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Leishmaniasis: from screening to the study of mechanisms of action, a contribution to the discovery of new bioactive molecules

Grant number: 17/03552-5
Support type:Regular Research Grants
Duration: May 01, 2017 - October 31, 2019
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Marcia Aparecida Silva Graminha
Grantee:Marcia Aparecida Silva Graminha
Home Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Leishmaniasis is a pathogenic disease found throughout the world caused by protozoan parasites of the Leishmania genus. Despite the numerous problems associated with existing treatments, pharmaceutical companies continue to neglect the development of better ones. The high toxicity of current drugs combined with emerging resistance to them makes providing new therapeutic alternatives urgent. We have been studying two new antileishmanial molecules: a binuclear cyclopalladated complex containing Pd(II) and N,N'-dimethylbenzylamine [Pd(dmba)(µ-N3)]2,, CP2, against Leishmania amazonensis and a furoxan derivative (E)-4-(4-((2-(3-hydroxybenzoyl)hydrazone)methyl)phenoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole 2-oxide, 14e.. Preliminary results showed that CP2 inhibits both promastigote (IC50 = 13.15 ± 0.67) and intracellular amastigote proliferation (IC50 = 10.14 ± 2.20), with high selectivity to the parasite. In vivo assays using L. amazonensis-infected BALB/c showed an 80% reduction in the parasite load when compared to infected and un-treated animals. Also, compared to amphotericin B treatment, CP2 did not show any side effects, which was corroborated by the analysis of plasma levels of different hepatic and renal biomarkers. Furthermore, CP2 was able to inhibit the Leishmania donovani Topoisomerase 1B (Ldtopo1B), one of the most important targets in Kinetoplastida. The furoxan 14e has shown good antileishmanial activity (EC50 = 3.14 µM) against intracellular amastigote forms of L. (L.) infantum and high selectivity to the parasite (SI = 66.35) was 2.8-times superior to that presented by amphotericin B (AmpB). Treatment of L. (L.) infantum-infected hamsters with compound 14e at 3.00 mg/Kg/day led to a meaningful reduction of parasite load in spleen (49.87%) and liver (54.24%), respectively; these data were corroborated by histopathological analysis, which also revealed reduction in the number of inflammatory cells in the liver and the spleen of the treated animals. The parasitemia reduction might be related to NO, since this molecule is a NO-donor. We did not observe neither side effects nor elevation of hepatic/ renal biomarkers in the plasma levels. Based on these data, we decided to further investigate the potential mechanism of action of these two molecules. For CP2, we are going to validate the proteomic data obtained during the development of the research project FAPESP number 2013/08248-1 as well as investigate if CP2 is interfering with calcium homoestasis. For 14e, proteomic analysis and validation will be made. In parallel, our research group will be doing screening for antileishmanial activity of synthetic or natural compounds. (AU)

Scientific publications (6)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DE ANNUNZIO, SARAH RAQUEL; SILVA COSTA, NATALIA CAROLINE; MEZZINA, RAFAELA DALBELLO; GRAMINHA, MARCIA A. S.; FONTANA, CARLA RAQUEL. Chlorin, Phthalocyanine, and Porphyrin Types Derivatives in Phototreatment of Cutaneous Manifestations: A Review. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 20, n. 16 AUG 2 2019. Web of Science Citations: 0.
DO ESPIRITO SANTO, RAFAEL DIAS; ARENAS VELASQUEZ, ANGELA MARIA; GUSHIKEN PASSIANOTO, LUANA VITORINO; LOPERA SEPULVEDA, ALEX ARBEY; CLEMENTINO, LEANDRO DA COSTA; ASSIS, RENATA PIRES; BAVIERA, AMANDA MARTINS; KALABA, PREDRAG; DOS SANTOS, FABIO NEVES; EBERLIN, MARCOS NOGUEIRA; JOSE DA SILVA, GIL VALDO; ZEHL, MARTIN; LUBEC, GERT; SILVA GRAMINHA, MARCIA APARECIDA; PEREZ GONZALEZ, EDUARDO RENE. N, N `, N `'-trisubstituted guanidines: Synthesis, characterization and evaluation of their leishmanicidal activity. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 171, p. 116-128, JUN 1 2019. Web of Science Citations: 0.
RANGEL, KAREN C.; DEBONSI, HOSANA M.; CLEMENTINO, LEANDRO C.; GRAMINHA, MARCIA A. S.; VILELA, LEONARDO Z.; COLEPICOLO, PIO; GASPAR, LORENA R. Antileishmanial activity of the Antarctic red algae Iridaea cordata (Gigartinaceae; Rhodophyta). JOURNAL OF APPLIED PHYCOLOGY, v. 31, n. 2, p. 825-834, APR 2019. Web of Science Citations: 0.
CLEMENTINO, LEANDRO DA COSTA; ARENAS VELASQUEZ, ANGELA MARIA; PASSALACQUA, THAIS GABAN; DE ALMEIDA, LETICIA; GRAMINHA, MARCIA A. S.; MARTINS, GILMARCIO Z.; SALGUEIRO, LIGIA; CAVALEIRO, CARLOS; SOUSA, MARIA DO CEU; MOREIRA, RAQUEL R. D. In vitro activities of glycoalkaloids from the Solanum lycocarpum against Leishmania infantum. REVISTA BRASILEIRA DE FARMACOGNOSIA-BRAZILIAN JOURNAL OF PHARMACOGNOSY, v. 28, n. 6, p. 673-677, NOV-DEC 2018. Web of Science Citations: 0.
LOPERA, A. A.; VELASQUEZ, A. M. A.; CLEMENTINO, L. C.; ROBLEDO, S.; MONTOYA, A.; DE FREITAS, L. M.; BEZZON, V. D. N.; FONTANA, C. R.; GARCIA, C.; GRAMINHA, M. A. S. Solution-combustion synthesis of doped TiO2 compounds and its potential antileishmanial activity mediated by photodynamic therapy. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY, v. 183, p. 64-74, JUN 2018. Web of Science Citations: 4.
DE ALMEIDA, LETICIA; PASSALACQUA, THAIS GABAN; DUTRA, LUIZ ANTONIO; VARONEZ DA FONSECA, JESSICA N.; QUEIROZ NASCIMENTO, RHAYANNE F.; IMAMURA, KELY BRAGA; DE ANDRADE, CLEVERTON ROBERTO; DOS SANTOS, JEAN LEANDRO; GRAMINHA, MARCIA A. S. In vivo antileishmanial activity and histopathological evaluation in Leishmania infantum infected hamsters after treatment with a furoxan derivative. BIOMEDICINE & PHARMACOTHERAPY, v. 95, p. 536-547, NOV 2017. Web of Science Citations: 5.

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