One-pot synthesis and anti-proliferative activity of hindered 5-amino-1-alkylimidazole-4-carboxamides

Abstract

One-pot procedure was developed for the synthesis of hindered 5-amino-1-alkylimidazole-4-carboxamides by using bulky alkyl amines with trimethyl orthoformate and 2-amino-2-cyanoacetamide. Under optimized conditions, the reactivity of a series of steric hindrance substrates was examined, producing the corresponding hindered 5-amino-1-alkylimidazole-4-carboxamides with good to excellent yields. This synthetic method has several advantages including metal- and additive-free, short reaction time and wide substrate scope with good to excellent yields. Besides, 5-amino-1-(4-fluorobenzyl)-1H-imidazole-4-carboxamide (3j) exhibited potent antiproliferative activity against A375(B-RAF^V600E) cells as a novel anti-tumor agent, and the molecular docking model showed that carboxamide moiety of 3j was a key active functional group, forming two hydrogen bonds with Lys483 and Phe595，which was similar to the function of sulfonamide of vemurafenib. To our delight, the imidazole scaffold of 3j formed a novel hydrogen bond with Asp594, and there was π…π interaction between the phenyl group of 3j and Phe583, which were different from binding mode of vemurafenib. The binding mode between 3j and B-RAF^V600E kinase provided a reasonable explanation for 3j as a potential B-RAF^V600E kinase inhibitor.