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

Abstract

Background: Several biological activities like anticancer, anti-inflammatory, analgesic, antitubercular activities are reported for pyrimidine scaffolds. Extensive work on pyrimidine indole scaffolds is required for antimitotic activity. Objective: To synthesize a novel Indole Pyrimidine scaffold via an efficient synthetic method and to evaluate 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 evaluated for cytotoxic activity. The structures were confirmed by IR, 1H NMR, C13NMR and Mass spectroscopy. The antiproliferative activities of the synthesized compounds were evaluated in vitro against 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-proliferative activity of the molecules. The IC50 values of the most promising compound 4h are 76.4µM and 88.2µM 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 efficiently with KSP binding site. The preliminary results made us investigate for further development of potent indole-pyrimidine scaffolds as cytotoxic agents