Design　of　novel　coumarin　derivatives　as　CK2　inhibitors　were　attempted　by　targeting　the　interaction　with　the　hinge　region.　A　set　of　substituents　capable　of　forming　a　hydrogen　bond　or　halogen　bond　with　the　hinge　region　were　screened　in　silico,　and　trifluoromethyl　emerges　as　a　promising　motif　by　forming　favorable　electrostatic　interaction　and　a　presumable　halogen　bond　with　the　hinge　region.　As　proof　of　concept,　three　trifluoromethyl　derivatives　of　coumarin　were　synthesized　and　tested　in　vitro.　The　results　indicated　that　replacement　of　methyl　by　trifluoromethyl　leads　to　a　modest　5-fold　improvement　in　potency,　with　the　most　active　compound　being　0.4　mu　M.　The　newly　designed　compounds　were　further　screened　on　one　lung　cancer　cell　line　A549,　showing　low　micromolar　anti-proliferative　activity.