Design, Synthesis of N-(Substituted Imidazo [1, 2-b] Pyridazine) Acetamides and Their Anti-Proliferative Studies on BRAFV600E Mutated A375 and Colo-205 Cell Lines.

Abstract

In the present investigation, a new series of imidazo[1,2-b]pyridazines were designed and synthesized and screened for their anti-proliferative activity. An efficient method is described for the synthesis of N-(substituted imidazo [1, 2-b] pyridazine) acetamides that consists of nucleophilic addition of 3-amino pyridazine which raises the electrophilicity of 4-Arylidine-2-methyl-oxazole5-ones followed by ring opening and cyclization steps. The synthesized compounds were evaluated for their possible anti-proliferative activity in A375 and colo-205 human cancer cell lines by employing MTT assay and most of the compounds were found to be highly active. The most active compounds of the series on both the cell lines were 5m, 5n with IC50 values of 21 nM, 20 nM on A375 cell lines and 38 nM, 31 nM on colo-205 cell lines respectively. The title compounds were employed to molecular docking studies to position the molecules into B-Raf Kinase v600E (PDBID: 3IDP) and to determine its binding interactions and the most probable binding sites. The results from the binding energies suggest that the compounds have moderate to strong affinity for the BRAFV600E kinase binding site with G-Scores ranging from -9.2 to -6.9 indicating their potential to be antitumor agents. The title compounds were also subjected to molecular toxicity prediction using OSIRIS property explorer. The results indicated that all the compounds are druggable candidates and are free from toxicity and mutagenicity.