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Biocidal Activity Against Trypanosoma Cruzi pharmaceutics Article Tambjamines and Prodiginines: Biocidal Activity against Trypanosoma cruzi Rocío Herráez 1, Roberto Quesada 2 , Norma Dahdah 3 , Miguel Viñas 1 and Teresa Vinuesa 1,* 1 Department of Pathology and Experimental Therapeutics, Medical School, University of Barcelona, 08021 Barcelona, Spain; [email protected] (R.H.); [email protected] (M.V.) 2 Departamento de Química, Universidad de Burgos, 09001 Burgos, Spain; [email protected] 3 Departament de Ciències Fisiològiques, Medical School, University of Barcelona, 08907 Barcelona, Spain; [email protected] * Correspondence: [email protected] Abstract: The aim of this work was to explore new therapeutic options against Chagas disease by the in vitro analysis of the biocidal activities of several tambjamine and prodiginine deriva- tives, against the Trypanosoma cruzi CLB strain (DTU TcVI). The compounds were initially screened against epimastigotes. The five more active compounds were assayed in intracellular forms. The tambjamine MM3 and both synthetic and natural prodigiosins displayed the highest trypanocidal profiles, with IC50 values of 4.52, 0.46, and 0.54 µM for epimastigotes and 1.9, 0.57, and 0.1 µM for trypomastigotes/amastigotes, respectively. Moreover, the combination treatment of these molecules with benznidazole showed no synergism. Finally, oxygen consumption inhibition determinations performed using high-resolution respirometry, revealed a potent effect of prodigiosin on parasite 1 respiration (73% of inhibition at 2 IC50), suggesting that its mode of action involves the mitochondria. Moreover, its promising selectivity index (50) pointed out an interesting trypanocidal potential and Citation: Herráez, R.; Quesada, R.; highlighted the value of prodigiosin as a new candidate to fight Chagas disease. Dahdah, N.; Viñas, M.; Vinuesa, T. Tambjamines and Prodiginines: Keywords: Trypanosoma cruzi; tambjamines; prodigiosin; obatoclax; anti-chagasic agents; cytotoxicity; Biocidal Activity against Trypanosoma targets; mitochondria cruzi. Pharmaceutics 2021, 13, 705. https://doi.org/10.3390/ pharmaceutics13050705 1. Introduction Academic Editor: Clive Prestidge Chagas disease, also known as American trypanosomiasis, is caused by the protozoan Trypanosoma cruzi. This neglected infectious disease affects 6 to 7 million people worldwide Received: 9 April 2021 and is endemic in 21 countries of Latin America [1,2]. Nowadays, due to migratory flows, Accepted: 10 May 2021 Published: 12 May 2021 Chagas disease has spread to non-endemic countries such as Spain, Canada, Australia, Japan, and North America, becoming a relevant public health challenge [3,4]. Chagas disease has two clinical phases. In the acute phase, the parasite disseminates Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in and can be detected by direct bloodstream examination [5]. In most cases, it courses published maps and institutional affil- without symptoms and if there are any symptoms, they are usually mild or nonspecific. iations. The acute phase usually lasts up to 2 months and resolves spontaneously. However, in 5–10% of infected subjects, the disease may become fatal because of heart failure or menin- goencephalitis [6,7]. After the acute phase, the disease enters the chronic phase, which can adopt two forms. In about 60–70% of cases, the disease remains in the indeterminate form, which may last 10–30 years or for the lifetime of the patient. This form is silent and free of Copyright: © 2021 by the authors. symptoms. In the remaining cases (30–40% of individuals), the patients develop a chronic Licensee MDPI, Basel, Switzerland. This article is an open access article form of the disease, which mostly involves severe cardiac, digestive, and neurological distributed under the terms and disorders [8–10]. conditions of the Creative Commons For more than 40 years, only two drugs have been available for the treatment of Chagas Attribution (CC BY) license (https:// disease: nifurtimox and benznidazole. Both have severe side effects that lead to treatment creativecommons.org/licenses/by/ discontinuation in 15–20% of cases [11–14]. This, coupled with their limited efficacy in 4.0/). the chronic phase of the disease [15] and the occurrence of naturally resistant strains [16], Pharmaceutics 2021, 13, 705. https://doi.org/10.3390/pharmaceutics13050705 https://www.mdpi.com/journal/pharmaceutics Pharmaceutics 2021, 13, 705 2 of 14 reinforces the need to identify new compounds to fight Chagas disease. Combination therapy has emerged as an alternative in the treatment of Chagas disease. Synergistic drug combinations could improve current regimens, allowing doses to be reduced and consequently diminishing side effects [17,18]. In our search for new trypanocidal drugs, we focused on tambjamines, a family of naturally occurring compounds isolated from bacteria and marine invertebrates such as ascidians, bryozoans, and nudibranchs [19]. Tambjamines are alkaloids structurally related to prodiginines, sharing with them the 4-methoxy-2,20-bipyrrole core and also a wide spectrum of useful biological properties that include antimicrobial, antifungal, antimalarial, and antitumor activities [20–22]. Although the mode of action of tambjamines has not been elucidated yet, it seems to be closely linked to its ability to act as anion transporters, a feature that is also shared by prodiginines [20,23]. Furthermore, the mitochondria of T. cruzi have been regarded as a potential target, since alterations in the mitochondria have catastrophic effects on respiration and, subsequently, on the survival of the parasite [24]. Surprisingly, to our knowledge, there are no studies on the use of tambjamines as antitrypanosomal agents. However, it has been postulated that these compounds exert a remarkable effect on other protozoans and have been proposed as antimalarial agents. Kancharla et al. [25] described the successful resolution of a Plasmodium yoelii infection in a murine model through treatment with tambjamines. Specifically, the synthetic tambjamine KAR425 had potent in vivo activity against the P. yoelii infection, showing no signs of cell toxicity. Our group recently studied prodigiosin of bacterial origin, reporting its remarkable activity against the epimastigotes of T. cruzi (CL strain, clone B5), with very low IC50 values (up to 0.8 µM), compared to benznidazole (18 µM). Additionally, we explored the effects of this pigment on the parasite cell surface by atomic force microscopy, which revealed relevant morphological alterations in the size, shape, and roughness [26]. Based on these encouraging preliminary results, we decided to continue exploring the trypanocidal effect of prodigiosin and related molecules against the intracellular forms of T. cruzi and investigate the targets presumably involved. The aims of the present work were to (1) determine the in vitro trypanocidal activity of natural and synthetic prodiginines as well as several tambjamine derivatives against the epimastigotes and trypomastigotes/amastigotes of the parasite, (2) evaluate the toxicity of these compounds in two cultured mammalian cell lines, (3) determine their biological activity in combination with the standard drug benznidazole, and (4) explore their mode of action. 2. Materials and Methods 2.1. Drugs Benznidazole (BNZ, Laboratorios ELEA, Buenos Aires, Argentina) was used as the reference drug. Tambjamine analogs, Obatoclax, and synthetic prodigiosin (prepared as a hydrochloride salt) were synthesized as reported elsewhere [27–29]. Natural prodigiosin was obtained as previously described [26]. In natural extracts, it is feasible that related fam- ily compounds may also be present and protonation state may vary with both protonated and neutral forms coexisting depending on the pH level. Figure1 shows the chemical structures of the synthesized molecules. Pharmaceutics 2021, 13, x FOR PEER REVIEW 3 of 14 Pharmaceutics 2021, 13, 705 3 of 14 FigureFigure 1.1. ChemicalChemical structurestructure ofof thethe studiedstudied compounds.compounds. 2.2.2.2. CulturesCultures 2.2.1. Cell Cultures 2.2.1. Cell Cultures Mouse L-929 fibroblasts (NCTC clone 929, ECACC 88102702) were used for both Mouse L-929 fibroblasts (NCTC clone 929, ECACC 88102702) were used for both drug toxicity and infection assays. Cell line was obtained from Dr. Concepció Soler, Dept.drug toxicity Pathology and & infection Experimental assays. therapeutics, Cell line was Faculty obtained of from Medicine Dr. Concepció and Health Soler, Sciences, Dept. UniversityPathology & of Experimental Barcelona, Spain. therapeutics, Human Facult hepatocarcinomay of Medicine Hep and G2 Health cells (AmericanSciences, Univer- Type Culturesity of Barcelona, Collection Spain. (ATCC Human HB-8065)) hepatocarcinoma were employed Hep only G2 in cells the drug(American toxicity Type assays Culture and wereCollection obtained (ATCC from HB-8065)) Dr. Neus Agell, were Cellemployed Biology only Research in the Group, drug toxicity Faculty assays of Medicine and were and Healthobtained Sciences, from Dr. University Neus Agell, of Barcelona, Cell Biolog Spain.y Research Group, Faculty of Medicine and HealthCell Sciences, lines were University maintained of Barcelona, in MEM Spain. and RPMI 1640 media (Biochrom AG, Berlin, Germany),Cell lines respectively, were maintained supplemented in MEM with and 10% RPMI fetal 1640 bovine media serum (Biochrom (FBS; Gibco,AG, Berlin, Life Technologies,Germany), respectively, Carlsbad, NY, supplemented USA) and 100 withµg/mL 10% of streptomycinfetal bovine
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