Title: Isolation, Derivative Synthesis, and Structure-Activity Relationships of Antiparasitic Bromopyrrole Alkaloids from the Marine Sponge Tedania brasiliensis
Author: Parra, Lizbeth L. L.; Miguel, Danilo C.; Gadelha, Fernanda R.; Ferreira, Antonio G.; Hajdu, Eduardo; Romo, Daniel; Berlinck, Roberto G. S.; Bertonha, Ariane F.; Severo, Ivan R. M.; Aguiar, Anna C. C.; De Souza, Guilherme E.; Oliva, Glaucius; Guido, Rafael V. C.; Grazzia, Nathalia; Costa, Tábata R.
Is part of: JOURNAL OF NATURAL PRODUCTS, v. 81, p. 01 - 15
Citation: Parra, Lizbeth L. L.; Miguel, Danilo C.; Gadelha, Fernanda R.; Ferreira, Antonio G.; Hajdu, Eduardo; Romo, Daniel; Berlinck, Roberto G. S.; Bertonha, Ariane F.; Severo, Ivan R. M.; Aguiar, Anna C. C.; De Souza, Guilherme E.; Oliva, Glaucius; Guido, Rafael V. C.; Grazzia, Nathalia; Costa, Tábata R.; Isolation, Derivative Synthesis, and Structure-Activity Relationships of Antiparasitic Bromopyrrole Alkaloids from the Marine Sponge Tedania brasiliensis. JOURNAL OF NATURAL PRODUCTS, v.81, p. 01-15, 2018
Abstract: The isolation and identification of a series of new pseudoceratidine (1) derivatives from the sponge Tedania brasiliensis enabled the evaluation of their antiparasitic 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 artifactual origin. N-12-Acetylpseudoceratidine (2) and N-12-formylpseudoceratidine (3) were obtained by derivatization of pseudoceratidine (1). The antiparasitic 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 antiparasitic assays. The measured antimalarial 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 antiparasitics against Leishmania amastigotes and against P. falciparum. The results obtained indicate that pseudoceratidine represents a promising scaffold for the development of new antimalarial drugs.
Funding: The authors thank Dr. H. Xue (Baylor University) for help in the characterization of some of the synthetic derivatives and Dr. D. E. Williams (Department of Earth, Ocean and Atmospheric Sciences, University of British Columbia), for his assistance in some of the HRMS measurements. Financial support was provided by a FAPESP BIOTA/BIOprospecTA grant (2013/50228-8) awarded to R.G.S.B., CEPID-CIBFar grant (2013/07600-3) to G.O., CNPq (grants 471509/2012-4 and 405330/2016-2) to R.V.C.G., FAPESP Young Investigators Grant (2014/21129-4) to D.C.M., and a FAPESP Regular Research Grant (2015/24595-9) to F.R.G. L.L.L.P. and A.F.B. thanks CAPES for a Ph.D. scholarship and also for a Science without Borders scholarship at Baylor University for A.F.B. D.R. acknowledges the financial support from NIH (R37 GM052964) and from the Robert A. Welch Foundation (AA-1280).