Triamino derivatives of triazolotriazine and triazolopyrimidine as adenosine A2a receptor antagonists

“…[13][14][15][16][17][18] Further, triazole fused with other heterocyclic rings is also found to possess diverse applications in the field of medicine. [19][20][21][22] The commonly known systems are triazolo-pyridines, 19) triazolo-pyridazines, 20) triazolo-pyrimidines, 21) triazolo-pyrazines, 22) triazolo-triazines 21) and triazolo-thiadiazines. 23) In addition, it has been reported that thiadiazoles exhibit a broad spectrum of biological effectiveness such as anti-parkinsonism, 24) hypoglycaemic, 25) anticancer, 26) anti-inflammatory, 27) anti-asthmatic 28) and anti-hypertensive 29) activities.…”

Section: -7)mentioning

confidence: 99%

Synthesis of New 1,2,4-Triazole[3,4-b][1,3,4]thiadiazoles Bearing Pyrazole as Potent Antimicrobial Agents

Reddy

Rao

Kumar

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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Pyrazole and its derivatives represent one of the most active classes of compounds possessing a wide spectrum of biological activities, including antibacterial, 1) antifungal, 2) herbicidal, 3) insecticidal 4) and other biological activities. 5-7)Similarly, the biological activities of various 1,2,4-triazole derivatives and their N-bridged heterocyclic analogs have been widely investigated as antitumor, 8) antiviral, 9) anti-inflammatory, 10) analgesic 11) and antidepressant. 12) 1,2,4-Triazole system is also an important starting material in the synthesis of biologically active heterocycles, which constitute an important class of organic compounds with diverse biological activities, including antiparasitic, analgesic, antibacterial and anti-inflammatory activities. [13][14][15][16][17][18] Further, triazole fused with other heterocyclic rings is also found to possess diverse applications in the field of medicine. [19][20][21][22] The commonly known systems are triazolo-pyridines, 19) triazolo-pyridazines, 20) triazolo-pyrimidines, 21) triazolo-pyrazines, 22) triazolo-triazines 21) and triazolo-thiadiazines. 23) In addition, it has been reported that thiadiazoles exhibit a broad spectrum of biological effectiveness such as anti-parkinsonism, 24) hypoglycaemic, 25) anticancer, 26) anti-inflammatory, 27) anti-asthmatic 28) and anti-hypertensive 29) activities. Inspired by the biological profile of pyrazole, triazole, thiadiazole, and in continuation of our research on biologically active heterocycles, [30][31][32][33][34][35] it was thought worthwhile to synthesize some new heterocyclic compounds containing pyrazole, triazole and thiadiazol rings in one molecular frame work. We report herein the synthesis of a new series of 1,2,4-triazole [3,4-b][1,3,4]thiadiazoles bearing pyrazole and their antimicrobial activity. Results and DiscussionSynthesis The starting material, (E)-2-acetyl-3-(dimethylamino)-2-propenoate (2), was obtained via condensation of ethyl acetoacetate (1) with N,N-dimethyldimethoxymethanamine, 36) which on cyclo-condensation with phenyl hydrazine resulted 5-methyl-1-phenyl-1H-4-pyrazolecarboxylate (3).36) The 5-methyl-1-phenyl-1H-4-pyrazolecarbohydrazide (4) was obtained in 72% yield via hydrazinolysis of compound 3 with hydrazine hydrate. The hydrazide 4 on reaction with carbon disulfide and potassium hydroxide, in ethanol, followed by acidification gave 5-(5-methyl-1-phenyl-1H-4-pyrazolyl)-1,3,4-oxadiazol-2-yl-hydrosulfide (5) in 70% yield. Reaction of 5 with hydrazine hydrate under reflux for 6 h resulted 4-amino-5-(5-methyl-1-phenyl-1H-4-pyrazolyl)-4H-1,2,4-triazol-3-yl-hydrosulfide (6) in 69% yield. The final compounds, 6-(aryl/heteryl)-3-(5-methyl-1-phenyl-1H-4-pyrazolyl)[1,2,4]triazolo [3,4-b] [1,3,4]thiadiazole (7a-j), were synthesized in 66-78% via the reaction of 6 with POCl 3 and the corresponding aryl/heteryl carboxylic acids, in ethanol at reflux temperature for 12 h (Chart 1). The structures of all the newly synthesized compounds were confirmed by their elemental analyses, electron...

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“…[9][10][11][12][13][14][15][16][17][18][19][20] We selected the training set using chosen molecules with human binding data, defined stereochemistry and biological data (e.g. structure with biological data such as Ki>500 were excluded from the training set).…”

Section: Pharmacophore Model Generationmentioning

confidence: 99%

Induced fit and pharmacophore generation approach applied to A2A adenosine receptor antagonists

Parenti¹,

Fioravanzo²,

Mabilia³

et al. 2006

Arkivoc

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Receptors A 2A have an important role in the regulation of mood and motor activity; the available evidence has provided the basis for the formulation of a theory according to which selective A 2A adenosine receptor antagonists can be useful for the treatment of Parkinson's Disease. To explore the binding properties of some adenosine-like antagonists, we have employed two different approaches: (1) induced fit applied to an apo 3D receptor model, and (2) 3D QSAR. We have applied the Glide/Prime induced fit protocol developed by Schrödinger, using the apo-receptor structure and one of its known antagonists, in order to obtain a 3D receptor-antagonist complex structure. The IF protocol led to a receptor structure able to bind adenosine-like antagonists that can be used in future docking studies. To highlight the spatial arrangement of chemical features that confers drug activity toward the A 2A receptor, two different pharmacophore hypotheses were generated with Phase, using 68 A 2A antagonists retrieved from literature. Both hypotheses suggested a binding mode consistent with previously published site-directed mutagenesis and SAR studies. The predictive power of these 3D QSAR models is still under development.

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Triamino derivatives of triazolotriazine and triazolopyrimidine as adenosine A2a receptor antagonists

Cited by 71 publications

References 20 publications

Synthesis of some pyridyl and cyclohexyl substituted 1,2,4 triazole, 1,3,4-thiadiazole and 1,3,4-oxadiazole derivatives

Synthesis of some pyridyl and cyclohexyl substituted 1,2,4 triazole, 1,3,4-thiadiazole and 1,3,4-oxadiazole derivatives

Synthesis of New 1,2,4-Triazole[3,4-b][1,3,4]thiadiazoles Bearing Pyrazole as Potent Antimicrobial Agents

Induced fit and pharmacophore generation approach applied to A2A adenosine receptor antagonists

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