119-39-1Relevant articles and documents
Synthesis of 4-alkylsulfanylphthalazin-1(2H)-ones via palladium catalyzed sulfanylation of substituted 4-bromophthalazin-1(2H)-ones
Malinowski, Zbigniew,Fornal, Emilia,Sierocińska, Beata,Czeczko, Renata,Nowak, Monika
, p. 7942 - 7951 (2016)
The synthesis of a series of new alkylsulfanyl phthalazinone and phthalazine derivatives is described. The target compounds were efficiently synthesized in a four step sequence, consisting of (1) cyclization of 2-formylbenzoic acid with hydrazine hydrate to form phthalazinone, (2) the direct bromination of phthalazinone core with KBr3, (3) alkylation of the obtained 4-bromolactam (Mitsunobu procedure) to make N- and also O-alkyl derivatives and finally (4) palladium-catalyzed coupling reactions of 2-alkyl-4-bromophthalazinone and 1-alkyloxy-4-bromophthalazine derivatives with aliphatic mercaptanes. Furthermore, the synthesis of 2-methyl-8-(propan-2-yl)sulfanyl-pyrido[3,4-d]pyridazin-1(2H)-one from 2-methyl-pyrido[3,4-d]pyridazin-1(2H)-one via bromination reaction with KBr3and subsequent sulfanylation by isopropyl mercaptan under catalyzed coupling reaction conditions is also described.
Reaction of Diazines and their Benzo derivatives with Benzonitrile oxide
Grassi, Giovanni,Risitano, Francesco,Foti, Francesco
, p. 11855 - 11862 (1995)
The reaction of diazines 1 and benzodiazines 2 with benzonitrile oxide in refluxing benzene affords regio, site and stereospecific cycloadducts to the diazine ring and/i43or products derived from them.
Inhibitory effects of drugs on the metabolic activity of mouse and human aldehyde oxidases and influence on drug–drug interactions
Takaoka, Naoki,Sanoh, Seigo,Okuda, Katsuhiro,Kotake, Yaichiro,Sugahara, Go,Yanagi, Ami,Ishida, Yuji,Tateno, Chise,Tayama, Yoshitaka,Sugihara, Kazumi,Kitamura, Shigeyuki,Kurosaki, Mami,Terao, Mineko,Garattini, Enrico,Ohta, Shigeru
, p. 28 - 38 (2018)
As aldehyde oxidase (AOX) plays an emerging role in drug metabolism, understanding its significance for drug–drug interactions (DDI) is important. Therefore, we tested 10 compounds for species-specific and substrate-dependent differences in the inhibitory effect of AOX activity using genetically engineered HEK293 cells over-expressing human AOX1, mouse AOX1 or mouse AOX3. The IC50 values of 10 potential inhibitors of the three AOX enzymes were determined using phthalazine and O6-benzylguanine as substrates. 17β-Estradiol, menadione, norharmane and raloxifene exhibited marked differences in inhibitory effects between the human and mouse AOX isoforms when the phthalazine substrate was used. Some of the compounds tested exhibited substrate-dependent differences in their inhibitory effects. Docking simulations with human AOX1 and mouse AOX3 were conducted for six representative inhibitors. The rank order of the minimum binding energy reflected the order of the corresponding IC50 values. We also evaluated the potential DDI between an AOX substrate (O6-benzylguanine) and an inhibitor (hydralazine) using chimeric mice with humanized livers. Pretreatment of hydralazine increased the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC0–24) of O6-benzylguanine compared to single administration. Our in vitro data indicate species-specific and substrate-dependent differences in the inhibitory effects on AOX activity. Our in vivo data demonstrate the existence of a DDI which may be of relevance in the clinical context.
Identification of new potent phthalazine derivatives with VEGFR-2 and EGFR kinase inhibitory activity
Amin, Kamilia M.,Barsoum, Flora F.,Awadallah, Fadi M.,Mohamed, Nehal E.
, p. 191 - 201 (2016)
Efforts to develop new antitumor agents are now directed towards multitarget therapies that are believed to have high potency and low tendency to resistance compared to conventional drugs. Herein, we highlighted the synthesis and antitumor activity of five series of phthalazine-based compounds featuring a variety of bioactive chemical fragments at position 1 of the phthalazine nucleus. The antitumor activity of the target compounds was performed against fourteen cancer cell lines where all compounds were active in the nanomolar level. In addition, the mechanism of action of the target compounds was investigated through an enzymatic inhibitory assay against VEGFR-2 and EGFR kinases, revealing potent and preferential activity toward VEGFR-2. Binding mode of the most active compounds was studied using docking experiment.
Synthesis of 4-Substituted Phthalazin-1(2H)-ones from 2-Acylbenzoic Acids: Controlling Hydrazine in a Pharmaceutical Intermediate through PAT-Guided Process Development
Mennen, Steven M.,Mak-Jurkauskas, Melody L.,Bio, Matthew M.,Hollis, L. Steven,Nadeau, Kelly A.,Clausen, Andrew M.,Hansen, Karl B.
, p. 884 - 891 (2015)
A simple one-pot, two-step process for the conversion of 2-acylbenzoic acids to phthalazin-1(2H)-ones was developed. A robust process was required that delivered the final isolated solid with consistently low levels of residual hydrazine, for further processing to the final drug substance. An in situ formed intermediate was critical to control reactivity and allowed for the controlled crystallization that prevented entrainment of hydrazine. Leveraging Process Analytical Technology (PAT), we investigated the reaction profile with in situ IR and Power Compensation Calorimetry (PCC) to aid development prior to a successful scale-up.
Identification of a suitable and selective inhibitor towards aldehyde oxidase catalyzed reactions
Nirogi, Ramakrishna,Kandikere, Vishwottam,Palacharla, Raghava Choudary,Bhyrapuneni, Gopinadh,Kanamarlapudi, Vijaya Bhargava,Ponnamaneni, Ranjith Kumar,Manoharan, Arun Kumar
, p. 197 - 204 (2014)
1.Aldehyde oxidase (AO) is a liver cytosolic molybdoflavoprotein enzyme whose importance in drug metabolism is gaining in the recent. The objective of this work is to find a potent and selective inhibitor for AO activity using phthalazine oxidation as a marker reaction. 2. Among organic solvents tested, it was identified that methanol was not a suitable choice for AO activity even at concentrations less than 0.2% v/v. Acetonitrile and DMSO did not show any effect till 0.5% v/v but thereafter activites tend to decrease. 3. For selectivity, 23 compounds were selected and evaluated for their effects on AO and nine CYP450 enzymes. Among the tested compounds chlorpromazine, estradiol, hydralazine, quetiapine and raloxifene were selected based on their potency of inhibition towards AO activity. 4. Raloxifene was found to be a non-specific inhibitor of all major tested CYP450 enzymes and was excluded as a selective inhibitor for AO. Quetiapine also showed a degree of inhibition towards the major CYP450 tested. Hydralazine used as a specific inhibitor during the past for AO activity demonstrated a stimulation of AO activity at high and low concentrations respectively and the inhibition noted to be time dependent while inhibiting other enzymes like monoamine oxidase. 5. Estradiol showed no inhibition towards the tested CYP450 enzymes and thus proved to be a selective and specific inhibitor for AO activity with an uncompetitive mode of inhibition.
Investigations of reactions of selected azaarenes with radicals in water. 1. Hydroxyl and sulfate radicals
Beitz, Toralf,Bechmann, Wolfgang,Mitzner, Rolf
, p. 6760 - 6765 (1998)
The oxidative degradation of binuclear azaarenes is studied in a number of environmentally relevant radical reactions. The comparison between oxidation mechanisms of hydroxyl and sulfate radicals, as well as between dark and photoreactions, is done. Most of the products formed are identified. With the change from dark to photoreactions of quinoline and isoquinoline, a shift of the oxidation center from the benzene to the pyridine rings is observed. The reaction behavior of the benzodiazines can be derived from the reaction patterns of quinoline and isoquinoline. The rate constants of second order are determined for the reactions of the azaarenes with carbonate radicals. The rate constants and the differences in the products formed conformably prove the importance of the inclusion of excited states in the reaction mechanism. The application of the frontier orbital concept allows an easy interpretation. Electron transfer reactions resulting in radical oxygen species are shown to be product determining in direct photolysis, too.
Tin Powder-Promoted Cascade Condensation/Allylation/Lactamization: Synthesis of Isoindolinones and Pyrazoloisoindol-8-ones
Wang, Xiaoping,Huang, Danfeng,Wang, Ke-Hu,Su, Yingpeng,Hu, Yulai
, p. 6946 - 6961 (2019/06/14)
An efficient tin powder-promoted cascade condensation/allylation/lactamization of 2-formylbenzoic acids, hydrazides, and allyl bromides was developed for the synthesis of isoindolinones in good to excellent yields under mild conditions without any other additives or catalysts. Further manipulation of isoindolinones by iodocyclization process afforded the tricyclic tetrahydro-8H-pyrazolo[5,1-a]isoindol-8-one derivatives, which could be converted into more complicated tetracyclic tetrahydro-4H-azirino[1′,2′:2,3]pyrazolo[5,1-a]isoindol-4-ones.
Design and synthesis of phthalazine-based compounds as potent anticancer agents with potential antiangiogenic activity via VEGFR-2 inhibition
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)
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.
Synthesis and Investigation of Phthalazinones as Antitubercular Agents
Santoso, Kristiana T.,Cheung, Chen-Yi,Hards, Kiel,Cook, Gregory M.,Stocker, Bridget L.,Timmer, Mattie S. M.
supporting information, p. 1278 - 1285 (2019/02/24)
A series of 2- and 7-substituted phthalazinones was synthesised and their potential as anti-tubercular drugs assessed via Mycobacterium tuberculosis (mc26230) growth inhibition assays. All phthalazinones tested showed growth inhibitory activity (MIC 100 μm), and those compounds containing lipophilic and electron-withdrawing groups generally exhibited better anti-tubercular activity. Several lead compounds were identified, including 7-((2-amino-6-(4-fluorophenyl)pyrimidin-4-yl)amino)-2-heptylphthalazin-1(2H)-one (MIC=1.6 μm), 4-tertbutylphthalazin-2(1H)-one (MIC=3 μm), and 7-nitro-phthalazin-1(2H)-one (MIC=3 μm). Mode of action studies indicated that selected pyrimidinyl-phthalazinones may interfere with NADH oxidation, however, the mode of action of the lead compound is independent of this enzyme. MIC=minimum inhibitory concentration.
