Novel 9-oxo-thiazolo[5,4-f]quinazoline-2-carbonitrile derivatives as dual cyclin-dependent kinase 1 (CDK1)/glycogen synthase kinase-3 (GSK-3) inhibitors: Synthesis, biological evaluation and molecular modeling studies

Logé, Cédric; Testard, Alexandra; Thiéry, Valérie; Lozach, Olivier; Blairvacq, Mélina; Robert, Jean‐Michel; Meijer, Laurent; Besson, Thierry

doi:10.1016/j.ejmech.2007.09.020

Cited by 58 publications

(41 citation statements)

References 20 publications

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“…These include the purine derivatives pyrazolo [3,4- b ] quinoxalines (Ortega et al, 2002), the pyrazolo[3,4- b ]pyridine ring system (Chioua et al, 2009), the 9-oxo-thiazolo [5,4- f ] quinazoline-2-carbonitrile derivatives (Loge et al, 2008), and the thiazolo[5,4- f ]quinazolin-9-ones (Testard et al, 2006). Aloisines (6-phenyl[5 H ]pyrrolo[2,3- b ]pyrazines) are a different class of dual CDK/GSK-3 inhibitors that inhibit the two kinases in the sub-micromolar range (Mettey et al, 2003).…”

Section: Organic Molecules As Gsk-3 Inhibitorsmentioning

confidence: 99%

GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS

Eldar-Finkelman

Martı́nez

2011

Front. Mol. Neurosci.

309

278

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Inhibiting glycogen synthase kinase-3 (GSK-3) activity via pharmacological intervention has become an important strategy for treating neurodegenerative and psychiatric disorders. The known GSK-3 inhibitors are of diverse chemotypes and mechanisms of action and include compounds isolated from natural sources, cations, synthetic small-molecule ATP-competitive inhibitors, non-ATP-competitive inhibitors, and substrate–competitive inhibitors. Here we describe the variety of GSK-3 inhibitors with a specific emphasis on their biological activities in neurons and neurological disorders. We further highlight our current progress in the development of non-ATP-competitive inhibitors of GSK-3. The available data raise the hope that one or more of these drug design approaches will prove successful at stabilizing or even reversing the aberrant neuropathology and cognitive deficits of certain central nervous system disorders.

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Section: Organic Molecules As Gsk-3 Inhibitorsmentioning

confidence: 99%

GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS

Eldar-Finkelman

Martı́nez

2011

Front. Mol. Neurosci.

309

278

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“…The benzothiazoles 128 and 129 (Table 14) are nonselective GSK-3 inhibitors and showed moderate activity against CDKs [130]. This stands in contrast to the thiazolylurea 130 ( AR-A014418 ), which strongly inhibited GSK-3 (IC 50 = 104 nM) but not any other kinase in the panel.…”

Section: Small-molecule Inhibitors Of Glycogen Synthase Kinasementioning

confidence: 99%

Small-Molecule Inhibitors of GSK-3: Structural Insights and Their Application to Alzheimer's Disease Models

Krämer

Schmidt

Monte

2012

International Journal of Alzheimer's Disease

106

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The world health organization (WHO) estimated that 18 million people are struck by Alzheimer's disease (AD). The USA, France, Germany, and other countries launched major programmes targeting the identification of risk factors, the improvement of caretaking, and fundamental research aiming to postpone the onset of AD. The glycogen synthase kinase 3 (GSK-3) is implicated in multiple cellular processes and has been linked to the pathogenesis of several diseases including diabetes mellitus, cancer, and AD. Inhibition of GSK-3 leads to neuroprotective effects, decreased β-amyloid production, and a reduction in tau hyperphosphorylation, which are all associated with AD. Various classes of small molecule GSK-3 inhibitors have been published in patents and original publications. Herein, we present a comprehensive summary of small molecules reported to interact with GSK-3. We illustrate the interactions of the inhibitors with the active site. Furthermore, we refer to the biological characterisation in terms of activity and selectivity for GSK-3, elucidate in vivo studies and pre-/clinical trials.

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“…(9) was discovered by Loge et al bearing an Nisopropyl side chain on the N-8 nitrogen and an amidine function with a bulky N,N-dimethylethylenediamine group at the C-2 position of the thiazole moiety. This compound (structure 25) showed submicromolar IC 50 against GSK-3 as well as moderate activity against CDKs [21]. 3,4-Dihydro-lH,6H-[1,4]-oxazino-[3,4-b]-quinazolin-6-one (structure 26) is known to be the partial structure of some toxic fungus metabolites, and can be variously substituted at position-l.…”

Section: Protein Kinase Inhibitionmentioning

confidence: 99%

“…Among the 518 human kinases [20], two classes i.e. cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3 (GSK-3) are particularly explored [21].…”

Section: Protein Kinase Inhibitionmentioning

confidence: 99%

Quinazolinone Analogs as Potential Therapeutic Agents

Sharma¹,

Kaur²,

Pahwa

et al. 2011

CMC

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Quinazolinone scaffold has been considered as a magic moiety possessing myriad spectrum of medicinal activities. Diversity of biological response profile has attracted considerable interest of several researchers across the globe to explore this skeleton for its assorted therapeutic significance. Various novel classes of structurally different quinazolinones have been designed and synthesized depicting potential interventions such as antibacterial, antifungal, antiviral, anticonvulsant, CNS depressant, antiinflammatory, antihistaminic, anticancer and so on. Moreover, the nucleus constitutes an integral structural component in a number of drugs currently employed in several clinical therapies. The present paper is an earnest attempt to provide an insight view on the current medicinal aspects of quinazolinone heterocycles alongwith brief discussion of their chemistry.

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Novel 9-oxo-thiazolo[5,4-f]quinazoline-2-carbonitrile derivatives as dual cyclin-dependent kinase 1 (CDK1)/glycogen synthase kinase-3 (GSK-3) inhibitors: Synthesis, biological evaluation and molecular modeling studies

Cited by 58 publications

References 20 publications

GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS

GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS

Small-Molecule Inhibitors of GSK-3: Structural Insights and Their Application to Alzheimer's Disease Models

Quinazolinone Analogs as Potential Therapeutic Agents

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