- Synthesis and anti-inflammatory activity evaluation of a novel series of 6-phenoxy-[1,2,4]triazolo[3,4-a]phthalazine-3-carboxamide derivatives
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The transcription factor nuclear factor-κB (NF-κB) controls many physiological processes including inflammation, immunity, and apoptosis. In this study, a novel series of 6-phenoxy-[1,2,4]triazolo[3,4-a]phthalazine-3-carboxamide derivatives were synthesized as potent anti-inflammatory agents, which acted on tumor necrosis factor (TNF-α) as inhibitors of NF-κB activation. We showed that compounds 6h (6-(2,4-dichlorophenoxy)-[1,2,4]triazolo[3,4-a]phthalazine-3-carboxamide) and 6i (6-(3-tolyloxy)-[1,2,4]triazolo[3,4-a]phthalazine-3-carboxamide) showed more prominent anti-inflammatory activity than other compounds, with similar activities as the reference drug dihydrotanshinone; compound 6i showed the lowest cellular toxicity among the tested compounds. In vivo evaluation of the anti-inflammatory activity showed that compound 6i exhibited excellent anti-inflammatory activity with 58.19% inhibition at 50?mg/kg intraperitoneal (i.p.), with equal efficacy as the positive control indomethacin (100?mg/kg i.p.; 59.21% inhibition).
- Liu, Da-Chuan,Gong, Guo-Hua,Wei, Cheng-Xi,Jin, Xue-Jun,Quan, Zhe-Shan
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Read Online
- 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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- 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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- Discovery and biological evaluation of phthalazines as novel non-kinase TGFβ pathway inhibitors
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TGFβ is crucial for the homeostasis of epithelial and neural tissues, wound repair, and regulating immune responses. Its dysregulation is associated with a vast number of diseases, of which modifying the tumor microenvironment is one of vital clinical interest. Despite various attempts, there is still no FDA-approved therapy to inhibit the TGFβ pathway. Major mainstream approaches involve impairment of the TGFβ pathway via inhibition of the TGFβRI kinase. With the purpose to identify non-receptor kinase-based inhibitors to impair TGFβ signaling, an in-house chemical library was enriched, through a computational study, to eliminate TGFβRI kinase activity. Selected compounds were screened against a cell line engineered with a firefly luciferase gene under TGFβ-Smad-dependent transcriptional control. Results indicated moderate potency for a molecule with phthalazine core against TGFβ-Smad signaling. A series of phthalazine compounds were synthesized and evaluated for potency. The most promising compound (10p) exhibited an IC50 of 0.11 ± 0.02 μM and was confirmed to be non-cytotoxic up to 12 μM, with a selectivity index of approximately 112-fold. Simultaneously, 10p was confirmed to reduce the Smad phosphorylation using Western blot without exhibiting inhibition on the TGFβRI enzyme. This study identified a novel small-molecule scaffold that targets the TGFβ pathway via a non-receptor-kinase mechanism.
- Frett, Brendan,Kharbanda, Anupreet,Leung, Yuet-Kin,Li, Hong-yu,Li, Ming O.,Saha, Debasmita,Tran, Phuc,Xu, Ke,Zhang, Lingtian
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supporting information
(2021/07/13)
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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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- Design, synthesis, molecular modeling, in vivo studies and anticancer activity evaluation of new phthalazine derivatives as potential DNA intercalators and topoisomerase II inhibitors
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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.
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- Efficient Phosphorus-Free Chlorination of Hydroxy Aza-Arenes and Their Application in One-Pot Pharmaceutical Synthesis
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The chlorination of hydroxy aza-arenes with bis(trichloromethyl) carbonate (BTC) and SOCl2 has been effectively performed by refluxing with 5 wt % 4-dimethylaminopyridine (DMAP) as a catalyst. Various substrates are chlorinated with high yields. The obtained chlorinated aza-arenes can be used directly with simple workup for succedent one-pot synthesis on a large scale.
- Wang, Jian,Li, Yan-Hui,Pan, Song-Cheng,Li, Ming-Fang,Du, Wenting,Yin, Hong,Li, Jing-Hua
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supporting information
p. 146 - 153
(2020/03/10)
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- Preparation method of chloro-substituted polyhydroxy aza-aromatic ring compound (by machine translation)
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The invention discloses a preparation method, namely BTC and SOCl, of a chloropolyhydroxyl aza heteroaromatic ring compound as a raw material with a polyhydroxy aza heteroaromatic ring compound as a raw material, and a preparation method thereof. 2 As the double chlorination reagent, a chloropolyhydroxyl aza-aromatic ring compound is produced by chlorination reaction with 4 - dimethylaminopyridine (DMAP) as a catalyst at room temperature to reflux temperature of the reaction, as a catalyst. BTC TC TC TC2 /DMDMAP chlorination system has high efficiency, high selectivity and chlorine substitution on a polyhydroxy nitrogen heterocyclic compound; the system can replace POCl3 , The production of phosphorus-containing wastewater is avoided. Using BTC as a chlorination reagent, the reaction by-product was HCl and CO. 2 . From the aspects of industrial wastewater treatment, environmental protection and the like, the advantages thereof are obvious; SOCl is distilled off after the reaction is ended. 2 The quantity is almost no loss, can be used repeatedly, and reduces the process cost. (by machine translation)
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Paragraph 0019; 0020; 0021-0024
(2019/10/01)
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- Method using microchannel reactor to continuously prepared 1,4-dichlorophthalazine
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The invention relates to the field of pharmaceutical intermediates, in particular to a method using a microchannel reactor to continuously prepare 1,4-dichlorophthalazine. The synthesis of 1,4-dichlorophthalazine belongs to typical chlorination reaction, is a dangerous process, has high potential safety hazard and is high in pollution and low in production efficiency. The method which uses continuous flow to continuously synthesize the 1,4-dichlorophthalazine can overcome the defects above. According to the technical scheme, the method includes the steps of firstly, , grinding dried raw material phthalic hydrazide into particles with the particle size being smaller than 100 micrometers, and stirring the particles, trichloromethane and phosphorus trichloride in a reaction flask to form turbid liquid; secondly, pumping the turbid liquid and chlorine into the microchannel reactor, preheating to reaction temperature, and feeding into a first microchannel reaction module to perform mixing reaction; thirdly, subjecting the obtained mixture to complete reaction in a subsequent microchannel reaction module or serially connected 2-5 microchannel reaction modules to obtain a mixture containing the 1,4-dichlorophthalazine; fourthly, subjecting the mixture containing the 1,4-dichlorophthalazine to simple separation and purification. Compared with the prior art, the method is simple in process, capable of greatly reducing three wastes, accurate in reaction condition control, high in production efficiency, essentially safe, high in product purity, capable of achieving continuous production and the like.
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Paragraph 0007; 0023-0027
(2019/10/17)
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- Design and synthesis of 3-aminophthalazine derivatives and structural analogues as PDE5 inhibitors: anti-allodynic effect against neuropathic pain in a mouse model
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Neuropathic pain is a chronic pain caused by a lesion or disease affecting the somatosensory nervous system. To date, no specific treatment has been developed to cure this pain. Antidepressants and anticonvulsant drugs are used, but they do not demonstrate universal efficacy, and they often cause detrimental adverse effects. Some studies highlighted the efficacy of sildenafil, a well-known inhibitor of phosphodiesterase 5 (PDE5, (IC50 = 3.3 nM)), in models of pain. Based on these results, we focused our attention on MY 5445, another known PDE5 inhibitor. Homologues, isosteres and structural analogues of MY 5445 were designed and all synthesized compounds were evaluated for their inhibitory activity toward PDE5. Selectivity profiles towards other PDE1-4 isoenzymes, water solubility and stability in acidic medium of the most potent PDE5 inhibitors were determined and the aminophthalazine 16h and its mimetic 41n (3-aminoindazole)were evaluated in comparison to MY 5445 (4b)in vivo in a model of neuropathic pain induced by sciatic nerve cuffing in mice (3 and 0.5 mg/kg, ip twice a day). Both compounds showed the same efficacy on neuropathic allodynia as MY 5445, and thus produced a significant relief of mechanical hypersensitivity after 12 days of treatment.
- Bollenbach, Maud,Lugnier, Claire,Kremer, Mélanie,Salvat, Eric,Megat, Salim,Bihel, Frédéric,Bourguignon, Jean-Jacques,Barrot, Michel,Schmitt, Martine
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p. 269 - 290
(2019/06/05)
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- TOLL-LIKE RECEPTOR 8 (TLR8)-SPECIFIC ANTAGONISTS AND METHODS OF MAKING AND USES THEREOF
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Toll-like receptor 8 (TLR8)-specific inhibitors and methods of using the same in individuals having an autoimmune disease or an inflammatory disorder.
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Page/Page column 52
(2019/05/22)
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- Preparation method of 1,4-dichlorophthalazine
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The invention relates to a preparation method of 1,4-dichlorophthalazine. Phthalhydrazide is taken as a raw material, 4-diaminopyridine or 1,8-diazabicycloundec-7-ene is taken as a catalyst, acetonitrile is taken as a solvent, and only equivalent phosphorus trichloride is required to be used as a chlorination reagent to synthesize 1,4-dichlorophthalazine. An obtained crude product is subjected tomixed recrystallization purification by using two or more solvents. The preparation method has the advantages that the raw materials are cheap and easily available, the yield is high, production costis favorably controlled, process conditions are mild, safety and reliability are achieved, environment friendliness is achieved, and the method is suitable for industrial production.
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Paragraph 0016-0018
(2019/09/16)
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- Design and synthesis of phthalazine-based compounds as potent anticancer agents with potential antiangiogenic activity via VEGFR-2 inhibition
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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.
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p. 1347 - 1367
(2019/07/29)
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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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- 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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p. 6070 - 6076
(2016/07/16)
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- 3-substituted-6 - (1-substituted piperazinyl) - 1, 2, 4-triazole [3,4-a] [...] compound, preparation method thereof, and use thereof
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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.
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Paragraph 0037
(2016/10/08)
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- 3,6-substituted -1, 2, 4-triazole [3,4-a] [...] compound and its preparation and use
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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.
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Paragraph 0044
(2017/02/02)
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- Synthesis and in vitro evaluation of hydrazinyl phthalazines against malaria parasite, Plasmodium falciparum
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In this report, we describe the synthesis of 1-(Phthalazin-4-yl)-hydrazine using bronsted acidic ionic liquids and demonstrate their ability to inhibit asexual stage development of human malaria parasite, Plasmodium falciparum. Through computational studies, we short-listed chemical scaffolds with potential binding affinity to an essential parasite protein, dihydroorotate dehydrogenase (DHODH). Further, these compounds were synthesized in the lab and tested against P. falciparum. Several compounds from our library showed inhibitory activity at low micro-molar concentrations with minimal cytotoxic effects. These results indicate the potential of hydralazine derivatives as reference scaffolds to develop novel antimalarials.
- Subramanian, Gowtham,Babu Rajeev,Mohan, Chakrabhavi Dhananjaya,Sinha, Ameya,Chu, Trang T.T.,Anusha, Sebastian,Ximei, Huang,Fuchs, Julian E.,Bender, Andreas,Rangappa, Kanchugarakoppal S.,Chandramohanadas, Rajesh,Basappa
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supporting information
p. 3300 - 3306
(2016/07/12)
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- POLY (ADP-RIBOSE) POLYMERASE INHIBITOR
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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.
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Paragraph 0098; 0099
(2015/02/25)
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- Substances for treatment or relief of pain
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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.
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Paragraph 0289; 0290
(2016/01/25)
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- 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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- Synthesis and anticancer activities of novel 1,2,4-triazolo[3,4-a] phthalazine derivatives
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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
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p. 235 - 244
(2014/08/18)
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- POLY (ADP-RIBOSE) POLYMERASE INHIBITOR
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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.
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Paragraph 0050; 0072; 0073
(2014/11/13)
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- Synthesis and positive inotropic evaluation of [1,2,4]triazolo[3,4-a] phthalazine and tetrazolo[5,1-a]phthalazine derivatives bearing substituted piperazine moieties
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Four series of [1,2,4]triazolo[3,4-a]phthalazine and tetrazolo[5,1-a] phthalazine derivatives bearing substituted piperazine moieties were synthesized and evaluated for their positive inotropic activity by measuring the left atrium stroke volume in isolated rabbit-heart preparations. Several compounds were developed and showed favorable activities compared to the standard drug milrinone, with (4-([1,2,4]triazolo[3,4-a]phthalazin-6-yl)piperazin-1-yl)(p- tolyl)methanone (5g) being identified as the most potent with an increased stroke volume of 19.15 ± 0.22% (milrinone: 2.46 ± 0.07%) at a concentration of 3 × 10-5 M. A preliminary study of mechanism of action revealed that 5g displayed its positive inotropic effect may be related to the PDE-cAMP-PKA signaling pathway. Compounds exhibiting inotropic effects were also evaluated in terms of the chronotropic effects.
- Ma, Long-Xu,Cui, Bai-Ri,Wu, Yan,Liu, Jia-Chun,Cui, Xun,Liu, Li-Ping,Piao, Hu-Ri
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p. 1737 - 1741
(2014/04/17)
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- Synthesis and biological evaluation of [1,2,4]triazolo[3,4-a]phthalazine and tetrazolo[5,1-a]phthalazine derivatives bearing substituted benzylpiperazine moieties as positive inotropic agents
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Two series of [1,2,4]triazolo[3,4-a]phthalazine and tetrazolo[5,1-a]phthalazine derivatives bearing substituted benzylpiperazine moieties have been synthesized and evaluated for their positive inotropic activity by measuring left atrium stroke volume on isolated rabbit heart preparations. The majority of the derivatives exhibited better in vitro activity than the existing drug, milrinone, and 6-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)tetrazolo[5,1-a]phthalazine. 8 m in particular was identified as the most potent with an increased stroke volume of 12.02 ± 0.20% (milrinone: 2.46 ± 0.07%) at a concentration of 3 × 10-5 m. The chronotropic effects of the compounds that exhibited good potency were also evaluated.
- Wu, Yan,Sun, Liang-Peng,Ma, Long-Xu,Che, Jian,Song, Ming-Xia,Cui, Xun,Piao, Hu-Ri
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p. 591 - 599
(2013/06/27)
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- Design, synthesis, and molecular modelling of pyridazinone and phthalazinone derivatives as protein kinases inhibitors
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The design and synthesis of pyridazinone and phthalazinone derivatives are described. Newly synthesized compounds were tested on a panel of four kinases in order to evaluate their activity and potential selectivity. In addition, the promising compounds were tested on four cancer cell lines to examine cytotoxic effects. The compounds inhibited DYRK1A and GSK3 with different activity. SAR analysis and docking calculations were carried out to aid in the interpretation of the results. Taken together, our findings suggest that pyridazinone and phthalazinone scaffolds are interesting starting points for design of potent GSK3 and DYRK1A inhibitors.
- Elagawany, Mohamed,Ibrahim, Mohamed A.,Ali Ahmed, Hany Emary,El-Etrawy, A.Sh.,Ghiaty, Adel,Abdel-Samii, Zakaria K.,El-Feky, Said A.,Bajorath, Juergen
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supporting information
p. 2007 - 2013
(2013/05/09)
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- Synthesis and anticonvulsant activity evaluation of 6-substituted-[1,2,4] triazolo[3,4-a](tetrazolo[5,1-a])phthalazine derivatives
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With the aim of finding new anticonvulsant drugs, new 6-substituted-[1,2,4] triazolo[3,4-a] (tetrazolo[5,1-a]) phthalazine derivatives (1-34) have been designed and synthesized. All the compounds were evaluated for their anticonvulsant activities using the maximal electroshock test (MES). Most of the synthesized compounds exhibited potent anticonvulsant activities in the MES. The most promising compound 14 showed significant anticonvulsant activity in MES test with ED50 value of 9.3 mg/kg. It displayed a wide margin of safety with protective index much higher than the standard drug Carbamazepine. And the potency of compound 14 against seizures induced by Pentylenetetrazole, Isoniazid, Thiosemicarbazide and 3-Mercaptopropionic acid in the chemical-induced seizure tests suggested that compound 14 displayed wide spectrum of activity in several models.
- Bian, Ming,Deng, Xian-Qing,Gong, Guo-Hua,Wei, Cheng-Xi,Quan, Zhe-Shan
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p. 792 - 800
(2013/07/26)
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- Synthesis and anticonvulsant activity evaluation of some 1-alkoxy-4-(1H-1,2,4-triazol-1-yl)phthalazines
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A series of 1-alkoxy-4-(1H-1,2,4-triazol-1-yl)phthalazine derivatives were synthesized using 2,3- dihydrophthalazine-1,4-dione as starting material. The structures of the compounds were characterized by elemental analysis, IR, 1H-NMR and MS data. Anticonvulsant activities of these compounds were evaluated by maximal electroshock (MES) test following intraperitoneal injection in mice. Among the synthesized compounds 3a-3t, compound 3e was the most active compound with an ED50 of 28.9 mg/kg, TD50 of 173.6 mg/kg and protective index (PI) of 6.0.
- Wang, Shi-Ben,Deng, Xian-Qing,Song, Ming-Xia,Quan, Zhe-Shan
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experimental part
p. 409 - 414
(2012/07/01)
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- Organocatalytic asymmetric direct vinylogous Michael addition of α,β-unsaturated γ-butyrolactam to nitroolefins
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The first organocatalytic enantioselective direct vinylogous Michael reaction of α,β-unsaturated γ-butyrolactam to nitroolefins is developed using cinchona alkaloids as the catalysts. Both product enantiomers are accessible with moderate to good enantioselectivity.
- Choudhury, Abhijnan Ray,Mukherjee, Santanu
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p. 7313 - 7320
(2012/10/07)
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- Synthesis and anticonvulsant activity 6-alkoxy-[1,2,4]triazolo[3,4-a] phthalazin-3(2H)-ones
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A new series of 6-alkoxy-[1,2,4]triazolo[3,4-a]phthalazin-3(2H)-one derivative was synthesized by condensation of appropriate 1-chloro-4-alkoxy phthalazine with methyl hydrazine carboxylate. All the compounds 5a-5r, characterized by IR, 1H NMR and MS, have been evaluated for their anticonvulsant activity against MES-induced seizure. The result illustrats that 6-pentyloxy-[1,2,4]triazolo[3,4-a]phthalazin-3(2H)-one (5b) possessed the most potential anticonvulsant activity.
- Cheng-Xi, Wei,Zhou, Guo,Fu-Nan, Li,Zhe-Shan, Quan
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experimental part
p. 127 - 131
(2011/11/13)
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- Multigram synthesis of glyceollin i
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Scaled-up procedures and preparation of glyceollin I in multigram quantities are described. The synthesis features construction of a cis-fused ring system in high enantiomeric excess after Sharpless asymmetric dihydroxylation of a key intermediate that is initially produced by an intramolecular Wittig reaction to afford the requisite alkene while simultaneously forming the first ring. The overall yield is 12% after 11 steps.
- Luniwal, Amarjit,Malik, Neha,Erhardt, Paul,Khupse, Rahul,Reese, Michael,Liu, Jidong,El-Dakdouki, Mohammad,Fang, Lei
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supporting information; experimental part
p. 1149 - 1162
(2012/01/05)
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- Synthesis and anti-inflammatory activity evaluation of some novel 6-alkoxy(phenoxy)-[1,2,4]triazolo[3,4-a]phthalazine-3-amine derivatives
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Starting from phthalic anhydride, several new 6-alkoxy(phenoxy)-[1,2,4] triazolo[3,4-a]phthalazine-3-amine derivatives were synthesized as potent anti-inflammatory agent. The study showed that the compounds 6h (6-(2-chlorophenoxy)-[1,2,4]triazolo[3,4-a]phthalazine-3-amine) and 6s (6-(4-aminophenoxy)-[1,2,4] triazolo[3,4-a]phthalazine-3-amine) exhibited the highest anti-inflammatory activity (81% and 83% inhibition, respectively, at 0.5 h after i.p. administration) which were slightly more potent than the reference drug Ibuprofen (61%). Furthermore, the peak activity of 6h and 6s was observed at the 3 h after p.o. administration, and they exhibited stronger anti-inflammatory activity than Ibuprofen at the dose of 50 mg/kg at the peak time.
- Sun, Xian-Yu,Hu, Chuan,Deng, Xian-Qing,Wei, Cheng-Xi,Sun, Zhi-Gang,Quan, Zhe-Shan
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experimental part
p. 4807 - 4812
(2010/12/20)
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- Synthesis and primary anticonvulsant activity evaluation of 6-alkyoxyl-tetrazolo[5,1-a]phthalazine derivatives
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A new series of 6-alkyoxyl-tetrazolo[5,1-a] phthalazine derivatives (4 a-4 o) were synthesized as potential anticonvulsant agents. Anticonvulsant activity was evaluated by the maximal electroshock (MES) test. Neurotoxicity was evaluated by the rotarod neurotoxicity test. The pharmacological results showed that 6-(4-chlorophenyoxyl)-tetrazolo[5,1-a]phthalazine (4 m) was the most potent agent, with a median effective dose (ED50) of 6.8 mg/kg and a median neurotoxic dose (TD50) of 456.4 mg/kg. The protective index (PI = TD50/ED50) for compound 4m was 67.1, which was significantly higher than that for the reference drug carbamazepine (PI = 6.4). ECV Editio Cantor Verlag.
- Sun, Xian-Yu,Wei, Cheng-Xi,Deng, Xian-Qing,Sun, Zhi-Gang,Quan, Zhe-Shan
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body text
p. 289 - 292
(2011/09/20)
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- Total syntheses of racemic and natural glycinol
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Total syntheses of racemic and (-)-glycinol (1) are described. A Wittig reaction produced the isoflav-3-ene from which a Sharpless dihydroxylation introduced either the racemic or enantiomeric 6a-hydroxy group. A 5.5% overall yield of racemic material was obtained after 12 steps. A method was devised for a one-pot switch of protecting groups masking a sensitive resorcinolic para-functionality, and conditions were optimized to prompt spontaneous closure of the pterocarpanolic dihydrofuran upon subsequent exposure of its ortho-functionality. These improvements eliminated two steps and increased the overall yield to 9.8% during production of the natural enantiomer.
- Luniwal, Amarjit,Khupse, Rahul S.,Reese, Michael,Fang, Lei,Erhardt, Paul W.
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supporting information; experimental part
p. 2072 - 2075
(2010/04/29)
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- PHARMACEUTICAL COMPOUNDS AS ACTIVATORS OF CASPASES AND INDUCERS OF APOPTOSIS AND THE USE THEREOF
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Disclosed are 1-arylamino-phthalazines, 4-arylamino-benzo[d][1,2,3]triazines, and analogs thereof effective as activators of caspases and inducers of apoptosis. The compounds of this invention are useful in the treatment of a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.
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Page/Page column 59
(2008/06/13)
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- HEPATITIS C VIRUS INHIBITORS
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Hepatitis C virus inhibitors are disclosed having the general formula:(I) wherein R1, R2, R3, R', B, Y and X are described in the description. Compositions comprising the compounds and methods for using the compounds toinhibit HCV are also disclosed.
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Page 277-278
(2008/06/13)
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