(−)-Agelastatin A (AA), isolated from the coral sea axinellid sponge Agelas dendromorpha, has shown a high antineoplastic activity. We have synthesized eighteen AA analogues and analyzed their cytotoxicities towards three cancer cell lines. By the structure–activity relationship (SAR) study, we identified three novel analogues with higher or comparable cytotoxic activities to AA. They were subjected to chemoinformatic analysis, which revealed physicochemical properties favoring excellent central nervous system (CNS) penetration. CNS pharmacokinetic analysis in murine models validated the chemoinformatic prediction and revealed that these analogues indeed had better CNS penetration than AA. These novel potent AA analogues deserve further evaluation for therapeutic use against cancers, particularly primary and secondary brain tumors.