Synthesis of Substituted Aminopyrimidines as Novel Promising Tyrosine Kinase Inhibitors

Stolpovskaya, Nadezhda V.; Kruzhilin, Alexey A.; Zorina, Anna V.; Шихалиев, Х. С.; Леденева, И. В.; Kosheleva, E. A.; Vandyshev, Dmitriy Yu.

doi:10.1134/s1070428019090094

Cited by 9 publications

(6 citation statements)

References 13 publications

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“…Compound B4 (Figure 6) showed exhibited great inhibitory action in kinases assay with an IC 50 value of 0.038 μM, along with significant anti-tumor effects toward H1975-IGF1R cell lines of IC 50 = 0.013 mM with moderate selectivity index based on a group of 468 kinases (Table 3). Based on structural T A B L E 2 Biological activity of 2-amino-pyrimidine derivatives (An et al, 2019;Basu et al, 2015;Cross et al, 2014;Finlay et al, 2014;Flanagan et al, 2014;Gao et al, 2017;Romu et al, 2017;Singh & Silakari, 2018;Stolpovskaya et al, 2019;Xiao et al, 2016;Zhang et al, 2017;Zhao et al, 2019; analysis, it was confirmed that the lipophilic substitution of a chlorine atom at the C-5 position of the pyrimidine ring and the NH substituent present at the C-4 position was beneficial for the inhibition of the compound making it valuable as a new lead compound dual IGF1R and EGFR L858R/T790M inhibitors (Chan et al, 2015). A rationalized study based on the application of three-step structure-based design molecules was done from precursory structure to obtain more than 27 molecules were synthesized and structurally analyzed from which B5 and B6 (Figure 6) were found to have potential activity with IC 50 of 4.1 and 3.2 nM with EGFR L858R/T790M mutant cell line of NSCLC showing about 60% selectivity over wild-type EGFR (Table 3).…”

Section: -Amino-pyrimidine Derivativesmentioning

confidence: 99%

“…Stolpovskaya et al looked into amino pyrimidine fragment in EGFR TK inhibitors, thereby synthesizing a group of thiourea and thiazole-based amino pyrimidine derivatives. In vitro data obtained identified compounds, A7 and A8 (Figure 5) have inhibition rates of 85-89% in EGFR L858R and 62%-76% in EGFR L858R/T790M in kinase assay conducted (Table 2; Stolpovskaya et al, 2019). Romu et al utilizing WZ4002 structure allowed the design and synthesis of 32 derivatives of amino pyrimidine moiety by incorporating electrophilic and non-electrophilic moieties with varied hydrophilic and lipophilic properties to expand the SAR of WZ4002.…”

Section: Introductionmentioning

confidence: 99%

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Pyrimidine derivatives as EGFR tyrosine kinase inhibitors in non‐small‐cell lung cancer: A comprehensive review

et al. 2022

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EGFR-positive non-small-cell lung cancer (NSCLC) due to primary mutation (EGFR DEL19 & L858R) has been recognized as a crucial mediator of tumor progression. This led to the development and approval of EGFR tyrosine kinase inhibitors, which addresses EGFR-mediated NSCLC but fail to show potency after initial months of therapy due to acquired resistance (EGFR T790M, EGFR C797S). Extensive research allowed identification of drugs for EGFR-positive NSCLC, wherein the majority of compounds have a pyrimidine substructure offering marked therapeutic benefits compared with chemotherapy. This current review outlines the diverse pyrimidine derivatives with amino-linked and fused pyrimidine scaffolds such as furo-pyrimidine, pyrimido-pyrimidine, thienopyrimidine, highlighting pyrimidine EGFR TK inhibitors reported in research emphasizing structural aspects, design approaches, inhibition potential, selectivity profile toward mutant EGFR conveyed through biological evaluation studies.Furthermore, mentioning the in-silico interaction profile of synthesized compounds for evaluating the binding affinity with key amino acids. The epilogue of review focuses on the recent research that drives forward to aid in the discovery and development of substituted amino and fused scaffolds of pyrimidine that can counteract the mutations and effectively manage EGFR-positive NSCLC.

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Section: -Amino-pyrimidine Derivativesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pyrimidine derivatives as EGFR tyrosine kinase inhibitors in non‐small‐cell lung cancer: A comprehensive review

et al. 2022

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“…The compounds are small drug-like molecules. Among them there are hydroquinoline derivatives with antibacterial, antifungal, anticoagulant activity [22,25,34,37,38], aminopyrimidines and pyrrolo[3,2,1-ij]quinolin-2-ones, which are factor Xa and protein kinases inhibitors [50,54], various plant growth stimulants of the getarylcarboxylic acid class [63,64].…”

Section: Database and Ligand 3d Structure Preparationmentioning

confidence: 99%

In Search of Non-covalent Inhibitors of SARS-CoV-2 Main Protease: Computer Aided Drug Design Using Docking and Quantum Chemistry

2020

JSFI

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Two stages virtual screening of a database containing several thousand low molecular weight organic compounds is performed with the goal to find inhibitors of SARS-CoV-2 main protease. Overall near 41000 different 3D molecular structures have been generated from the initial molecules taking into account several conformers of most molecules. At the first stage the classical SOL docking program is used to determine most promising candidates to become inhibitors. SOL employs the MMFF94 force field, the genetic algorithm (GA) of the global energy optimization, takes into account the desolvation effect arising upon protein-ligand binding and the internal stress energy of the ligand. Parameters of GA are selected to perform the meticulous global optimization, and for docking of one ligand several hours on one computing core are needed on the average. The main protease model is constructed on the base of the protein structure from the Protein Data Bank complex 6W63. More than 1000 ligands structures have been selected for further postprocessing. The SOL score values of these ligands are more negative than the threshold of −6.3 kcal/mol obtained for the native X77 ligand docking. Subsequent calculation of the protein-ligand binding enthalpy by the PM7 quantum-chemical semiempirical method with COSMO solvent model have narrowed down the number of best candidates. Finally, the diverse set of 20 most perspective candidates for the in vitro validation are selected.

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“…Another urgent task in organic chemistry is to study the reactions of polynucleophilic compounds with polyelectrophiles which, depending on the reaction conditions utilized, can lead to the formation of various heterocyclic systems. [13][14][15][16] In this regard, amidinothiourea is a polynucleophilic substrate that, depending on the structure of the electrophile, behaves like a 1,3-N,S-, [17][18][19] 1,3-N,N- [19][20] or 1,5-N,N- 21 binucleophile. In addition, imethylacetylene dicarboxylate is widely used in organic synthesis for the construction of five-, six-, and seven-membered heterocyclic systems.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and some reactions of 5-carbmethoxymethylidene-4-oxo-1,3-thiazol-2-ylguanidine

Stolpovskaya¹,

Quy²,

Kruzhilin³

et al. 2022

Arkivoc

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Methyl (2Z)-[2[(diaminomethylene)amino]-4-oxothiazol-5(4H)-ylidene]acetate was obtained by the reaction of N-amidinothiourea and dimethyl acetylenedicarboxylate (DMAD) under various conditions: methanol, ethanol, acetonitrile, ethyl acetate, dioxane, acetic acid, ethanol/TsOH. The structure of the product has been proven by X-ray diffraction analysis. A series of new N-(5-R-1,3,5-triazinan-2-ylidene)-N-1,3-thiazol-2-amines was obtained as a result of the multicomponent condensation of methyl (2Z)-[2[(diaminomethylene)amino]-4oxothiazol-5(4H)-ylidene]acetate with alkylamines and formaldehyde.

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Synthesis of Substituted Aminopyrimidines as Novel Promising Tyrosine Kinase Inhibitors

Cited by 9 publications

References 13 publications

Pyrimidine derivatives as EGFR tyrosine kinase inhibitors in non‐small‐cell lung cancer: A comprehensive review

Pyrimidine derivatives as EGFR tyrosine kinase inhibitors in non‐small‐cell lung cancer: A comprehensive review

In Search of Non-covalent Inhibitors of SARS-CoV-2 Main Protease: Computer Aided Drug Design Using Docking and Quantum Chemistry

Synthesis and some reactions of 5-carbmethoxymethylidene-4-oxo-1,3-thiazol-2-ylguanidine

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