Synthesis of 1,4-disubstituted 1,2,3-triazole Derivatives Using Click Chemistry and their Src Kinase Activities

Author(s): Alexandre Lebeau, Cyril Abrioux, David Bénimèlis, Zohra Benfodda, Patrick Meffre

Journal Name: Medicinal Chemistry

Volume 13 , Issue 1 , 2017

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Graphical Abstract:


Background: Tyrosine kinases (TK) are enzymes that catalyze the phosphorylation of tyrosine residues on proteins by the transfer of phosphate moiety of ATP. TK are key regulators of various cell functions, such as cellular growth, proliferation, migration, differentiation, and apoptosis.

Src mutations and/or overexpression has been correlated with tumor growth, metastasis, and angiogenesis [4,5]. Thus, the design and the discovery of novel Src kinase inhibitors remains critically important.

Methods: A series of 1,4-disubstituted 1,2,3-triazoles derivatives were designed and prepared as potential inhibitors for Src kinase. In this manuscript, all of the designed compounds were screened via molecular docking using PLANTS as virtual screening software to identify new inhibitors of Src kinase. Subsequently, all of the screened compounds were synthesized via Huisgen's 1,3-dipolar cycloaddition between terminal alkynes (1) and methyl 2-azidoacetate (2) with Cu(I) in excellent yields at room temperature.

Results: In the present study, we report the design and the synthesis of a series of 1,4-disubstituted 1,2,3-triazoles involving one pot condensation of methyl 2-azidoacetate and different terminal alkynes. All the synthesized triazoles were characterized by IR, 1 H, 13 C, 19 F NMR, and HRMS. They were investigated as inhibitors of Src kinase.

Conclusion: A series of 1,4-disubstituted 1,2,3-triazole compounds were synthesized through an easy, convenient Cu(I) catalyzed click reaction and evaluated for their Src kinase activity. Compound 3m exhibited significant inhibitory activity against Src Kinase. These results, along with molecular design docking observations, are significant evidence to demonstrate the compound 3m could be optimized as a potential Src kinase inhibitor in further studies.

Keywords: 1, 2, 3-triazole, molecular docking, Huisgen's 1, 3-dipolar cycloaddition, PEG400, click chemistry, Src kinase.

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Article Details

Year: 2017
Published on: 21 December, 2016
Page: [40 - 48]
Pages: 9
DOI: 10.2174/1573406412666160404125718
Price: $65

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