Isolation, Derivative Synthesis, and Structure−Activity Relationships of Antiparasitic Bromopyrrole Alkaloids from the Marine Sponge Tedania brasiliensis

Abstract

The isolation and identification of a series of new pseudoceratidine (1) derivatives from the sponge Tedania brasiliensis enabled the evaluation of their anti-parasitic activity against Plasmodium falciparum, Leishmania (Leishmania) amazonensis, Leishmania (Leishmania) infantum and Trypanosoma cruzi, the causative agents of malaria, cutaneous leishmaniasis, visceral leishmaniasis and Chagas disease, respectively. The new 3-debromopseudoceratidine (4), 20-debromopseudoceratidine (5), 4-bromopseudoceratidine (6), 19-bromopseudoceratidine (7) and 4,19-dibromopseudoceratidine (8) are reported. New tedamides A – D (9 – 12), with an unprecedented 4-bromo-4-methoxy-5-oxo-4,5-dihydro-1H-pyrrole-2-carboxamide moiety, are also described. Compounds 4 and 5, 6 and 7, 9 and 10, and 11 and 12 have been isolated as pairs of inseparable structural isomers differing in their sites of bromination or oxidation. Tedamides 9+10 and 11+12 were obtained as optically active pairs, indicating an enzymatic formation rather than an artefactual origin. N12-Acetyl pseudoceratidine (2) and N12-formyl pseudoceratidine (3) were obtained by derivatization of pseudoceratidine (1). The anti-parasitic activity of pseudoceratidine (1) led us to synthesize 23 derivatives (16, 17, 20, 21, 23, 25, 27 – 29, 31, 33, 35, 38, 39, 42, 43, 46, 47, 50 and 51) with variations in the polyamine chain and aromatic moiety in sufficient amounts for biological evaluation in anti-parasitic assays. The measured anti-malarial activity of pseudoceratidine (1) and derivatives 4, 5, 16, 23, 25, 31 and 50 provided an initial SAR evaluation of these compounds as potential leads for anti-parasitics against Leishmania amastigotes and against Plasmodium falciparum. The results obtained indicate that pseudoceratidine represents a promising scaffold for the development of new anti-malarial drugs.