Identification of triazolo[4,5-b]pyrazine derivatives as hepatocyte growth factor receptor inhibitors through structure–activity relationships and molecular docking simulations

Dong, Min; Ren, Yujie; Gao, Xiao‐Dong

doi:10.1016/j.bmcl.2015.08.025

Cited by 9 publications

(2 citation statements)

References 30 publications

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“…The inhibition of hepatocyte growth factor receptor (c-Met) signalling inhibition was proposed as the main mechanism of savolitinib biological activity (Gavine et al, 2013). Both s-triazoles and as-triazoles fused with a sixmembered heterocycle are known to inhibit c- MET,including [1,2,3]triazolo [4,5-b]pyrazine (Dong et al, 2015;Cui et al, 2013;Jia et al, 2014) and [1,2,4]triazolo [4,3-b]pyridazine (Cui et al, 2013;Jia et al, 2014). However, there are other targets for anticancer activity among fused triazoles, such as hsp90 (Xu et al, 2016;Casale et al, 2014), kinase (Sun et al, 2019;Hou et al, 2019;Martínez-Gonzá lez et al, 2019), topoisomerase II (Ribeiro et al, 2019) and tubulin (Briguglio et al, 2017;Zaki et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

The different modes of chiral [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines: crystal packing, conformation investigation and cellular activity

Обыденнов

Калинина

Vysokova

et al. 2020

Acta Crystallogr C Struct Chem

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The crystal structures of four new chiral [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines are described, namely, ethyl 5′-benzoyl-5′H,7′H-spiro[cyclohexane-1,6′-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3′-carboxylate, C19H22N4O3S, ethyl 5′-(4-methoxybenzoyl)-5′H,7′H-spiro[cyclohexane-1,6′-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3′-carboxylate, C20H24N4O4S, ethyl 6,6-dimethyl-5-(4-methylbenzoyl)-6,7-dihydro-5H-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine-3-carboxylate, C17H20N4O3S, and ethyl 5-benzoyl-6-(4-methoxyphenyl)-6,7-dihydro-5H-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine-3-carboxylate, C21H20N4O4S. The crystallographic data and cell activities of these four compounds and of the structures of three previously reported similar compounds, namely, ethyl 5′-(4-methylbenzoyl)-5′H,7′H-spiro[cyclopentane-1,6′-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3′-carboxylate, C19H22N4O3S, ethyl 5′-(4-methoxybenzoyl)-5′H,7′H-spiro[cyclopentane-1,6′-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3′-carboxylate, C19H22N4O4S, and ethyl 6-methyl-5-(4-methylbenzoyl)-6-phenyl-6,7-dihydro-5H-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine-3-carboxylate, C22H22N4O3S, are contrasted and compared. For both crystallization and an MTT assay, racemic mixtures of the corresponding [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines were used. The main manner of molecular packing in these compounds is the organization of either enantiomeric pairs or dimers. In both cases, the formation of two three-centre hydrogen bonds can be detected resulting from intramolecular N—H...O and intermolecular N—H...O or N—H...N interactions. Molecules of different enantiomeric forms can also form chains through N—H...O hydrogen bonds or form layers between which only weak hydrophobic contacts exist. Unlike other [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines, ethyl 5′-benzoyl-5′H,7′H-spiro[cyclohexane-1,6′-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3′-carboxylate contains molecules of only the (R)-enantiomer; moreover, the N—H group does not participate in any significant intermolecular interactions. Molecular mechanics methods (force field OPLS3e) and the DFT B3LYP/6-31G+(d,p) method show that the compound forming enantiomeric pairs via weak N—H...N hydrogen bonds is subject to greater distortion of the geometry under the influence of the intermolecular interactions in the crystal. For intramolecular N—H...O and S...O interactions, an analysis of the noncovalent interactions (NCIs) was carried out. The cellular activities of the compounds were tested by evaluating their antiproliferative effect against two normal human cell lines and two cancer cell lines in terms of half-maximum inhibitory concentration (IC50). Some derivatives have been found to be very effective in inhibiting the growth of Hela cells at nanomolar and submicromolar concentrations with minimal cytotoxicity in relation to normal cells.

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Section: Introductionmentioning

confidence: 99%

The different modes of chiral [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines: crystal packing, conformation investigation and cellular activity

Обыденнов

Калинина

Vysokova

et al. 2020

Acta Crystallogr C Struct Chem

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“…The three-dimensional quantitative structure activity relationship (3D-QSAR) studies, including comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) [ 27 , 28 ], help to identify the interaction fields surrounding the compounds according to their corresponding activity, which may shed light on designing of novel B-Raf and KDR inhibitors and help with the issue of commonality and selectivity among B-Raf and KDR members. Therefore, combined docking and 3D-QSAR studies [ 29 , 30 , 31 , 32 , 33 ] may offer useful information for designing and obtaining more potent new dual kinase inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Studies on [5,6]-Fused Bicyclic Scaffolds Derivatives as Potent Dual B-RafV600E/KDR Inhibitors Using Docking and 3D-QSAR Approaches

Liu

Tang

Lü

et al. 2015

IJMS

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Research and development of multi-target inhibitors has attracted increasing attention as anticancer therapeutics. B-RafV600E synergistically works with vascular endothelial growth factor receptor 2 (KDR) to promote the occurrence and progression of cancers, and the development of dual-target drugs simultaneously against these two kinds of kinase may offer a better treatment advantage. In this paper, docking and three-dimensional quantitative structure activity relationship (3D-QSAR) studies were performed on a series of dual B-Raf/KDR inhibitors with a novel hinge-binding group, [5,6]-fused bicyclic scaffold. Docking studies revealed optimal binding conformations of these compounds interacting with both B-Raf and KDR. Based on these conformations, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) 3D-QSAR models were constructed, and the best CoMFA (q2 = 0.542, r2 = 0.989 for B-Raf; q2 = 0.768, r2 = 0.991 for KDR) and CoMSIA models (q2 = 0.519, r2 = 0.992 for B-Raf; q2 = 0.849, r2 = 0.993 for KDR) were generated. Further external validations confirmed their predictability, yielding satisfactory correlation coefficients (r2pred = 0.764 (CoMFA), r2pred = 0.841 (CoMSIA) for B-Raf, r2pred = 0.912 (CoMFA), r2pred = 0.846 (CoMSIA) for KDR, respectively). Through graphical analysis and comparison on docking results and 3D-QSAR contour maps, key amino acids that affect the ligand-receptor interactions were identified and structural features influencing the activities were discussed. New potent derivatives were designed, and subjected to preliminary pharmacological evaluation. The study may offer useful references for the modification and development of novel dual B-Raf/KDR inhibitors.

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Quinolinyl-pyrazoles: synthesis and pharmacological evolution in the recent decennial

et al. 2021

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Identification of triazolo[4,5-b]pyrazine derivatives as hepatocyte growth factor receptor inhibitors through structure–activity relationships and molecular docking simulations

Cited by 9 publications

References 30 publications

The different modes of chiral [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines: crystal packing, conformation investigation and cellular activity

The different modes of chiral [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines: crystal packing, conformation investigation and cellular activity

Studies on [5,6]-Fused Bicyclic Scaffolds Derivatives as Potent Dual B-RafV600E/KDR Inhibitors Using Docking and 3D-QSAR Approaches

Quinolinyl-pyrazoles: synthesis and pharmacological evolution in the recent decennial

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