Anticancer Properties of N-Alkyl-2, 4-Diphenylimidazo [1, 2-A] Quinoxalin-1-Amine Derivatives; Kinase Inhibitors Publisher Pubmed



Rezaei Z¹ ; Mahdi Didehvar M² ; Mahdavi M³ ; Azizian H⁴ ; Hamedifar H⁵ ; Mohammed EHM⁶ ; Ostad S⁷ ; Amini M⁸ Show Affiliations
Source: Bioorganic Chemistry Published:2019

Abstract

Structure activity correlation revealed that the quinoxaline ring is a satisfactory backbone for anticancer activity and a specific functional group at position 1 and 2 can improve the activity. In this basis, besides quinoxaline, imidazoles as potential anticancer agents were used as a supplementary agents for cancer treatment. In this paper, a new series of N-alkyl-2, 4-diphenylimidazo [1, 2-a] quinoxalin-1-amine derivatives were synthesized in a simple and efficient step. The products are fully characterized by 1H NMR, 13C NMR, FT-IR, HRMS, and CHN elemental analysis. Several starting materials with different functionalities have been used for the synthesis of the final products with high isolated yields. The biological activities of the synthesized compounds were evaluated in kinase inhibition and cytotoxic activity in several cancerous cell lines. All compounds (6) were evaluated for inhibition of the cell proliferation using 4 cancerous cell lines. Five of the more active compounds were studied for determination of IC50%. Compounds 6(32–34) showed good activity on some of cancerous cell lines. The results showed that compound 6–32 has the highest biological activity (IC50% 9.77 for K562 cell line). An IC50% value of 15.84 µM was observed for 6–34. Furthermore 6–34 exhibited inhibition of ABL1 and c-Src kinases with an IC50% value of 5.25 µM and 3.94 µM respectively. Docking simulation was performed to position active synthesized compounds 6–32, 6–33, and 6–34 over the ABL1 active site in two different wild-type (DFG-in and DFG-out motif conformer) and T315I mutant to determine the probable binding orientation, conformation and mode of interaction. According to docking study, the docked location in wild type forms is similar and can be found near the P-loop region while in the case of T315I mutant form, the compounds have a distinct docked location which is close to the αC helix and activation loop. Also, it concluded the role of R1 substituent on phenyl ring produced higher interaction energy. Additionally, the detailed inter-molecular energy and types of non-bonding interaction of these compounds over the wild-type and mutant form of ABL1. © 2019