Synthesis of novel imino-coumarin and acrylonitrile 2-benzazole hybrids as potent anticancer agents targeting tubulin.

Building on previous research indicating the robust biological effects of coumarins, we focused on exploring imino-coumarin 2-benzazole conjugates. Compounds were tested for antiproliferative activity in vitro, with the most active ones further examined to determine the mechanism of biological action. Five derivatives exhibited significant antiproliferative activity against all tested cancer cells (IC ₅₀ ranging from 0.04 to 8.5 μM), falling within the low micromolar/submicromolar range of inhibitory concentrations. Three compounds had remarkable antiproliferative effects against Capan-1 (IC ₅₀ 0.04-0.05 μM) and DND-41 (IC ₅₀ 0.06-0.07 μM). Promising compounds were further investigated, confirming their mechanism of action through tubulin polymerization inhibition. Computational docking and molecular dynamics simulations confirmed the high affinity of potent derivatives for the tubulin colchicine site and justified the suitability of the employed skeleton by identifying crucial protein-ligand interactions promoting binding. This insight highlights a strategy for further potency improvements through substituents that can donate hydrogen bonds or bear a positive charge, allowing such ligands to more optimally adapt to the identified anionic binding site environment.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Marijana Hranjec, Robert Vianello reports financial support was provided by Croatian Science Foundation. Marijana Hranjec, Robert Vianello reports a relationship with Croatian Science Foundation that includes: funding grants. − If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)