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Bromopyrrole Alkaloids as Lead Compounds against Protozoan Parasites
Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli “Federico II”, Via D. Montesano, 49, I-80131, Napoli, Italy
Department of Pharmaceutical and Biological Chemistry, School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK
Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, Socinstr. 57, CH-4002, Basel, Switzerland
University of Basel, Petersplatz 1, CH-4051 Basel, Switzerland
* Authors to whom correspondence should be addressed.
Received: 7 June 2010; in revised form: 24 June 2010 / Accepted: 9 July 2010 / Published: 14 July 2010
Abstract: In the present study,13 bromopyrrole alkaloids, including the oroidin analogs hymenidin (2), dispacamide B (3) and dispacamide D (4), stevensine (5) and spongiacidin B (6), their derivatives lacking the imidazole ring bromoaldisin (7), longamide B (8) and longamide A (9), the dimeric oroidin derivatives sceptrin (10) and dibromopalau’amine (11), and the non-oroidin bromopyrrolohomoarginin (12), manzacidin A (13), and agelongine (14), obtained from marine sponges belonging to Axinella and Agelas generahave been screened in vitro against four parasitic protozoa, i.e., two Trypanosoma species (T. brucei rhodesiense and T. cruzi), Leishmania donovani and Plasmodium falciparum (K1 strain, a chloroquine resistant strain), responsible of human diseases with high morbidity and, in the case of malaria, high mortality. Our results indicate longamide B (8) and dibromopalau’amine (11) to be promising trypanocidal and antileishmanial agents, while dispacamide B (3) and spongiacidin B (6) emerge as antimalarial lead compounds.In addition,evaluation of the activity of the test alkaloids (2–14) against three different enzymes (PfFabI, PfFabG, PfFabZ) involved in the de novo fatty acid biosynthesis pathway of P. falciparum (PfFAS-II) identified bromopyrrolohomoarginin (12) as a potent inhibitor of PfFabZ. The structural similarity within the series of tested molecules allowed us to draw some preliminary structure-activity relationships. Tests against the mammalian L6 cells revealed important clues on therapeutic index of the metabolites. This is the first detailed study on the antiprotozoal potential of marine bromopyrrole alkaloids.
Keywords: bromopyrrole alkaloids; antiprotozoal activity; enzyme inhibition; Trypanosoma; Leishmania; Plasmodium
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Scala, F.; Fattorusso, E.; Menna, M.; Taglialatela-Scafati, O.; Tierney, M.; Kaiser, M.; Tasdemir, D. Bromopyrrole Alkaloids as Lead Compounds against Protozoan Parasites. Mar. Drugs 2010, 8, 2162-2174.
Scala F, Fattorusso E, Menna M, Taglialatela-Scafati O, Tierney M, Kaiser M, Tasdemir D. Bromopyrrole Alkaloids as Lead Compounds against Protozoan Parasites. Marine Drugs. 2010; 8(7):2162-2174.
Scala, Fernando; Fattorusso, Ernesto; Menna, Marialuisa; Taglialatela-Scafati, Orazio; Tierney, Michelle; Kaiser, Marcel; Tasdemir, Deniz. 2010. "Bromopyrrole Alkaloids as Lead Compounds against Protozoan Parasites." Mar. Drugs 8, no. 7: 2162-2174.