Anti-parasitic Guanidine and Pyrimidine Alkaloids from the Marine Sponge Monanchora arbuscula Mario F. C. Santos, † Philip M. Harper, ‡ David E. Williams, § Juliana T. Mesquita, ⊥ E ́ rika G. Pinto, ⊥,∥ Thais A. da Costa-Silva, ⊥ Eduardo Hajdu, # Antonio G. Ferreira, ∇ Raquel A. Santos, ⊗ Patrick J. Murphy, ‡ Raymond J. Andersen, § Andre G. Tempone,* ,⊥,∥ and Roberto G. S. Berlinck* ,† † Instituto de Química de Sã o Carlos, Universidade de Sã o Paulo, CP 780, CEP 13560-970 Sã o Carlos, SP, Brazil ‡ School of Chemistry, Bangor University, Bangor, Gwynedd LL57 2UW, U.K. § Departments of Chemistry and Earth, Ocean & Atmospheric Sciences, University of British Columbia, Vancouver, BC, V6T 1Z1 Canada ⊥ Centro de Parasitologia e Micologia, Instituto Adolfo Lutz, Av. Dr. Arnaldo 351, 8° andar, Cerqueira Cesar, CEP 01246-000 Sã o Paulo, SP, Brazil ∥ Instituto de Medicina Tropical de Sã o Paulo, Universidade de Sã o Paulo, Av. Dr. Ene ́ as de Carvalho Aguiar, 470, CEP 05403-000 Sã o Paulo, SP, Brazil # Museu Nacional, Universidade Federal do Rio de Janeiro, Quinta da Boa Vista, s/n, CEP 20940-040 Rio de Janeiro, RJ, Brazil ∇ Departamento de Química, Universidade Federal de Sã o Carlos, Rod. Washington Luiz, km 235 - SP-310, CEP 13565-905, Sã o Carlos, SP, Brazil ⊗ Laborató rio de Gene ́ tica e Biologia Molecular, Programa de Pó s-Graduaç ã o em Ciê ncias, Universidade de Franca, Av. Dr. Armando Salles Oliveira, 201, CEP 14404 600 Franca, SP, Brazil * S Supporting Information ABSTRACT: HPLC-UV-ELSD-MS-guided fractionation of the anti-parasitic extract obtained from the marine sponge Monanchora arbuscula, collected off the southeastern coast of Brazil, led to the isolation of a series of guanidine and pyrimidine alkaloids. The pyrimidines monalidine A (1) and arbusculidine A (7), as well as the guanidine alkaloids batzellamide A (8) and hemibatzelladines 9−11, represent new minor constituents that were identified by analysis of spectroscopic data. The total synthesis of monalidine A confirmed its structure. Arbusculidine A (7), related to the ptilocaulin/mirabilin/netamine family of tricyclic guanidine alkaloids, is the first in this family to possess a benzene ring. Batzellamide A (8) and hemibatzelladines 9−11 represent new carbon skeletons that are related to the batzelladines. Evaluation of the anti-parasitic activity of the major known metabolites, batzelladines D (12), F (13), L (14), and nor-L (15), as well as of synthetic monalidine A (1), against Trypanosoma cruzi and Leishmania infantum is also reported, along with a detailed investigation of parasite cell-death pathways promoted by batzelladine L(14) and norbatzelladine L (15). L eishmaniasis and Chagas disease are neglected diseases affecting over 12 million people worldwide, 1−4 and are considered by the World Health Organization as the neglected diseases with the highest mortality level. 5 Current treatment of leishmaniasis is exclusively based on chemotherapeutics. 1,5 Usual anti-leishmanial chemotherapy relies on antimonium salts, miltefosine, and amphotericin B. 6 Problems are associated with such a narrow choice of anti-leishmanial drugs, including parasite resistance, high toxicity and long-term treatment with sodium stibogluconate, and the high treatment cost with liposomal amphotericin B. 1,3 Similarly, the only two drugs currently used in the treatment of Chagas disease, nifurtimox and benznidazole, also present pronounced adverse effects due to long periods of administration. 7 Therefore, new approaches toward the discovery of new anti-leishmanial and anti-Chagas agents are in need. 1−8 Marine organisms have been continuously investigated as a source of new anti-parasitic agents during the past two decades. 6,9 Recent examples include the almiramides isolated from the cyanobacterium Lyngbya majuscula, active against intracellular Leishmania donovani amastigotes, 3 sesquiterpene− Received: January 24, 2015 Article pubs.acs.org/jnp © XXXX American Chemical Society and American Society of Pharmacognosy A DOI: 10.1021/acs.jnatprod.5b00070 J. Nat. Prod. XXXX, XXX, XXX−XXX