Isolation, Derivative Synthesis, and Structure-Activity Relationships of Anti-Parasitic Bromopyrrole Alkaloids from the Marine Sponge Tedania brasiliensis

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-1 H -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. N 12 -Acetyl pseudoceratidine ( 2 ) and N 12 -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.