Structure-Based Design and Synthesis of Novel Coumarin–Diketopiperazine Hybrids as future Promising Microtubule Inhibitor Scaffolds

Abstract

Marine-derived natural products have inspired numerous anticancer agents, exemplified by Plinabulin, a synthetic derivative of phenylahistin currently in phase III clinical trials for non-small cell lung cancer [5,11,12]. Building on this paradigm, we report the structure-based design and synthesis of coumarin–diketopiperazine hybrids as novel scaffolds for microtubule inhibition. Guided by molecular docking, rational modifications integrated pharmacophoric features of coumarin and diketopiperazine frameworks [4,6,8,13]. A concise synthetic route was developed, combining peptide chemistry with heterocyclic condensation to afford key intermediates and a small library of derivatives [7,9,10]. Structural confirmation was achieved by NMR and LC-MS. Preliminary suggests these hybrids possess favourable physicochemical properties and potential for tubulin binding [14–17]. This work establishes coumarin–diketopiperazine hybrids as synthetically accessible scaffolds for future anticancer drug discovery [1–3,18].