Potent quinoxaline-Based inhibitors of PDGF receptor tyrosine kinase activity. Part 1: SAR Exploration and Effective Bioisosteric Replacement of a phenyl substituent

Myers, Michael R.; He, Wei; Hanney, Barbara; Setzer, Natalie N.; Maguire, Martin P.; Zulli, Allison L.; Bilder, Glenda E.; Galzcinski, Helen; Amin, Dilip; Needle, Saul; Spada, Alfred P.

doi:10.1016/s0960-894x(03)00654-1

Cited by 41 publications

(17 citation statements)

References 6 publications

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“…Analogous results were obtained by using the chloro-substituted diamine (entries 9 and 10), whereas by using the dimethyl-substituted diamine the quinoxaline yields were optimized, when the stronger base DBU was used (entries [11][12][13]. DBU was also the best base, when heterocyclic aldehydes were used (entries 14-18), though the yields were generally lower.…”

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confidence: 74%

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Heterocyclizations via TosMIC-Based Multicomponent Reactions: A New Approach to One-Pot Facile Synthesis of Substituted Quinoxaline Derivatives

Neochoritis¹,

Stephanidou‐Stephanatou²,

Tsoleridis³

2009

Synlett

9
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0

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A novel multicomponent reaction involving o-phenylenediamines, aldehydes and p-toluenesulfonylmethyl isocyanide (TosMIC) in the presence of a base leading to the formation of quinoxalines in very good yields is described.Quinoxalines are widely used as intermediates in medicinal chemistry, 1,2 since they exhibit a wide range of biological activities, such as antiviral, antibacterial, antiinflammatory and kinase inhibitor properties. 3-10 The echinomycin 11 and the triostins 12 are well-known antibiotic families of quinoxaline derivatives. Furthermore, they have found applications as dyes, 13a efficient electroluminescent materials, 13b organic semiconductors, 13c dehydroannulenes, 13d cavidands 13e and chemically controllable switches. 13f Thus, a number of methods have been developed for the synthesis of substituted quinoxalines involving condensation of 1,2-phenylenediamines with adiketones, also under microwave irradiation, 14 1,4-addition of 1,2-diamines to diazenylbutenes, 15 oxidation trapping of a-hydroxyketones with 1,2-diamines, 16 oxidative cyclization of phenacyl bromides 17 or vicinal diols with ophenylenediamines, 18 oxidative coupling of epoxides 19 or ketones 20 with 1,2-diamines. Very recently, quinoxalines were also synthesized in 33-55% yield, through a twostep reaction sequence, the first step involving a multicomponent reaction between o-phenylenediamines, aldehydes and isonitriles in hydrochloric methanolic solution, whereas in the second step a DDQ oxidation of the isolated dihydroquinoxalines was involved. 21 Sequential transformations and one-pot multicomponent reactions (MCRs) offer significant advantages over conventional linear step syntheses, by reducing time and saving money, energy and raw material thus resulting in both economic and environmental benefits. 22 Moreover, multicomponent synthesis has been established as a valuable tool to the pharmaceutical industry for construction of low molecular weight compound libraries through combinatorial strategies and parallel synthesis. 23 Although p-toluenesulfonylmethyl isocyanide (TosMIC) is a versatile, widely applicable reagent that constitutes a densely functionalized building block bearing an active methylene group apart from its inherent advantage of possessing also an isonitrile functionality, which can serve as a handle for further manipulation, the possibility of its use in multicomponent reactions has not been greatly appreciated. TosMIC has most commonly been used in heterocyclic ring construction, 24 in particular, of oxazole and pyrrole moieties, but comparatively rarely in multicomponent reactions. 25 Since the reaction between imines and TosMIC in basic media constitutes a trusted method for the synthesis of 1,5-disubstituted imidazoles 26 and in continuation to our previous work 27 we speculated that formation of quinoxalines would be possible, through a multicomponent reaction, by using o-phenylenediamines with equimolar amounts of an aldehyde and TosMIC.Initially, a three-component reaction was performed between o-phen...

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mentioning
confidence: 74%

“…[3][4][5][6][7][8][9][10] The echinomycin 11 and the triostins 12 are well-known antibiotic families of quinoxaline derivatives. Furthermore, they have found applications as dyes, 13a efficient electroluminescent materials, 13b organic semiconductors, 13c dehydroannulenes, 13d cavidands 13e and chemically controllable switches.…”

mentioning
confidence: 99%

Heterocyclizations via TosMIC-Based Multicomponent Reactions: A New Approach to One-Pot Facile Synthesis of Substituted Quinoxaline Derivatives
Neochoritis¹,
Stephanidou‐Stephanatou²,
Tsoleridis³
2009
Synlett
9
0
0
0
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“…PDGF-induced cell proliferation is caused by the ligand binding to its cell surface receptor, followed by dimerization of the receptor and auto-phosphorylation of tyrosine kinase domain. [12][13][14][15][16] Various recent approaches to blocking the pathways mediated by PDGFR tyrosine kinase have led to the discovery of a wide range of small-molecule inhibitors, e.g., the indole-2-ones, [17][18][19][20] the quinoxalines, [21][22][23] the tyrophostines, 24,25) the pyridylpyrimidines, 26,27) the quinolines and quinazolines, [28][29][30][31][32][33][34] the indoles, 35,36) the imidazoles, 37,38) the pyrazoles. 39) We also found previously that the in-house compound 7-[3-(cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo [2,3-b]pyridin-3-yl}quinoxalin-2(1H)-one (7d-6) showed potent inhibitory activity toward PDGF-induced CPA and APA.…”

Section: Pdgfmentioning
confidence: 99%

Potent Platelet-Derived Growth Factor-.BETA. Receptor (PDGF-.BETA.R) Inhibitors: Synthesis and Structure-Activity Relationships of 7-[3-(Cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}quinoxalin-2(1H)-one Derivatives
Aoki
¹
,
Obata
²
,
Yamazaki
³

et al. 2007
Chem. Pharm. Bull.
39
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5
0
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PDGF1-3) is a glycoprotein that is produced by a large number of normal as well as transformed cell types, and it acts not only on connective tissue cells but also on other types of cells. It is also well known that PDGF participates in the onset of illness, e.g., arteriosclerosis and restenosis, [4][5][6][7][8] fibrosis, 9,10) nephritis, 11) along with its role in physiological phenomena such as generating processes in living organisms and aiding the wound healing process. An attractive target to treat proliferative disorders is to block abnormal PDGF-induced cell proliferation. PDGF-induced cell proliferation is caused by the ligand binding to its cell surface receptor, followed by dimerization of the receptor and auto-phosphorylation of tyrosine kinase domain. [12][13][14][15][16] Various recent approaches to blocking the pathways mediated by PDGFR tyrosine kinase have led to the discovery of a wide range of small-molecule inhibitors, e.g., the indole-2-ones, [17][18][19][20] the quinoxalines, 21-23) the tyrophostines, 24,25) the pyridylpyrimidines, 26,27) the quinolines and quinazolines, [28][29][30][31][32][33][34] the indoles, 35,36) the imidazoles, 37,38) the pyrazoles. 39) We also found previously that the in-house compound 7-[3-(cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo [2,3-b]pyridin-3-yl}quinoxalin-2(1H)-one (7d-6) showed potent inhibitory activity toward PDGF-induced CPA and APA. Table 1 shows the inhibitory activity of 7d-6 (IC 50 ϭ0.05 mmol/l in CPA, 0.03 mmol/l in APA) against PDGF compared to the inhibitory activity of 26,27) CT52923 28) and SU6668, 17) which have been evaluated in a clinical trial. As the data show, 7d-6 had a more potent inhibitory activity in CPA and APA against PDGF than did the other compounds. Encouraged by these promising results, we carried out a more extensive Structure-Activity Relationships (SAR) study of 3-

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“…Syntheses of quinoxalines have attracted a great deal of attention in view of their potent biological and pharmacological activities including anticonvulsant [1–4], antibacterial [5], antifungal [6], antiviral [7], antitubercular [8], antileishmanial [9], antiamoebic [10], analgesic [11], antihistaminic [12], antineoplastic [13], hypoglycemic [14], MAO-A inhibitor [15], antiarrhythmic [16], antiatherosclerotic [17], antiobese [18], and other diverse pharmacological activities.…”

Section: Introductionmentioning
confidence: 99%

Synthesis and Biological Evaluation of Some [1,2,4]Triazolo[4,3-a]quinoxaline Derivatives as Novel Anticonvulsant Agents
Alswah
¹
,
Ghiaty
²
,
El-Morsy
³

et al. 2013
ISRN Organic Chemistry
32
0
18
0
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2-([1,2,4]Triazolo[4,3-a]quinoxalin-4-ylthio)acetic acid hydrazide (10) was used as a precursor for the syntheses of novel quinoxaline derivatives with potential anticonvulsant properties. The newly synthesized compounds have been characterized by IR, 1H NMR, and mass spectral data followed by elemental analysis. The anticonvulsant evaluation was carried out for eleven of the synthesized compounds using metrazol induced convulsions model and phenobarbitone sodium as a standard. Among this set of tested compounds, two of them (14, and 15b) showed the best anticonvulsant activities.

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Potent quinoxaline-Based inhibitors of PDGF receptor tyrosine kinase activity. Part 1: SAR Exploration and Effective Bioisosteric Replacement of a phenyl substituent

Cited by 41 publications

References 6 publications

Heterocyclizations via TosMIC-Based Multicomponent Reactions: A New Approach to One-Pot Facile Synthesis of Substituted Quinoxaline Derivatives

Heterocyclizations via TosMIC-Based Multicomponent Reactions: A New Approach to One-Pot Facile Synthesis of Substituted Quinoxaline Derivatives

Potent Platelet-Derived Growth Factor-.BETA. Receptor (PDGF-.BETA.R) Inhibitors: Synthesis and Structure-Activity Relationships of 7-[3-(Cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}quinoxalin-2(1H)-one Derivatives

Synthesis and Biological Evaluation of Some [1,2,4]Triazolo[4,3-a]quinoxaline Derivatives as Novel Anticonvulsant Agents

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