- Phthalazine-based VEGFR-2 inhibitors: Rationale, design, synthesis, in silico, ADMET profile, docking, and anticancer evaluations
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In the designed compounds, a new linker was inserted in the form of fragments with verified VEGFR-2 inhibitory potential, including an α,β-unsaturated ketonic fragment, pyrazole, and pyrimidine. Also, new distal hydrophobic moieties were attached to these
- Khedr, Fathalla,Ibrahim, Mohamed-Kamal,Eissa, Ibrahim H.,Abulkhair, Hamada S.,El-Adl, Khaled
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- 1-Piperazinylphthalazines as potential VEGFR-2 inhibitors and anticancer agents: Synthesis and in vitro biological evaluation
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In our endeavor towards the development of effective VEGFR-2 inhibitors, three novel series of phthalazine derivatives based on 1-piperazinyl-4-arylphthalazine scaffold were synthesized. All the newly prepared phthalazines 16a-k, 18a-e and 21a-g were evaluated in vitro for their inhibitory activity against VEGFR-2. In particular, compounds 16k and 21d potently inhibited VEGFR-2 at sub-micromolar IC50 values 0.35 ± 0.03 and 0.40 ± 0.04 μM, respectively. Moreover, seventeen selected compounds 16c-e, 16g, 16h, 16j, 16k, 18c-e and 21a-g were evaluated for their in vitro anticancer activity according to US-NCI protocol, where compounds 16k and 21d proved to be the most potent anticancer agents. While, compound 16k exhibited potent broad spectrum anticancer activity with full panel GI50 (MG-MID) value of 3.62 μM, compound 21d showed high selectivity toward leukemia and prostate cancer subpanels [subpanel GI50 (MG-MID) 3.51 and 5.15 μM, respectively]. Molecular docking of compounds16k and 21d into VEGFR-2 active site was performed to explore their potential binding mode.
- Abou-Seri, Sahar M.,Eldehna, Wagdy M.,Ali, Mamdouh M.,Abou El Ella, Dalal A.
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- New 1,4-disubstituted phthalazines: Synthesis, structure and herbicidal evaluation
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The rapid synthesis of eighteen new 1,4-disubstituted phthalazines bearing an aryl or benzyl substituent at C-4 and a variety of aryloxy groups at C-1 is reported; full structural assignments are provided by NMR and MS data together with the biological evaluation for some representative terms of the series.
- Bele, Constantin,Darabantu, Mircea
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- New antithrombotic 1-Phthalazinamines with Serotonin Antagonistic Properties
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We report nineteen 4-aryl- and 4-arylalkyl-1-phthalazinamines (5-8) which we prepared and tested for antithrombotic properties. All compounds were assayed for their antiplatelet activity in the "Born test" with collagen as inducer of the aggregation. N-[4-(1H-1,2,4-triazol-1-yl)butyl]-4-phenyl-1-phthalazin-amine (7c) was the most potent compound, having an IC50 of 8 μM. When 5-HT (Serotonin) was used to start aggregation the N-(furan-2-yl-methyl)-4-phenyl-1-pthtalazinamine (8a) had an IC50 of 2 μM. In vivo potencies were highly significant. N-[5-(1H-1,2,4-triazol-1-yl)pentyl]-4-phenyl-1-phthalazinamine (7d) inhibited thrombus formation by 12% (P 2A receptor, which is most likely the mechanism of the inhibition of aggregation by this compound.
- Johnsen, Matthias,Rehse, Klaus,Pertz, Heinz,Stasch, Johannes Peter,Bischoff, Erwin
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- N-Substituted-4-phenylphthalazin-1-amine-derived VEGFR-2 inhibitors: Design, synthesis, molecular docking, and anticancer evaluation studies
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In accordance with the significant impetus of the discovery of potent vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitors, herein, we report the design, synthesis, and anticancer evaluation of 12 new N-substituted-4-phenylphthalazin-1-amine
- El-Adl, Khaled,Ibrahim, Mohamed-Kamal,Khedr, Fathalla,Abulkhair, Hamada S.,Eissa, Ibrahim H.
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- Synthesis and in vitro anti-proliferative activity of some novel isatins conjugated with quinazoline/phthalazine hydrazines against triple-negative breast cancer MDA-MB-231 cells as apoptosis-inducing agents
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Treatment of patients with triple-negative breast cancer (TNBC) is challenging due to the absence of well- defined molecular targets and the heterogeneity of such disease. In our endeavor to develop potent isatin-based anti-proliferative agents, we utiliz
- Eldehna, Wagdy M.,Almahli, Hadia,Al-Ansary, Ghada H.,Ghabbour, Hazem A.,Aly, Mohamed H.,Ismael, Omnia E.,Al-Dhfyan, Abdullah,Abdel-Aziz, Hatem A.
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p. 600 - 613
(2017/11/10)
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- A novel method for heterocyclic amide-thioamide transformations
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In this paper, we introduce a novel and convenient method for the transformation of heterocyclic amides into heteocyclic thioamides. A two-step approach was applied for this transformation: Firstly, we applied a chlorination of the heterocyclic amides to afford the corresponding chloroheterocycles. Secondly, the chloroherocycles and N-cyclohexyl dithiocarbamate cyclohexylammonium salt were heated in chloroform for 12 h at 61°C to afford heteocyclic thioamides in excellent yields.
- Fathalla, Walid,Ali, Ibrahim A. I.,Pazdera, Pavel
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supporting information
p. 174 - 181
(2017/02/15)
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- A the cu 2+ a responsive polymers containing iridium complex and its preparation method and application
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The invention belongs to the field of photoelectric phosphorescent materials and discloses an iridium complex in response to Cu2, and a preparation method and an application thereof. The iridium complex in response to Cu2 has a structure shown in fo
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- Synthesis of 1,2-dihydro-1-oxophthalazin-4-yl trifluoromethanesulfonate and its application in the synthesis of 4-(aryl/heteroaryl/alkynyl)phthalazin-1(2H)-one
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The regioselective synthesis of 1,2-dihydro-1-oxophthalazin-4-yl trifluoromethanesulfonate (3a) has been reported. The reaction of Tf2O (2a) with phthalhydrazide (1a) provides a rapid access to 3a with an excellent yield and a high level of reg
- Dhage, Ganesh Raosaheb,Deshmukh, Santosh Rangnath,Thopate, Shankar Ramchandra
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p. 33377 - 33384
(2015/04/27)
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- Design of 1-piperazinyl-4-arylphthalazines as potent Smoothened antagonists
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The Hedgehog (Hh) signaling pathway regulates cell proliferation and differentiation in developing tissues, and abnormal activation of the Hh pathway has been linked to several tumor subsets. As a transducer of Hh signaling, the GPCR-like protein Smoothened (Smo) is a promising target for disruption of unregulated Hh signaling. A series of 1-amino-4-arylphthalazines was developed as potent and orally bioavailable inhibitors of Smo. A representative compound from this class demonstrated significant tumor volume reduction in a mouse medulloblastoma model.
- Lucas, Brian S.,Aaron, Wade,An, Songzhu,Austin, Richard J.,Brown, Matthew,Chan, Hon,Chong, Angela,Hungate, Randall,Huang, Tom,Jiang, Ben,Johnson, Michael G.,Kaizerman, Jacob A.,Lee, Gary,McMinn, Dustin L.,Orf, Jessica,Powers, Jay P.,Rong, Minqing,Toteva, Maria M.,Uyeda, Craig,Wickramasinghe, Dineli,Xu, Guifen,Ye, Qiuping,Zhong, Wendy
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scheme or table
p. 3618 - 3622
(2010/09/04)
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- Hydrazine derivatives and o-benzoylbenzoic acid as a source of phthalazines with their antimicrobial activities
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Starting from 2-benzoylbenzoic acid (1) and prototype hydrazine itself or some of its simple congeners produce phthalazin-1(2H)-one derivatives 2a-d. Reactions of 2 with P2S5 or POCl3 gave their thione derivatives 3a-c or
- Hemdan, Magdy M.,Taha, Sherif M.,Gabr, Adel M.,Elkady, Mohamed Y.
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experimental part
p. 102 - 105
(2010/06/19)
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- HETEROCYCLIC DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE THEREOF
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The present invention relates to novel quinoxaline, quinazoline and phthalazine derivatives as well as multimeric derivatives, methods for their preparation, pharmaceutical compositions including such compounds, and methods of using these compounds for the treatment and prevention of brain damage resulting from brain injury, especially secondary brain damage due to traumatic brain injury (TBI). The compounds of the invention are also useful in treating and preventing neurodegenerative diseases.
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Page/Page column 34
(2010/03/02)
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- Phthalazine compounds, compositions and methods of use
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The present invention relates generally to compounds represented in Formula I, pharmaceutical compositions comprising them and methods of treating of diseases or disorders such as cancer.
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Page/Page column 21-22
(2009/03/07)
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- HETEROCYCLIC DERIVATIVES BINDING TO THE PERIPHERAL-TYPE BENZODIAZEPINE RECEPTOR (PBR)
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The present invention relates to novel quinoxaline, quinazoline and phthalazine derivatives as well as multimeric derivatives, methods for their preparation, pharmaceutical compositions including such compounds, and methods of using these compounds for the treatment and prevention of brain damage resulting from brain injury, especially secondary brain damage due to traumatic brain injury (TBI). The compounds of the invention are also useful in treating and preventing neurodegenerative diseases.
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Page/Page column 73; Sheet 9/26
(2008/06/13)
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- Functionalization by metalation of the benzene moiety of benzodiazines. Determination of structures by long-range 1H-15N correlation at natural abundance. Diazines XXV
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The first lithiation of the benzene moiety of various quinazolinones, quinoxalines, and phthalazines has been performed. The effects of kind and positions of various directing groups towards the regioselectivity of the metalation have been studied. Unambi
- Chapoulaud, V. Gautheron,Salliot,Ple,Turck,Queguiner
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p. 5389 - 5404
(2007/10/03)
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- 5-HT3 antagonists derived from aminopyridazine-type muscarinic M1 agonists
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A conformational analysis, performed on muscarinic M1 agonists, identified four structural features characteristic of the muscarinic M1 pharmacophore: (i) a protonable basic or quaternary nitrogen acting as a cationic head; (ii) an electronegative dipole usually part of a planar mesomeric ester, amide, or amidine function which can be replaced by an ether (muscarine) or a dioxolane (AF 30); (iii) an intercharge distance of 5 ± 0.5 A? between the cationic head and the electronegative atom of the dipole; (iv) an elevation of 0.5 ± 0.03 A? of the cationic head over the plane containing the electronegative dipole. During a reinvestigation of the conformational behavior of published structures of 5-HT3 antagonists, similar features were observed for the 5-HT3 pharmacophore. However many 5-HT3 antagonists possess additional aromatic planes not present in the muscarinic M1 agonists. These observations brought us to predict the chemical modifications that would change muscarinic M1 agonists into 5-HT3 antagonists. Four of the predicted aminopyridazines were actually synthesized and submitted to testing. The observed IC50 values for 5-HT3 receptor binding ([3H] BRL 43694) ranged from 10 to 425 nM, whereas the affinities for the muscarinic receptor preparations ([2SH] pirenzepine) layed over 10 000 nM. In electrophysiological studies the two most active compounds 10 and 13 produced antagonist-like effects on the 5-HT receptor channel complexes responsible for the generation of the rapidly desensitizing ionic currents, and agonist- like effects on those responsible for the slowly desensitizing components.
- Rival, Yveline,Hoffmann, Rémy,Didier, Bruno,Rybaltchenko, Volodymyr,Bourguignon, Jean-Jacques,Wermuth, Camille G.
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p. 311 - 317
(2007/10/03)
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- Physicochemical Study on Leuco Triarylmethane Dyes; Unusual Carbon-Carbon Bond Cleavage Involving an Elimination of Dimethylaniline
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Upon heating of the leuco triarylmethane dyes (2a) and (2b) with excess phosphoryl chloride under reflux, these compounds underwent a normal chlorination followed by a de-anilination process to give (3a) and (3b),respectively.Replacement of the p-dimethyl
- Kuzuya, Masayuki,Usui, Tamotsu,Miyake, Fumio,Ito, Seiji,Nozawa, Sigenori,Okuda, Takachiyo
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p. 2856 - 2861
(2007/10/02)
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- Synthesis and Reactions of Phthalazine Derivatives
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Hydrazones (Ia-c) fail to undergo cyclisation under different conditions to yield phthalazines (IIa-c). o-Aroylbenzoic acids (IVa-c) on treatment with hydrazine hydrate give 4-aryl-1(2H)-phthalazinones (Va-c) which react with POCl3 to yield 4-aryl-1-chlor
- Merchant, J. R.,Kulkarni, S. D.,Venkatesh, M. S.
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p. 914 - 916
(2007/10/02)
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