New manzamine alkaloids, zamamidine C (1), 3,4-dihydro-6-hydroxy-10,11-epoxymanzamine A (2), and 3,4-dihydromanzamine J N-oxide (3). have been isolated from an Okinawan marine sponge Amphimedon species. The Structures and stereochemistries of 1-3 were elucidated from the spectroscopic data and chemical derivatization. Zamamidine C (1) is a new manzamine alkaloid possessing a second beta-carboline ring via an ethylene unit at N-2 of manzamine D, while 3,4-dihydro-6-hydroxy-10,11-epoxymanzamine A (2) is the first manzamine alkaloid possessing an epoxide ring at C-10 and C-11. Zamamidine C (1) showed significant antitrypanosomal activity against Trypanosoma brucei brucei, the parasite associated with sleeping sickness, and antimalarial activity against Plasmodium falciparum, the causative agent of malaria in vitro. (C) 2009 Elsevier Ltd. All rights reserved.