Abstract
Recent studies have shown that combining kinase inhibitors has additive and synergistic effects. BRAF(V600E) and p38 alpha have been extensively studied as potential therapeutic targets for a variety of diseases. In keeping with our interest in developing multi-targeted anticancer agents, a series of novel triaryl-imidazole-based analogues containing 3-aryl-1,2,4-oxadiazoles moiety (4a-h, Scaffold B) and their reaction intermediates aryl carboximidamides moiety (3a-h, Scaffold A) have been rationally designed, synthesized, and evaluated in vitro for their antiproliferative activity as dual p38 alpha/BRAF(V600E) inhibitors. The results revealed that the presence of the carboximidamide moiety is required for activity, and the best activity correlates with the Ar = 1,2-benzodioxole (3e) >= 4-CH3O-C6H5-(3c) > 2-naphthyl (3h) > 4-Cl-C6H5 (3b). Ring closure of carboximidamide to 1,2,4-oxadiazole significantly reduces the activity. The results of docking study into p38 alpha revealed higher binding affinities for compounds 3c, 3e, and 3h compared to the co-crystallized ligand, SB2. However, the docking study of compounds 3c and 3e into BRAF(V600E) revealed slightly lower affinities than vemurafenib. (C) 2021 Elsevier B.V. All rights reserved.