125?μgm/kg, while compounds 7a and 10 exhibited 83.33% protection at the same dose level. These agents exerted low neurotoxicity and high safety margin in comparison with valproate as a reference drug. Most of our designed compounds exhibited good ADMET profile.
- El-Helby, Abdel-Ghany A.,Ayyad, Rezk R. A.,El-Adl, Khaled,Elkady, Hazem
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- On-water, catalyst-free and room-temperature construction of 2-aryl-1,3,4-oxadiazole derivatives from 1,1-dichloro-2-nitroethene and hydrazides
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2-Aryl-1,3,4-oxadiazoles are important functional molecules in many research fields. A green synthetic method for preparation of 2-aryl-1,3,4-oxadiazoles was developed using hydrazides and highly reactive 1,1-dichloro-2-nitroethene. This eco-friendly protocol featured high yields, purification simplicity, water-based reaction medium, energy efficiency and no addition of catalysts.
- Zhu, Fengjuan,Zou, Minming,Shao, Xusheng,Li, Zhong
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- Green and efficient synthesis of 1H-indazolo[1,2-b] phthalazine-1,6,11(13H)-triones using ZrO(NO3)2.2H2O as a novel catalyst and theoretical study of synthesized compounds
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The one-pot three-component synthesis for the preparation of 1H-indazolo[1,2-b] phthalazine-1,6,11(13H)-triones through condensation of phthalimide, hydrazine monohydrate, dimedone, and aromatic aldehydes in the presence of a novel catalytic amount of ZrO(NO3)2.2H2O at reflux conditions in water has been reported. Quantum theoretical calculations for the three structures of compounds (5a, 5b, and 5c) were performed using the G3MP2, LC-ωPBE, MP2, and B3LYP methods with the 6-311 + G** basis set. After optimizing the structures, geometric parameters were obtained and experimental measurements were compared with the calculated data. The structures of the products were confirmed by IR, 1H NMR, 13C NMR, and elemental analysis. IR spectra data and 1H NMR and 13C NMR chemical shifts computations of the 1H-indazolo[1,2-b]phthalazine-1,6,11(13H)-trione derivatives in the ground state were calculated. Frontier molecular orbitals, total density of states, thermodynamic parameters, and molecular electrostatic potentials of the title compounds were investigated by theoretical calculations. Molecular properties such as the ionization potential (I), electron affinity (A), chemical hardness (η), electronic chemical potential (μ), and electrophilicity (ω) were investigated for the structures. Consequently, there was an excellent agreement between experimental and theoretical results.
- Saberi Biroon, Shabnam,Shajari, Nahid,Yahyaei, Hooriye
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- Reaction of α-Acetoxy-N-nitrosopyrrolidine with Deoxyguanosine and DNA
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We investigated the reactions of α-acetoxy-N-nitrosopyrrolidine (α-acetoxyNPYR) with dGuo and DNA. α-AcetoxyNPYR is a stable precursor to the major proximate carcinogen of NPYR, α-hydroxyNPYR (3). Our goal was to develop appropriate conditions for the analysis of DNA adducts of NPYR formed in vivo. Products of the α-acetoxyNPYR-dGuo reactions were analyzed directly by HPLC or after treatment of the reaction mixtures with NaBH3CN. Products of the α-acetoxyNPYR-DNA reactions were released by enzymatic or neutral thermal hydrolysis of the DNA, then analyzed by HPLC. Alternatively, the DNA was treated with NaBH3CN prior to hydrolysis and HPLC analysis. The reactions of α-acetoxyNPYR with dGuo and DNA were complex. We have identified 13 products of the dGuo reaction - 6 of these were characterized in this reaction for the first time. They were four diastereomers of N2-(3-hydroxybutylidene)-dGuo (20,21), 7-(N-nitrosopyrrolidin-2-yl)Gua (2), and 2-(2-hydroxypyrrolidin-1-yl)deoxyinosine (12). Adducts 20 and 21 were identified by comparison to standards produced in the reaction of 3-hydroxybutanal with dGuo. Adduct 2 was identified by its spectral properties while adduct 12 was characterized by comparison to an independently synthesized standard. With the exception of adduct 2, all products of the dGuo reactions were also observed in the DNA reactions. The major product in both the dGuo and DNA reactions was N2-(tetrahydrofuran-2-yl)dGuo (10), consistent with previous studies. Several other previously identified adducts were also observed in this study. HPLC analysis of reaction mixtures treated with NaBH3CN provided improved conditions for adduct identification, which should be useful for in vivo studies of DNA adduct formation by NPYR.
- Wang, Mingyao,McIntee, Edward J.,Shi, Yongli,Cheng, Guang,Upadhyaya, Pramod,Villalta, Peter W.,Hecht, Stephen S.
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- Heterocyclic synthesis via enaminones: Novel synthesis of (1H)-pyridin-2-one, pyrazolo[1,5-a]pyrimidine and isoxazole derivatives incorporating a N-methylphthalimide and their biological evaluation
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Novel synthesis of (1H)-pyridin-2-one, pyrazolo[1,5-a]pyrimidine and isoxazole derivatives incorporating N-methylphthalimide moiety are reported. Reaction of enaminone 2 with malononitrile affords 4. Condensation of 2 with cyanothioacetamide or benzoylacetonitrile affords compounds 6 and 7 respectively. Reaction of 2 with hydrazine hydrate afford 2,3- dihydrophthalazine-1,4-dione (10). Condensation of 2 with hydroxylamine and 3-aminopyrazole derivatives affords compounds 12 and 15a,b respectively. Antimicrobial and antifungal activity were determined for representative compounds and most of them showed moderate activity as antimicrobial agents, while compounds 2 and 7 show strong activity against Aspergillus niger. The structure of the newly synthesized compounds was elucidated by elemental analyses and 1H nmr spectra and some cases by 13C nmr investigation.
- Al-Omran, Fatima,El-Khair, Adel A.
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- An improved procedure for the preparation of aminomethyl polystyrene resin and its use in solid phase (peptide) synthesis
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2-Aminoethanol was used to successively replace hydrazine in the preparation of aminomethyl polystyrene resin thereby facilitating purification and by-product removal. The syntheses of the polypeptides ACP (65-74) and oxytocin demonstrated that the use of aminomethyl polystyrene resin prepared in this manner was equal to or better than that prepared using the hydrazine method.
- Harris, Paul W.R.,Yang, Sung Hyun,Brimble, Margaret A.
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- One-Pot Four Component Synthesis of 3-Amino-1-(1H-indol-2-yl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine Derivatives Mediated by [DBUH][OAc]
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One-pot, four component, green, and efficient synthesis of 3-amino-1-(5-nitro-1H-indol-2-yl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine derivatives by reaction of phthalic anhydride with hydrazine hydrate, 5-nitro-1H-indole-3-carboxaldehyde–indole-3-carboxaldehydes and malononitrile–ethyl cyanoacetate in the presence of [DBUH][OAc] at 60–65°C is developed. The method is characterized by short reaction time, high yields, and purity of products formed.
- Jeevan Raghavendra,Siddaiah
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- A Peptide Backbone Stapling Strategy Enabled by the Multicomponent Incorporation of Amide N-Substituents
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The multicomponent backbone N-modification of peptides on solid-phase is presented as a powerful and general method to enable peptide stapling at the backbone instead of the side chains. This work shows that a variety of functionalized N-substituents suitable for backbone stapling can be readily introduced by means of on-resin Ugi multicomponent reactions conducted during solid-phase peptide synthesis. Diverse macrocyclization chemistries were implemented with such backbone N-substituents, including the ring-closing metathesis, lactamization, and thiol alkylation. The backbone N-modification method was also applied to the synthesis of α-helical peptides by linking N-substituents to the peptide N-terminus, thus featuring hydrogen-bond surrogate structures. Overall, the strategy proves useful for peptide backbone macrocyclization approaches that show promise in peptide drug discovery.
- Ricardo, Manuel G.,Marrrero, Javiel F.,Valdés, Oscar,Rivera, Daniel G.,Wessjohann, Ludger A.
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- Blue highly fluorescent boron difluoride complexes based on phthalazine-pyridine
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Three new boron difluoride complexes based on phthalazine-pyridine, denoted (6), (7) and (8), have been synthesized and their photophysical and electrochemical properties have been studied. Solutions of these new BF2-complexes exhibit an intense blue fluorescence under UV light at low concentrations. Fluorescence quantum yields (QYs) have been determined by photoluminescence (PL) spectroscopy and decay times (τ) by semi-empirical methods. QYs of (6), (7) and (8) vary from 25% to 79%. HOMO and LUMO energy levels have been estimated by cyclic voltammetry and PL spectroscopy. The HOMO and LUMO energy levels, at ～-5.3 eV and ～-2.3 eV, respectively, make these new complexes interesting candidates as blue emitters in OLED applications.
- Vuong, Thi Minh Ha,Weimmerskirch-Aubatin, Jennifer,Lohier, Jean-Fran?ois,Bar, Nathalie,Boudin, Sophie,Labbé, Christophe,Gourbilleau, Fabrice,Nguyen, Hien,Dang, Tung Thanh,Villemin, Didier
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- Single-particle and ensemble diffusivitiesa-test of ergodicity
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To prove the ergodic theorem experimentally the diffusivities of guest molecules inside a nanostructured porous glass were measured by using two conceptually different approaches under identical conditions. The data obtained through the direct observation of dye-molecule diffusion by single-molecule tracking experiments (red circles) was in perfect agreement with the ensemble value obtained in pulsed-field gradient NMR experiments (black squares). Copyright
- Feil, Florian,Naumov, Sergej,Michaelis, Jens,Valiullin, Rustem,Enke, Dirk,Kaerger, Joerg,Braeuchle, Christoph
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- Generation of Molecular Complexity from Cyclooctatetraene: Preparation of Aminobicyclo[5.1.0]octitols
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A series of eight stereoisomeric N-(tetrahydroxy bicyclo-[5.1.0]oct-2S-yl)phthalimides were prepared in one to four steps from N-(bicyclo[5.1.0]octa-3,5-dien-2-yl)phthalimide (±)-7, which is readily available from cyclooctatetraene (62% yield). The structural assignments of the stereoisomers were established by 1H NMR spectral data as well as X-ray crystal structures for certain members. The outcomes of several epoxydiol hydrolyses, particularly ring contraction and enlargement, are of note. The isomeric phthalimides as well as the free amines did not exhibit β-glucosidase inhibitory activity at a concentration of less than 100 μM. Ringing the changes: A spectrum of stereoisomeric protected aminobicyclo[5.1.0]octitols were prepared from the simple hydrocarbon cyclooctatetraene in 6-9 steps (see figure). Whereas certain hydrolyses of epoxydiols proceeded to form tetraols, others resulted in either ring-expanded or ring- contracted structures.
- El-Mansy, Mohamed F.,Flister, Matthew,Lindeman, Sergey,Kalous, Kelsey,Sem, Daniel S.,Donaldson, William A.
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- Design, synthesis, molecular modeling and biological evaluation of novel 2,3-dihydrophthalazine-1,4-dione derivatives as potential anticonvulsant agents
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In view of their expected anticonvulsant activity, some novel derivatives of 2,3-dihydrophthalazine-1,4-dione 4–22 were designed, synthesized and evaluated using pentylenetetrazole (PTZ) and picrotoxin as convulsion-inducing models. Moreover, the most active compounds were tested against electrical induced convulsion using maximal electroshock (MES) models of seizures. Most of the tested compounds showed considerable anticonvulsant activity in at least one of the anticonvulsant tests. Compounds 13 and 14g were proved to be the most potent compounds of this series with relatively low toxicity in the median lethal dose test when compared with the reference drug. Molecular modeling studies were done to verify the biological activity. The obtained results showed that the most potent compounds could be useful as a template for future design, optimization, and investigation to produce more active analogues.
- El-Helby, Abdel Ghany A.,Ayyad, Rezk R.,Sakr, Helmy M.,Abdelrahim, Adel S.,El-Adl,Sherbiny, Farag S.,Eissa, Ibrahim H.,Khalifa, Mohamed M.
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- Design, Synthesis, Molecular Docking, and Anticancer Activity of Phthalazine Derivatives as VEGFR-2 Inhibitors
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Novel series of phthalazine derivatives 6–11 were designed, synthesized, and evaluated for their anticancer activity against two human tumor cell lines, HCT-116 human colon adenocarcinoma and MCF-7 breast cancer cells, targeting the VEGFR-2 enzyme. Compounds 7a,b and 8b,c showed the highest anticancer activities against both HCT116 human colon adenocarcinoma cells with IC50 of 6.04 ± 0.30, 13.22 ± 0.22, 18 ± 0.20, and 35 ± 0.45 μM, respectively, and MCF-7 breast cancer cells with IC50 of 8.8 ± 0.45, 17.9 ± 0.50, 25.2 ± 0.55, and 44.3 ± 0.49 μM, respectively, in comparison to sorafenib as reference drug with IC50 of 5.47 ± 0.3 and 7.26 ± 0.3 μM, respectively. Eleven compounds in this series were further evaluated for their inhibitory activity against VEGFR-2, where compounds 7a, 7b, 8c, and 8b also showed the highest VEGFR-2 inhibition with IC50 of 0.11 ± 0.01, 0.31 ± 0.03, 0.72 ± 0.08, and 0.91 ± 0.08 μM, respectively, in comparison to sorafenib as reference ligand with IC50 of 0.1 ± 0.02. Furthermore, molecular docking studies were performed for all synthesized compounds to predict their binding pattern and affinity towards the VEGFR-2 active site, in order to rationalize their anticancer activity in a qualitative way.
- El-Helby, Abdel-Ghany A.,Ayyad, Rezk R. A.,Sakr, Helmy,El-Adl, Khaled,Ali, Mamdouh M.,Khedr, Fathalla
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- Effects of mixed H2O-CH3CN solvents on the rate of hydrazinolysis of N-phenylphthalimide: Spectral and kinetic evidence for the occurrence of N-aminophthalimide on the reaction path
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Kinetic study on the cleavage of N-phenylphthalimide (NPhPT) in the presence of 0.05 M NH2NH2 and mixed H2O-CH 3CN solvents reveals the occurrence of reaction scheme B ← A → C →-An C1↑E → F where A, B, C, C1, An, E, and F represent NPhPT, 0-CO2 -C6H4CONHC6H5, 0-CONHNH2C6H4-CONHC6H5, N-aminophthalimide, aniline, 0-CO2-C6H 4CONHNH2, and 0-CONHNH2C6H 4-CONHNH2, respectively. But, in the presence of either nonbuffered ≥0.20 M NH2NH2 or hydrazine buffer of pH～7.30-8.26 with total buffer concentration ([Buf]T) of > 0.02 M, further conversion of F to 2,3-dihydrophthalazine-1,4-dione (DHPD) has been detected depending upon the length of the reaction time (t), the values of [Buf]T, and pH. It has been shown that the rate of conversion of C1 to F is much faster than that of C to C1 which is much faster than that of F to DHPD. The reaction step A → C involves general base (GB) catalysis, while step C → C1 seems to involve specific base-general acid (GA) and GB-GB catalysis.
- Ariffin, Azhar,Leng, Sim Yoke,Lan, Lai Chwee,Khan, M. Niyaz
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- Synthesis of Some New Heterocycles Derived from Novel 2-(1,3-Dioxisoindolin-2-yl)Benzoyl Isothiocyanate
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Novel 2-(1,3-Dioxisoindolin-2-yl)benzoyl isothiocyanate was prepared and underwent addition-cyclization reactions with some nucleophilic reagents. Simultaneous or subsequent cyclization of the obtained adducts gave a diverse range of differently sized heterocycles and thioureas. The structures of the synthesized compounds were confirmed by microanalytical and spectral data.
- Hemdan, Magdy M.,El-Sayed, Amira A.
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- Pharmacological evaluation of some new 1-substituted-4-hydroxy-phthalazines
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In the present study, a series of 1-substituted-4-hydroxyphthalazines were synthesized and characterized by IR, 1H-NMR and Elemental analysis. The compounds were assayed against seizures induced by maximal electroshock (MES) and pentylenetetrazole (scMet). Neurologic deficit was evaluated by the rotarod test. The decrease in the elevated motor activity by introceptive chemical stimuli (amphetamine antagonistic activity) was studied at the dose level of 25 and 50 mg kg-1 and cardiac activity was also studied. All the compounds exhibited significant anticonvulsant activity. Compounds 4, 12, 13 and 17 were most active of the seriesagainst MES-induced seizures. Compounds 2, 4, 13 and 17 exhibited significant decrease in the elevated motor activity at the dose of 50 mg kg-1. Remarkable sympathetic blocking activity was observed with 3, 5, 6, 7, 9 and 15 only.
- Sivakumar, Ramaiya,Kishore Gnanasam, Sundararaj,Ramachandran, Somasundaram,Thomas Leonard, Joseph
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- Kinetic Evidence for the Occurence of a Stepwise Mechanism in Hydrazinolysis of Phthalimide
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The apparent second-order rate constants, knapp, for the reaction of hydrazine with phthalimide at a constant pH follow the empirical relationship knapp = A1T/(1 + A2T), where T represents the total hydrazine buffer concentration.The nonlinear variation of knapp against T is attributed to the change in the rate-determining step with change in T at a constant pH, and this provides evidence for the existence of an intermediate on the reaction path.The cyclization of o-(aminocarbamoyl)benzamide to 2,3-dihydrophthalazine-1,4-dione involves N-aminophthalimide as the intermediate.
- Khan, M. Niyaz
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- Implementation of a combinatorial cleavage and deprotection scheme. 1. Synthesis of phthalhydrazide libraries
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Phthalhydrazide libraries are synthesized in solution from substituted hydrazines and phthalimides in several different library formats including single compounds, indexed sub-libraries and a full library. When carried out during solid-phase synthesis, this combinatorial cleavage and deprotection scheme offers the possibility for generating a diverse library of substituted phthalhydrazides. Copyright
- Nielsen, John,Rasmussen, Palle H.
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- Artificial Iron Proteins: Modeling the Active Sites in Non-Heme Dioxygenases
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An important class of non-heme dioxygenases contains a conserved Fe binding site that consists of a 2-His-1-carboxylate facial triad. Results from structural biology show that, in the resting state, these proteins are six-coordinate with aqua ligands occupying the remaining three coordination sites. We have utilized biotin-streptavidin (Sav) technology to design new artificial Fe proteins (ArMs) that have many of the same structural features found within active sites of these non-heme dioxygenases. An Sav variant was isolated that contains the S112E mutation, which installed a carboxylate side chain in the appropriate position to bind to a synthetic FeII complex confined within Sav. Structural studies using X-ray diffraction (XRD) methods revealed a facial triad binding site that is composed of two N donors from the biotinylated ligand and the monodentate coordination of the carboxylate from S112E. Two aqua ligands complete the primary coordination sphere of the FeII center with both involved in hydrogen bond networks within Sav. The corresponding FeIII protein was also prepared and structurally characterized to show a six-coordinate complex with two exogenous acetato ligands. The FeIII protein was further shown to bind an exogenous azido ligand through replacement of one acetato ligand. Spectroscopic studies of the ArMs in solution support the results found by XRD.
- Batyuk, Alexander,Bhowmick, Asmit,Borovik, A. S.,Brewster, Aaron S.,Follmer, Alec H.,Fuller, Franklin D.,Green, Michael T.,Gul, Sheraz,Heinisch, Tillmann,Kern, Jan,Kim, In-Sik,Miller, Kelsey R.,Mittra, Kaustuv,Paretsky, Jonathan D.,Sauter, Nicholas K.,Sutherlin, Kyle D.,Ward, Thomas R.,Yano, Junko
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- Wavelength dependent photoextrusion and tandem photo-extrusion reactions of ninhydrin bis-acetals for the synthesis of 8-ring lactones, benzocyclobutenes and orthoanhydrides
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Ninhydrin bis-acetals give access to 8-ring lactones, benzocyclo-butenes and spirocyclic orthoanhydrides through photoextrusion and tandem photoextrusion reactions. Syntheses of fimbricalyxlactone B, isoshihunine and numerous biologically-relevant heteroc
- George, Michael W.,Hanson-Heine, Magnus W. D.,Harrowven, David C.,Kayal, Surajit,Light, Mark E.,Raimbach, William A. T.,Sun, Wei,Sun, Xue-Zhong
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supporting information
p. 1546 - 1549
(2022/02/14)
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- Structural identification between phthalazine-1,4-diones and n-aminophthalimides via vilsmeier reaction: Nitrogen cyclization and tautomerization study
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N-aminophthalimides and phthalazine 1,4-diones were synthesized from isobenzofuran1,3-dione, isoindoline-1,3-dione, furo [3,4-b] pyrazine-5,7-dione, or 1H-pyrrolo [3,4-c] pyridine-1,3dione with monohydrate hydrazine to carry out the 5-exo or 6-endo nitrogen cyclization under the different reaction conditions. Based on the control experimental results, 6-endo thermodynamic hydrohydrazination and kinetical 5-exo cyclization reactions were individually selective formation. Subsequently, Vilsmeier amidination derivatization was successfully developed to probe the structural divergence between N-aminophthalimide 2 and phthalazine 1,4-dione 3. On the other hand, the best tautomerization of N-aminophthalimide to diazinone was also determined under acetic acid mediated solution.
- Chung, Cheng-Yen,Li, Sin-Min,Lin, Hui-Yi,Tsai, Shuo-En,Tseng, Ching-Chun,Wong, Fung Fuh
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supporting information
(2021/05/31)
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- Discovery of novel triazolophthalazine derivatives as DNA intercalators and topoisomerase II inhibitors
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A new series of triazolophthalazine derivatives was designed and synthesized as topoisomerase II (Topo II) inhibitors and DNA intercalators. The synthesized derivatives were evaluated in vitro for their cytotoxic activities against three human cancer cell lines: HepG2, MCF-7, and HCT-116 cells. Compound IXb was the most potent counterpart with IC50 values of 5.39 ± 0.4, 3.81 ± 0.2, and 4.38 ± 0.3 μM, as it was about 1.47, 1.77, and 1.19 times more active than doxorubicin (IC50 = 7.94 ± 0.6, 6.75 ± 0.4, and 5.23 ± 0.3 μM) against HepG2, MCF-7, and HCT-116 cells, respectively. Additionally, the binding affinity of the synthesized compounds toward the DNA molecule was assessed using the DNA/methyl green assay. Compound?IXb showed an excellent DNA binding affinity with an IC50 value of 27.16 ± 1.2 μM, which was better than that of the reference drug doxorubicin (IC50 = 31.02 ± 1.80 μM). Moreover, compound IXb was the most potent member among the tested compounds when investigated for their Topo II inhibitory activity. Furthermore, compound IXb induced apoptosis in HepG2 cells and arrested the cell cycle at the G2/M phase. Additionally, compound IXb showed Topo II poisoning effects at 2.5 μM and Topo II catalytic inhibitory effects at 5 and 10 μM. Finally, molecular docking studies were carried out against the DNA–Topo II complex and DNA, to investigate the binding patterns of the designed compounds.
- Sakr, Helmy,Ayyad, Rezk R.,El-Helby, Ali A.,Khalifa, Mohamed M.,Mahdy, Hazem A.
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- N-Amino-1,8-Naphthalimide is a Regenerated Protecting Group for Selective Synthesis of Mono-N-Substituted Hydrazines and Hydrazides
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A new route to synthesis of various mono-N-substituted hydrazines and hydrazides by involving in a new C?N bond formation by using N-amino-1,8-naphthalimide as a regenerated precursor was invented. Aniline and phenylhydrazines are reproduced upon reacting these individually with 1,8-naphthalic anhydride followed by hydrazinolysis. The practicality and simplicity of this C?N dihalo alkanes; developed a synthon for bond formation protocol was exemplified to various hydrazines and hydrazides. N-amino-1,8-naphthalimide is suitable synthon for transformation for selective formation of mono-substituted hydrazine and hydrazide derivatives. Those are selective mono-amidation of hydrazine with acid halides; mono-N-substituted hydrazones from aldehydes; synthesis of N-aminoazacycloalkanes from acetohydrazide scaffold and inserted to hydroxy derivatives; distinct synthesis of N,N-dibenzylhydrazines and N-benzylhydrazines from benzyl halides; synthesis of N-amino-amino acids from α-halo esters. Ecofriendly reagent N-amino-1,8-naphthalimide was regenerated with good yields by the hydrazinolysis in all procedures.
- Manoj Kumar, Mesram,Venkataramana, Parikibanda,Yadagiri Swamy, Parikibanda,Chityala, Yadaiah
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supporting information
p. 17713 - 17721
(2021/11/10)
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- Novel triazolophthalazine-hydrazone hybrids as potential PCAF inhibitors: Design, synthesis, in vitro anticancer evaluation, apoptosis, and molecular docking studies
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Three novel series of triazolophthalazine derivatives bearing hydrazone moiety were designed, synthesized, and evaluated for their anticancer activity against four human cancer cell lines by MTT assay. Six derivatives demonstrated comparable activity with Doxorubicin reference drug against the selected cancer cells. Especially, compound 16 showed the most potent activity with IC50 values of 5.70, 8.04, 11.15, and 4.25, μM against HePG2, MCF-7, PC3, and HCT-116 respectively. Also, compound 26 exhibited comparable inhibitory effect with that of Doxorubicin against the selected cancer cell lines with IC50 values of 6.45, 8.63, 12.28, and 7.03 μM against HePG2, MCF-7, PC3, and HCT-116 respectively. Investigation of the apoptotic activity of the two most active compounds revealed that compounds 16 and 26 could induce both the early and the late apoptosis of HePG2. Further mechanistic study of the HePG2 cell cycle confirmed the spectacular cytotoxic and apoptotic effects of both compounds. Compounds 16 and 26 showed a pronounced increase in cells in G2/M and Pre G1 phases with a concomitant reduction of cells in G0-G1 and S phases. A follow up enzymatic assay indicated that these two compounds have comparable activities with that of bromosporine as PCAF inhibitors with IC50 values of 8.13 and 5.31 μM respectively. Moreover, molecular docking study for all the synthesized compounds was performed to predict their binding affinities toward the active site of histone acetyltransferase GCN5. Results of molecular docking were strongly correlated with that of the cytotoxicity study.
- Abulkhair, Hamada S.,Ahmed, Hany E. A.,Bayoumi, Ashraf H.,Ghiaty, Adel,Turky, Abdallah
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- Design, synthesis, and antitumor activity of novel compounds based on 1,2,4-triazolophthalazine scaffold: Apoptosis-inductive and PCAF-inhibitory effects
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The antitumor activity of newly synthesised triazolophthalazines (L-45 analogues) 10–32 was evaluated in human hepatocellular carcinoma (HePG-2), breast cancer (MCF-7), prostate cancer (PC3), and colorectal carcinoma (HCT-116) cells. Compounds 17, 18, 25, and 32 showed potent antitumor activity (IC50, 2.83–13.97 μM), similar to doxorubicin (IC50, 4.17–8.87 μM) and afatinib (IC50, 5.4–11.4 μM). HePG2 was inhibited by compounds 10, 17, 18, 25, 26, and 32 (IC50, 3.06–10.5 μM), similar to doxorubicin (IC50, 4.50 μM) and afatinib (IC50, 5.4 μM). HCT-116 and MCF-7 were susceptible to compounds 10, 17, 18, 25, and 32 (IC50, 2.83–10.36 and 5.69–11.36 μM, respectively), similar to doxorubicin and afatinib (IC50 = 5.23 and 4.17, and 11.4 and 7.1 μM, respectively). Compounds 17, 25, and 32 exerted potent activities against PC3 (IC50, 7.56–12.28 μM) compared with doxorubicin (IC50, 8.87 μM) and afatinib (IC50 7.7 μM). Compounds 17 and 32 were the strongest PCAF inhibitors (IC50, 5.31 and 10.30 μM, respectively) and compounds 18 and 25 exhibited modest IC50 values (17.09 and 32.96 μM, respectively) compared with bromosporine (IC50, 5.00 μM). Compound 17 was cytotoxic to HePG2 cells (IC50, 3.06 μM), inducing apoptosis in the pre-G phase and arresting the cell cycle in the G2/M phase. Molecular docking for the most active PCAF inhibitors (17 and 32) was performed.
- Turky, Abdallah,Bayoumi, Ashraf H.,Ghiaty, Adel,El-Azab, Adel S.,A.-M. Abdel-Aziz, Alaa,Abulkhair, Hamada S.
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- N-Chlorination-induced, oxidative ring contraction of 1,4-dimethoxyphthalazines
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A rarely explored oxidative ring contraction of electron-rich 1,2-diazine is described. Upon treatment with an electrophilic chlorinating reagent (TCICA), 1,4-dimethoxyphthalazines undergo an N-chlorination-induced ring contraction that is accompanied by the loss of one nitrogen atom. The scope of this unusual reactivity was examined with a range of 1,4-dimethoxyphthalazine derivatives. In addition, a mechanism proceeding via a bicyclic species was proposed on the basis of an isolated reaction intermediate and DFT calculations.
- Im, Jeong Kyun,Yang, ByeongDo,Jeong, Ilju,Choi, Jun-Ho,Chung, Won-jin
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supporting information
(2020/06/03)
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- Utilization of cyanoacetohydrazide and 2-(1,3-dioxoisoindolin-2-yl) acetyl chloride in the synthesis of some novel anti-proliferative heterocyclic compounds
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Owing to its high reactivity and commercial availability, 2-cyanoacetohydrazide can be utilized as a versatile and appropriate intermediate for synthesis of a broad variety of heterocyclic compounds. Thus, 2-cyanoacetohydrazide and 2-(1,3-dioxoisoindolin-2-yl) acetyl chloride were used as starting materials for construction of new heterocyclic compounds bearing 1,3-dioxoisoindoline moiety. The newly synthesized compounds were recognized by elemental analyses and spectral data (IR, 1H-NMR, and 13C-NMR spectra). The synthesized compounds were screened for their anti-proliferative activity against two human epithelial cell lines; breast (MCF-7) and liver (HepG2) as well as to normal fibroblasts (WI-38). The data showed distinctly that compounds 1 and 12 presented promising in-vitro anti-proliferative activity against two cell lines (MCF-7 and HepG2) without harming normal fibroblasts.
- Hekal, Mohamed H.,Ali, Yasmeen M.,Abu El-Azm, Fatma S. M.
-
p. 2839 - 2852
(2020/07/13)
-
- Design, synthesis, molecular modeling, in vivo studies and anticancer activity evaluation of new phthalazine derivatives as potential DNA intercalators and topoisomerase II inhibitors
-
Herein we report the design and synthesis of a new series of phthalazine derivatives as Topo II inhibitors and DNA intercalators. The synthesized compounds were in vitro evaluated for their cytotoxic activities against HepG-2, MCF-7 and HCT-116 cell lines. Additionally, Topo II inhibitory activity and DNA intercalating affinity were investigated for the most active compounds as a potential mechanism for the anticancer activity. Compounds 15h, 23c, 32a, 32b, and 33 exhibited the highest activities against Topo II with IC50 ranging from 5.44 to 8.90 μM, while compounds 27 and 32a were found to be the most potent DNA binders at IC50 values of 36.02 and 48.30 μM, respectively. Moreover, compound 32a induced apoptosis in HepG-2 cells and arrested the cell cycle at the G2/M phase. Besides, compound 32a showed Topo II poisoning effect at concentrations of 2.5 and 5 μM, and Topo II catalytic inhibitory effect at a concentration of10 μM. In addition, compound 32b showed in vivo a significant tumor growth inhibition effect. Furthermore, molecular docking studies were carried out against DNA-Topo II complex and DNA to investigate the binding patterns of the designed compounds.
- Khalifa, mohamed m.,Radwan, mohamed m.,Rashed, mahmoud,Sakr, Helmy,ayyad, Rezk R.,belal, amany,eissa, Ibrahim H.,el-Helby, abdel-Ghany a.,el-Sharkawy, abdou,elSohly, mahmoud a.,elhendawy, mostafa a.,mahdy, Hazem a.,metwaly, ahmed m.
-
-
- The synthesis and anti‐tumour properties of novel 4-substituted phthalazinones as Aurora B kinase inhibitors
-
A series of novel 4-substituted phthalazinones as Aurora B kinase inhibitors was synthesized and evaluated the anti-proliferative activities against A549, HCT116, MCF-7 and HepG2 cells. 1-(4-(2-((4-Oxo-3,4-dihydrophthalazin-1-yl)amino)ethyl) phenyl)-3-(3-(trifluoromethyl)phenyl)urea (17b) exhibited the most potent anti-proliferative activity against HCT116 cells with IC50 value of 4.35 ± 1.21 μM, as well as the moderate Aurora B inhibitory activity with the IC50 value of 142 nM. Furthermore, 17b inhibited the phosphorylation of Aurora B on Thr232, leading to cell cycle arrest in the G2/M phase by down-regulating the expression of CyclinB1 and Cdc2 proteins, and apoptosis by up-regulating the expression of BAD and Bax proteins in HCT116 cells. In addition, a docking study revealed that 17b could form key hydrogen bonds with Ala173, Glu171 and Glu177 in Aurora B. All the results reveal that 17b is worthy of further development as an Aurora B kinase inhibitor.
- Chen, Shi-Wu,Hao, Shu-Yi,Mou, Hong-Xia,Wang, Shuai,Xu, Yu,Zhang, Xiu-Juan
-
-
- Ultralow-Molecular-Weight Stimuli-Responsive and Multifunctional Supramolecular Gels Based on Monomers and Trimers of Hydrazides
-
The simpler, the better. A series of simple, neutral and ultralow-molecular-weight (MW: 140–200) hydrazide-derived supramolecular gelators have been designed and synthesized in two straightforward steps. For non-conjugated cyclohexane-derived hydrazides, their monomers can self-assemble to form gels through intermolecular hydrogen bonds and dipole-dipole interactions. Significantly, conjugated phthalhydrazide can self-aggregate into planar and circular trimers through intermolecular hydrogen bonds and then self-assemble to form gels through intermolecular π–π stacking interactions. It is interesting that these simple gelators exhibit unusual properties, such as self-healing, multi-response fluorescence, and visual and selective recognition of chiral (R)/(S)-1,1′-binaphthalene-2,2′-diamine and S2? through much different times of gel re-formation and blue-green color change, respectively. These results underline the importance of supramolecular gels and extend the scope of supramolecular gelators.
- Wu, Dehua,Song, Jintong,Qu, Lang,Zhou, Weilan,Wang, Lei,Zhou, Xiangge,Xiang, Haifeng
-
p. 3370 - 3378
(2020/10/02)
-
- TOLL-LIKE RECEPTOR 8 (TLR8)-SPECIFIC ANTAGONISTS AND METHODS OF MAKING AND USES THEREOF
-
Toll-like receptor 8 (TLR8)-specific inhibitors and methods of using the same in individuals having an autoimmune disease or an inflammatory disorder.
- -
-
Page/Page column 52
(2019/05/22)
-
- Design and synthesis of phthalazine-based compounds as potent anticancer agents with potential antiangiogenic activity via VEGFR-2 inhibition
-
In the designed compounds, either a biarylamide or biarylurea moiety or an N-substituted piperazine motif was linked to position 1 of the phthalazine core. The anti-proliferative activity of the synthesised compounds revealed that eight compounds (6b, 6e, 7b, 13a, 13c, 16a, 16d and 17a) exhibited excellent broad spectrum cytotoxic activity in NCI 5-log dose assays against the full 60 cell panel with GI50 values ranging from 0.15 to 8.41 μM. Moreover, the enzymatic assessment of the synthesised compounds against VEGFR-2 tyrosine kinase showed the significant inhibitory activities of the biarylureas (12b, 12c and 13c) with IC50s of 4.4, 2.7 and 2.5 μM, respectively, and with 79.83, 72.58 and 71.6% inhibition of HUVEC at 10 μM, respectively. Additionally, compounds (7b, 13c and 16a) were found to induce cell cycle arrest at S phase boundary. Compound 7b triggered a concurrent increase in cleaved caspase-3 expression level, indicating the apoptotic-induced cell death.
- Elmeligie, Salwa,Aboul-Magd, Asmaa M.,Lasheen, Deena S.,Ibrahim, Tamer M.,Abdelghany, Tamer M.,Khojah, Sohair M.,Abouzid, Khaled A. M.
-
p. 1347 - 1367
(2019/07/29)
-
- Reactivity of Z- and E-isomers of 2-benzamido-3-phenylacrylohydrazide towards some carbon electrophiles. A comparative study
-
Z- and E-isomers of 2-benzamido-3-phenylacrylohydrazide 2a, 2b have different relative reactivities towards some carbon electrophiles had been discussed.The Z-isomer underwent cyclization to give imidazole derivative 3 and triazine derivative 4, whereas the latter E-isomer does not undergo such cyclization. The reaction of 2a and/or 2b with 1,2-dibenzylidene hydrazine at different reaction conditions afforded the Schiff bases 6, 8 and the triazolidine derivative 9. Reactions of 2a, 2b with formic acid and phthalic anhydride gave the different cyclization products 10–14, respectively. The structures of all the new synthesized compounds were established from their IR, 1H-NMR and mass spectra as well as elemental analyses.
- Abou-Elregal, Mohsen K.,Youssef, Ahmed S. A.,Hemdan, Magdy M.,Samir, Sandy S.
-
p. 2369 - 2378
(2019/07/03)
-
- Medicine for anesthesia, and preparation method and use thereof
-
The invention relates to a pyridazinone-quinazolinone derivative, or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof. Test results show that the effective duration of local anesthesia of the above compound to guinea pig skins is 4 h or above and the sensory block time of the compound to rats is 6 h or above, so the compound has an excellent anesthetic effect and an excellent sensory block effect. So the compound is especially suitable for being used as an anesthetic, especially a local anesthetic.
- -
-
Paragraph 0091-0093
(2019/02/04)
-
- Synthesis and biological evaluation of 2,4-disubstituted phthalazinones as Aurora kinase inhibitors
-
A series of 2,4-disubstituted phthalazinones were synthesized and their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects were evaluated. Among them, N-cyclohexyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-1-oxophthalazin-2(1H)-yl) methyl) benzamide (12c) exhibited the most potent antiproliferation against five carcinoma cell lines (HeLa, A549, HepG2, LoVo and HCT116 cells) with IC50 values in range of 2.2–4.6 μM, while the IC50 value of reference compound VX-680 was 8.5–15.3 μM. Moreover, Aurora kinase assays exhibited that compound 12c was potent inhibitor of AurA and AurB kinase with the IC50 values were 118 ± 8.1 and 80 ± 4.2 nM, respectively. Molecular docking studies indicated that compound 12c forms better interaction with both AurA and AurB. Furthermore, compound 12c induced G2/M cell cycle arrest in HeLa cells by regulating protein levels of cyclinB1 and cdc2. These results suggested that 12c is a promising pan-Aurora kinase inhibitor for the potential treatment of cancer.
- Wang, Wei,Feng, Xiu,Liu, Huan-Xiang,Chen, Shi-Wu,Hui, Ling
-
p. 3217 - 3226
(2018/05/04)
-
- One-step green synthesized phthalylhydrazine
-
The invention relates to one-step green synthesized phthalylhydrazine: raw material phthalic anhydride is used, a phase transfer catalyst is added in a specific solvent, and a raw material II is dripped at a specific temperature; hydrazine hydrate with a certain concentration is subjected to a reaction, water diversion is performed, phthalylhydrazine is obtained, after the reaction is finished, the temperature is lowered to room temperature, and phthalylhydrazine is obtained through filtration. The preparation method only has one step; compared with a conventional production process for one-step synthesis of phthalylhydrazine, the preparation method has the reaction time greatly reduced, allows a recycled solvent not to need water treatment, has the recycling rate greatly improved, removesthe distillation steps, reduces the unsafe factors of worker operation, greatly reduces the energy consumption, and has the advantage of environmental friendliness. Meanwhile, the method has the advantages of simple equipment, convenient operation, direct reuse of the solvent, low cost and easy industrialized production, and has the purity of the liquid phase more than 99.0%.
- -
-
Paragraph 0011-0019
(2018/11/03)
-
- Amelioration of H4[W12SiO40] by nanomagnetic heterogenization: For the synthesis of 1H–pyrazolo[1,2-b]phthalazinedione derivatives
-
We conveniently coated silicotungstic acid (STA, H4[W12SiO40]) on amino-functionalized Si–magnetite nanoparticles, as surface functionalization of magnetic nanoparticles is an excellent way for green and efficient catalysis. The nanoparticles were structurally characterized using various techniques. The catalytic activity and recyclability of the STA–amine–Si–magnetite nanoparticles were probed through synthesis of 1H–pyrazolo[1,2-b]phthalazinedione derivatives. The reaction proceeds smoothly to provide products in excellent yields and short reaction times. The catalyst could be readily recovered using a simple external magnet and reused several times without any significant loss in activity. Herein, we report a comparison of the activity of H4[W12SiO40] as a homogeneous and heterogeneous catalyst, the latter being found to be more efficient. The findings offer effective methods for environmentally friendly synthesis of pyrazolo[1,2-b]phthalazinedione derivatives.
- Arora, Priya,Rajput, Jaspreet Kaur
-
-
- A Green Synthesis of Highly Functionalized 3-amino-2-phenylsulfonyl-1-alkyl/aryl-1H-pyrazolo[1,2-b]phthalazine-5,10-diones and Their Reduction and Photophysical Studies
-
3-Amino-2-benzenesulfonyl-1-alkyl/aryl-1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives were synthesized by the one-pot, three-component condensation of phthalhydrazide, aldehydes, and (phenylsulfonyl)acetonitrile in EtOH using 2-hydroxyethylammonium acetate as catalyst. The advantages of this method include environmental friendliness, easy work-up, and excellent yields. The reduction of some products and photophysical properties were also investigated.
- Shi, Xin,Ding, Maohua,Li, Conghao,Wang, Wang,Guo, Hongyun
-
p. 440 - 446
(2017/12/15)
-
- Carbonylation Access to Phthalimides Using Self-Sufficient Directing Group and Nucleophile
-
Herein we report a novel palladium-catalyzed oxidative carbonylation reaction for the synthesis of phthalimides with high atom- and step-economy. In our strategy, the imine and H2O, which are generated in situ from the condensation of aldehyde and amine, serve as self-sufficient directing group and nucleophile, respectively. This method provides rapid access to phthalimides starting from readily available materials in a one-pot manner. Various phthalimide derivatives are constructed efficiently, including medicinally and biologically active phthalimide-containing compounds.
- Ji, Fanghua,Li, Jianxiao,Li, Xianwei,Guo, Wei,Wu, Wanqing,Jiang, Huanfeng
-
p. 104 - 112
(2018/02/19)
-
- METAL BICYCLIC AMIDINATES
-
Compounds are synthesized with bicyclic amidinate ligands attached to one or more metal atoms. These compounds are useful for the synthesis of materials containing metals. Examples include pure metals, metal alloys, metal oxides, metal nitrides, metal phosphides, metal sulfides, metal selenides, metal tellurides, metal borides, metal carbides, metal silicides and metal germanides. Techniques for materials synthesis include vapor deposition (chemical vapor deposition and atomic layer deposition), liquid solution methods (sol-gel and precipitation) and solid-state pyrolysis. Copper metal films are formed on heated substrates by the reaction of copper(I) bicyclic amidinate vapor and hydrogen gas, whereas reaction with water vapor produces copper oxide. Silver and gold films were deposited on surfaces by reaction of their respective bicyclic amidinate vapors with hydrogen gas. Reaction of cobalt(II) bis(bicyclic amidinate) vapor, ammonia gas and hydrogen gas deposits cobalt metal films on heated substrates, while reaction with ammonia produces cobalt nitride and reaction with water vapor produces cobalt oxide. Ruthenium metal films are deposited by reaction of ruthenium(II) bis(bicyclic amidinate) or ruthenium(III) tris(bicyclic amidinate) at a heated surface either with or without a co-reactant such as hydrogen gas or ammonia or oxygen. Suitable applications include electrical interconnects in microelectronics and magnetoresistant layers in magnetic information storage devices. Hafnium oxide films are deposited by reaction of hafnium(IV) tetrakis(bicyclic amidinate) with oxygen sources such as water, hydrogen peroxide or ozone. The HfO2 films have high dielectric constant and low leakage current, suitable for applications as an insulator in microelectronics. The films have very uniform thickness and complete step coverage in narrow holes.
- -
-
Paragraph 0115; 0126; 0128
(2018/10/19)
-
- Preparation and characterization of nanomagnetic piperidinium benzene-1,3-disulfonate ionic liquid as a novel, green and heterogeneous catalyst and its use in the synthesis of 1H–pyrazolo[1,2-b]phthalazine-5,10-diones and 1H–pyrazolo[1,2-a] pyridazine-5,8-diones under solvent-free conditions
-
The one-pot four-component synthesis of 1H–pyrazolo[1,2-b]phthalazine-5,10-diones and 1H–pyrazolo[1,2-a]pyridazine-5,8-diones was carried out from the reaction between various aldehydes, malononitrile, hydrazine hydrate and phthalic anhydride or maleic anhydride at 110?°C in solvent-free conditions using piperidinium benzene-1,3-disulfonate nanomagnetic ionic liquid (NMIL) as a novel and reusable catalyst. Some advantages of the presented procedure are a significant reduction in cost, effective catalysis and reusability of the catalyst. NMIL was thoroughly characterized using Fourier transform infrared spectroscopy, X-ray diffraction, scanning and transmission electron microscopies, thermogravimetry, derivative thermogravimetry, Brunauer–Emmett–Teller analysis, vibrating sample magnetometry and energy-dispersive X-ray spectroscopy. The technique is developed as a suitable and safe method for the synthesis of 1H–pyrazolo[1,2-b]phthalazine-5,10-diones and 1H–pyrazolo[1,2-a]pyridazine-5,8-diones making use of an efficient and reusable green catalyst.
- Ghorbani-Vaghei, Ramin,Mahmoodi, Jafar,Maghbooli, Yaser
-
-
- One-pot four component reaction for the synthesis of 1-(1H-indol-2-YL)-1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives by self-catalysis
-
In this, we performed a four component domino reaction of phthaloyl dichloride, hydrazine hydrate, indole-3-carboxaldehydes and malononitrile/ethyl cyanoacetate to form 1-(1H-indol-2-yl)-1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives by in situ generation of HCl as catalyst in refluxing ethanol for 1 h in good yields. This four component domino reaction transformation presumably proceeds via addition/dehydrohalogenation/condensation/cyclization of reactions. The material was thoroughly characterized at various stages of its formation by means of FTIR, NMR spectroscopic and Mass spectrometric analysis and is confirmed to be the derivative of 1-(1H-indol-2-yl)-1H-pyrazolo[1,2-b]phthalazine-5,10-dione.
- Mohammad, Faruq,Al-Lohedan, Hamad A.
-
p. 1567 - 1572
(2017/08/02)
-
- 1, 2, 3, 4- [...] compound and process for the synthesis of
-
The invention provides a synthetic and technological method of a 1,2,3,4-tetrahydrophthalazine compound used as an intermediate of bactericides and anti HIV (human immunodeficiency virus) and other new drugs. The 1,2,3,4-tetrahydrophthalazine compound is obtained by using various cheap and easily accessible phthalic acid or phthalic anhydride as a raw material for two steps of reaction. The method is easily accessible in raw material, low in cost, simple in reaction, easy in control, simple in processing and easy in amplification, and a large number of industrial by-product hydrazide can be found to be directly used as a raw material for the second step. The method is convenient to economic, reuses the industrial by-product as the raw material, and provides a feasible synthetic production and technological method of the 1,2,3,4-tetrahydrophthalazine compound for green chemical industry.
- -
-
Paragraph 0015-0018
(2017/03/08)
-
- 3-substituted-6 - (1-substituted piperazinyl) - 1, 2, 4-triazole [3,4-a] [...] compound, preparation method thereof, and use thereof
-
The invention belongs to the field of medicinal chemistry and discloses a 3-substituted-6-(1-substituted piperazinyl)-1,2,4-triazoleo[3,4-a] phthalazine compound with antitumor activity as well as a preparation method and an application thereof. The compound has a structure as shown in a general formula I, wherein in the general formula I, R1 is hydrogen, methyl or phenyl; R2 is hydrogen, 4-fluorophenyl, 4-chlorphenyl, 3-trifluoromethylphenyl or 2-fluorophenyl. The preliminary in-vitro antitumor activity evaluation proves that the series of compounds have obvious effects of inhibiting and killing multiple tumor cells. The compound can serve as an active ingredient to be developed into a novel drug and is applied to clinical prevention and cancer therapy.
- -
-
Paragraph 0036
(2016/10/08)
-
- 3,6-substituted -1, 2, 4-triazole [3,4-a] [...] compound and its preparation and use
-
The invention belongs to the field of medicinal chemistry, and discloses a 3, 6 modified-[1, 2, 4] triazole [3, 4-alpha] phthalazine compound having antitumor activity as well as a synthesizing method and application of the 3, 6 modified-[1, 2, 4] triazole [3, 4-alpha] phthalazine compound. The 3, 6 modified-[1, 2, 4] triazole [3, 4-alpha] phthalazine compound has a structure as shown in a general formula I, wherein R1 refers to H, methyl or phenyl; R2 refers to 4-fluorophenyl, 4-chloroanilino, 4-bromophenyl, 4-methoxyphenyl, 4-hydroxydiphenyl, 2-fluorophenyl, 3-trifluoromethyl)phenyl]amino, naphthylamine-1-yl, pyrrolidone-1-yl, piperidine-1-yl, 3,5-dimethyl piperidine-1-yl, morpholine-4-yl, or piperazidine-1-yl. The preliminary in-vitro antitumor activity finds that the serial compounds have obvious inhibit and killing effects on multiple tumor cells, and the 3, 6 modified-[1, 2, 4] triazole [3, 4-alpha] phthalazine compound can act as an active ingredient to be applied to clinical prevention and cancer treatment after being developed into a novel medicament.
- -
-
Paragraph 0043
(2017/02/02)
-
- Addition of phthalimide and acetone to phosphorylated methylene quinones
-
New method for synthesis of phosphorylated methylene quinones via bromination of the sterically hindered phenol [prepared via benzylation of secondary chlorophosphines with 4-(methoxymethyl)-2,6-di-tert-butylphenol] with N-bromosuccinimide followed by dehydrobromination with trimethyl orthoformate has been developed. Tertiary phosphine oxides containing the fragment of sterically hindered phenol and amine or acetonyl group have been synthesized for the first time in the reaction of phosphorylated methylene quinones with N- and C-nucleophiles.
- Gazizov,Tarakanova,Ismagilov,Shamsutdinova,Karimova,Burangulova
-
p. 326 - 330
(2016/04/20)
-
- A highly sensitive fluorescent probe for detection of hydrazine in gas and solution phases based on the Gabriel mechanism and its bioimaging
-
A new probe 2-benzo[1,2,5]thiadiazol-4-yl-isoindole-1,3-dione (BTI) based on the Gabriel reaction mechanism was synthesized and characterized for the specific detection of hydrazine with high selectivity against other amines in an organo-aqueous solution. Upon hydrazinolysis of BTI in the presence of hydrazine in a H2O-DMSO (4:6, v/v) solution (10 mM HEPES buffer, pH 7.4) at room temperature, the chemosensor produces fluorescent aminobenzthiadiazole with a maximum emission at 498 nm along with a color change from colorless to green, allowing selective colorimetric and fluorometric detection of hydrazine by the naked eye. Probe BTI was also successfully applied in vapor phase hydrazine detection into a solid state over other interfering volatile analytes. Furthermore, the probe BTI coated with silica gel TLC plates could act as a visual and fluorimetric probe for hydrazine vapor detection. The experimental detection limit of hydrazine is 2.9 ppb, which is well below the accepted limit (10 ppb) for hydrazine set by the U.S. Environmental Protection Agency (EPA). DFT and TDDFT calculations were performed in order to demonstrate the sensing mechanism and the electronic properties of probe and hydrazinolysis products. Additionally, probe BTI could also be applied for the imaging of hydrazine in living cells.
- Maji, Rajkishor,Mahapatra, Ajit Kumar,Maiti, Kalipada,Mondal, Sanchita,Ali, Syed Samim,Sahoo, Prithidipa,Mandal, Sukhendu,Uddin, Md Raihan,Goswami, Shyamaprosad,Quah, Ching Kheng,Fun, Hoong-Kun
-
p. 70855 - 70862
(2016/08/05)
-
- SO3H-functionalized mesoporous silica materials as solid acid catalyst for facile and solvent-free synthesis of 2H-indazolo[2,1-b]phthalazine-1,6,11-trione derivatives
-
SO3H-functionalized mesoporous silica materials (SO3H-FMSM), as an efficient, mild, recoverable and environmentally friendly heterogeneous mesoporous nanocatalyst, was used to synthesize 2H-indazolo[2,1-b]phthalazine-1,6,11-trione derivatives in a one-pot three-component condensation reaction of 2,3-dihydrophthalazine-1,4-dione, dimedone, and benzaldehyde derivatives under thermal solvent-free (SF) conditions in excellent yields and short reaction times.
- Amiri, Ali Alinasab,Javanshir, Shahrzad,Dolatkhah, Zahra,Dekamin, Mohammad G.
-
p. 9665 - 9671
(2015/12/01)
-
- POLY (ADP-RIBOSE) POLYMERASE INHIBITOR
-
Disclosed are a phthalic hydrazide (phthalazine ketone) compound, and a pharmaceutical composition comprising the same. As a DNA repair enzyme poly (ADP-ribozyme) polymerase inhibitor, the compound and the pharmaceutical composition can effectively treat diseases involving PARP enzymatic activity, including cancer, neural degenerative diseases, inflammation and the like.
- -
-
Paragraph 0094; 0095
(2015/02/25)
-
- Vitamin B1 supported on alumina as an efficient heterogeneous catalyst for synthesis of tetrahydro-2,6-dioxopyrimidin-4-yl)-2,3-dihydrophthalazine-1,4-dione derivatives
-
The efficient synthesis of tetrahydro-2,6-dioxopyrimidin-4-yl)-2,3-dihydrophthalazine-1,4-dione derivatives via four-component reaction of hydrazine hydrate, phthalic anhydride, aromatic aldehydes and barbituric acid using vitamin B1 supported on alumina (VB1-Al2O3) as a heterogeneous catalyst under thermal solvent-free conditions in excellent yields is described.
- Biabangard, Asiyeh,Shaterian, Hamid Reza
-
p. 1529 - 1534
(2015/07/07)
-
- Substances for treatment or relief of pain
-
Disclosed is the use of an inverse agonist for alpha-subunit-containing gamma-aminobutyric acid A receptor in the preparation of a medicine for the prevention, alleviation, or treatment of pain.
- -
-
Paragraph 0289; 0290
(2016/01/25)
-
- Green and efficient synthesis of 2-(4-oxo-3,4-dihydroquinazolin-2-yl)-2,3-dihydropthalazine-1,4-dione
-
2-Hydrazinoquinazolin-3H-4-ones 1a,b were reacts with each of the anhydrides, phthalic anhydride 2a, succinic anhydride 2b and maleic anhydride 2c independently in PEG-600 at RT to yield 2-(2-(4-oxo-3,4-dihydroquinazolin-2-yl)hydrazineecarbonyl) benzoic acid 3a,b, 4-oxo-4-(2-(4-oxo-3,4-dihydroquinazolin-2-yl)hydrazinyl)butanoic acid 3c,d and 4-oxo-4-(2-(4-oxo-3,4-dihydroquinazolin-2-yl)hydrazinyl)but-2-enoic acid 3e,f, respectively. 3a, b, 3c,d, 3e,f have been transformed into 2-(4-oxo-3,4-dihydroquinazolin-2-yl)-2,3-dihydrophthalazine-1,4-dione 4a,b, 1-(4-oxo-3,4-dihydroquinazolin-2-yl)piperazine-3,6-dione 4c,d and 1-(4-oxo-3,4-dihydroquinazolin-2-yl)-1,2-dihydropyridazine-3,6-dione 4e,f, respectively by heating each in PEG-600 at 100°C for 3-3.5 hr in high yields and in high purity, involving a dehydrative ring closure. The final compounds 4a-f have also been prepared alternatively by reacting 1 with 2 in PEG-600 at 100°C for 3.5-4 hr.
- Rafeeq,Srinivasa Reddy,Venkata Ramana Reddy,Naidu,Dubey
-
p. 412 - 417
(2015/03/31)
-
- A phthalimidation protocol that follows protein defined parameters
-
This work outlines the first phthalimidation protocol suitable for protein labeling and performed in aqueous media at room temperature and neutral pH with no catalyst or co-reagent required. The methodology is suitable for a range of amines and its efficiency was determined with chemoselective and site-selective protein labeling. This journal is
- Singudas, Rohith,Adusumalli, Srinivasa Rao,Joshi, Pralhad Namdev,Rai, Vishal
-
p. 473 - 476
(2015/01/09)
-
- POLY (ADP-RIBOSE) POLYMERASE INHIBITOR
-
Disclosed are a phthalic hydrazide (phthalazine ketone) compound, and a pharmaceutical composition comprising the same. As a DNA repair enzyme poly (ADP-ribozyme) polymerase inhibitor, the compound and the pharmaceutical composition can effectively treat diseases involving PARP enzymatic activity, including cancer, neural degenerative diseases, inflammation and the like.
- -
-
Paragraph 0049; 0068; 0069
(2014/11/13)
-
- Synthesis and anticancer activities of novel 1,2,4-triazolo[3,4-a] phthalazine derivatives
-
Trying to develop potent and selective anticancer agents, two series of novel 1,2,4-triazolo[3,4-a]phthalazine derivatives were designed and synthesized. Their antitumor activities were evaluated by MTT method against four selected human cancer cell lines (MGC-803, EC-9706, HeLa and MCF-7). Our results showed that compound 11h exhibited good anticancer activities compared to 5-fluorouracil against the four tested cell lines, with IC50 values ranging from 2.0 to 4.5 μM. Flow cytometry analysis indicated that compound 11h induced the cellular early apoptosis and cell cycle arrest at G2/M phase in EC-9706.
- Xue, Deng-Qi,Zhang, Xu-Yao,Wang, Chao-Jie,Ma, Li-Ying,Zhu, Nan,He, Peng,Shao, Kun-Peng,Chen, Peng-Ju,Gu, Yi-Fei,Zhang, Xiao-Song,Wang, Cai-Feng,Ji, Cong-Hui,Zhang, Qiu-Rong,Liu, Hong-Min
-
p. 235 - 244
(2014/08/18)
-
- Synthesis and antimicrobial activities of novel 1,2,4-triazolo [3,4-a] phthalazine derivatives
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A series of novel 1,2,4-triazolo [3,4-a] phthalazine derivatives were synthesized in five steps from a common precursor, phthalic anhydride. Most of synthesized phthalazine derivatives showed inhibitory activity against Staphylococcus aureus. One of phthalazine derivatives 5l showed inhibitory activity against all tested bacterial and fungal strains.
- Zhang, Qiu-Rong,Xue, Deng-Qi,He, Peng,Shao, Kun-Peng,Chen, Peng-Ju,Gu, Yi-Fei,Ren, Jing-Li,Shan, Li-Hong,Liu, Hong-Min
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supporting information
p. 1236 - 1238
(2014/03/21)
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- Design, synthesis and structure-activity relationship studies of morpholino-1H-phenalene derivatives that antagonize Mcl-1/Bcl-2
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We report herein characteristic studies of Mcl-1 and Bcl-2 dual inhibitors. It was found that a protruding carbonyl group forming hydrogen bond with R263 plays a predominant role compared with the hydrophobic group that occupies the p2 pocket. A series of dual inhibitors representing different parts of the morpholino-1H-phenalene were designed, synthesized and evaluated.
- Li, Xiangqian,Liang, Xiaomeng,Song, Ting,Su, Pengchen,Zhang, Zhichao
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p. 5738 - 5746
(2015/02/02)
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- Mild preparation of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives with magnetic Fe3O4 nanoparticles coated by (3-aminopropyl)-triethoxysilane as catalyst under ambient and solvent-free conditions
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An efficient, one-pot quantitative procedure for preparation of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives from four-component condensation reaction of hydrazine monohydrate, phthalic anhydride, malononitrile or ethyl cyanoacetate, and aromatic aldehydes in the presence of magnetic Fe3O4 nanoparticles coated by (3-aminopropyl)-triethoxysilane as catalyst under mild, ambient, and solvent-free conditions is described. Simple procedure, high yield, short reaction time, and environmentally benign method are advantages of this protocol. The magnetic Fe3O4 nanoparticles coated by (3-aminopropyl)-triethoxysilane can be recovered and reused several times without loss of activity.
- Shaterian, Hamid Reza,Mohammadnia, Majid
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p. 371 - 383
(2014/02/14)
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