Discovery of pyrido[3,4-g]quinazoline derivatives as CMGC family protein kinase inhibitors: Design, synthesis, inhibitory potency and X-ray co–crystal structure

Esvan, Yannick J.; Zeinyeh, Waël; Boibessot, Thibaut; Nauton, Lionel; Théry, Vincent; Knapp, Stefan; Chaikuad, A.; Meijer, Laurent; Anizon, Fabrice; Giraud, F; Moreau, Pascale

doi:10.1016/j.ejmech.2016.04.004

Cited by 36 publications

(47 citation statements)

References 42 publications

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“…In addition, the process of our experiment was different from that reported in former papers [24,25]. Using small natural organic molecule L-proline as the catalyst, DMF as the solvent and under the condition where temperature gradually increased, the amount of by-product decreased and the yield of product 3 was the highest [26]. The influence of different experimental conditions on the yield of product 3 is shown in Table 1.…”

Section: Synthesis Of Target Compoundsmentioning

confidence: 85%

Synthesis and Biological Activity of Benzamides Substituted with Pyridine-Linked 1,2,4-Oxadiazole

Yang

Tian

et al. 2020

Molecules

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To find pesticidal lead compounds with high activity, a series of novel benzamides substituted with pyridine-linked 1,2,4-oxadiazole were designed by bioisosterism, and synthesized easily via esterification, cyanation, cyclization and aminolysis reactions. The structures of the target compounds were confirmed by 1H-NMR, 13C-NMR and HRMS. The preliminary bioassay showed that most compounds had good larvicidal activities against mosquito larvae at 10 mg/L, especially compound 7a, with a larvicidal activity as high as 100%, and even at 1 mg/L was still 40%; at 50 mg/L, all the target compounds showed good fungicidal activities against the eight tested fungi. Moreover, compound 7h exhibited better inhibitory activity (90.5%) than fluxapyroxad (63.6%) against Botrytis cinereal. Therefore, this type of compound can be further studied.

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Section: Synthesis Of Target Compoundsmentioning

confidence: 85%

Synthesis and Biological Activity of Benzamides Substituted with Pyridine-Linked 1,2,4-Oxadiazole

Yang

Tian

et al. 2020

Molecules

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“…CLK1 and CLK3 have been purified as described [ 36 , 52 ]. Crystallization was performed using sitting-drop vapor diffusion method at 4°C and various conditions as summarized in Table 3 .…”

Section: Methodsmentioning

confidence: 99%

“…Diffraction data were collected at Diamond Light Source and were processed and scaled with Mosflm [ 53 ] and Scala [ 54 ], respectively. Structures were solved by molecular replacement method using Phaser [ 55 ] and the coordinates of published CLK1 and CLK3 structure [ 36 , 52 ]. Model rebuilding was performed in COOT [ 56 ] and the structures were refined using REFMAC [ 57 ].…”

Section: Methodsmentioning

confidence: 99%

Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype

et al. 2018

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Cdc2-like kinases (CLKs) represent a family of serine-threonine kinases involved in the regulation of splicing by phosphorylation of SR-proteins and other splicing factors. Although compounds acting against CLKs have been described, only a few show selectivity against dual-specificity tyrosine phosphorylation regulated-kinases (DYRKs). We here report a novel CLK inhibitor family based on a 6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one core scaffold. Within the series, 3-(3-chlorophenyl)-6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one (KuWal151) was identified as inhibitor of CLK1, CLK2 and CLK4 with a high selectivity margin towards DYRK kinases. The compound displayed a potent antiproliferative activity in an array of cultured cancer cell lines. The X-ray structure analyses of three members of the new compound class co-crystallized with CLK proteins corroborated a molecular binding mode predicted by docking studies.

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“…While the catalytic domains of DYRK1A and DYRK1B have a sequence identity of 85%, their ATP binding pockets only differ in one amino acid: the gatekeeper (gk) +2 amino acid Met240 of DYRK1A is replaced by Leu192 in DYRK1B. Although DYRK1A and CLK1 feature an overall sequence identity of only 30%, their ATP binding pockets show an analogy of 70% [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Indole-3-Carbonitriles as DYRK1A Inhibitors by Fragment-Based Drug Design

et al. 2018

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Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a potential drug target because of its role in the development of Down syndrome and Alzheimer’s disease. The selective DYRK1A inhibitor 10-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acid (KuFal194), a large, flat and lipophilic molecule, suffers from poor water solubility, limiting its use as chemical probe in cellular assays and animal models. Based on the structure of KuFal194, 7-chloro-1H-indole-3-carbonitrile was selected as fragment template for the development of smaller and less lipophilic DYRK1A inhibitors. By modification of this fragment, a series of indole-3-carbonitriles was designed and evaluated as potential DYRK1A ligands by molecular docking studies. Synthesis and in vitro assays on DYRK1A and related protein kinases identified novel double-digit nanomolar inhibitors with submicromolar activity in cell culture assays.

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Discovery of pyrido[3,4-g]quinazoline derivatives as CMGC family protein kinase inhibitors: Design, synthesis, inhibitory potency and X-ray co–crystal structure

Cited by 36 publications

References 42 publications

Synthesis and Biological Activity of Benzamides Substituted with Pyridine-Linked 1,2,4-Oxadiazole

Synthesis and Biological Activity of Benzamides Substituted with Pyridine-Linked 1,2,4-Oxadiazole

Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype

Indole-3-Carbonitriles as DYRK1A Inhibitors by Fragment-Based Drug Design

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