Design and Synthesis of Indole Pyrimidine Scaffolds as Potential KSP Inhibitors and Anticancer Agents

摘要

Background: Several biological activities like anticancer, anti-inflammatory, analgesic,antitubercular activities are reported for pyrimidine scaffolds. Extensive work on pyrimidine indolescaffolds is required for antimitotic activity.Objective: To synthesize a novel Indole Pyrimidine scaffold via an efficient synthetic method and toevaluate cytotoxic activity using various human cancer cell lines.Methods: 4,4-(3-substituted phenyl)-6-methyl-N-[(Z)-(5-methyl-2-oxo-indolin-3-ylidene)amino]-2-oxo-3,4-dihydro-1H-pyrimidine-5-carboxamide derivatives were designed, synthesized and evaluatedfor cytotoxic activity. The structures were confirmed by IR, 1H NMR, C13NMR and Mass spectroscopy.The antiproliferative activities of the synthesized compounds were evaluated in vitroagainst human cancer cell lines including HeLa and MCF-7.Results: The results revealed that most of the compounds possessed moderate to excellent potency.Three among 10 molecules, showed more than 70% growth inhibition against all tested cancer cells.The nature of the substituent group (R) on the indole ring affected significantly the anti-proliferativeactivity of the molecules. The IC50 values of the most promising compound 4h are 76.4μM and88.2μM against HeLa and MCF-7 respectively, which are closer to the standard compound doxorubicin.Conclusion: Molecular docking analysis demonstrated that 4b and 4d interact and bind efficientlywith KSP binding site. The preliminary results made us investigate for further development of potentindole-pyrimidine scaffolds as cytotoxic agents.