Isolation, Derivative Synthesis, and Structure–Activity Relationships of Antiparasitic Bromopyrrole Alkaloids from the Marine Sponge <i>Tedania brasiliensis</i>

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