Synthesis and tripanocidal activity of ferrocenyl and benzyl diamines against Trypanosoma brucei and Trypanosoma cruzi

Velásquez, Angela María Arenas; Francisco, Acácio I.; Kohatsu, Andréa Akiko Nakaima; Silva, Flávia Alves de Jesus; Rodrigues, Danilo Fernando; Teixeira, Rafaela; Chiari, Bruna Galdorfini; Almeida, Maria Gabriela José de; Isaac, Vera Lúcia Borges; Vargas, Maria D.; Cicarelli, Regina Maria Barretto

doi:10.1016/j.bmcl.2014.02.046

Cited by 27 publications

(15 citation statements)

References 38 publications

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“…Thus, in order to improve the potency of the antileishmanial RP1, we coupled ferrocene at the N-terminus of the sequence. The ferrocene is a known anticancer, anti-Trypanosome brucei, anti-Plasmodium falciparum and anti-HIV molecule [37][38][39].…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial activity of RP-1 peptide conjugate with ferrocene group

et al. 2020

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Parasitic diseases are a neglected and serious problem, especially in underdeveloped countries. Among the major parasitic diseases, Leishmaniasis figures as an urgent challenge due to its high incidence and severity. At the same time, the indiscriminate use of antibiotics by the population is increasing together with resistance to medicines. To address this problem, new antibiotic-like molecules that directly kill or inhibit the growth of microorganisms are necessary, where antimicrobial peptides (AMPs) can be of great help. In this work, the ferrocene molecule, one active compound with low levels of in vivo toxicity, was coupled to the N-terminus of the RP1 peptide (derived from the human chemokine CXCL4), aiming to evaluate how this change modifies the structure, biological activity, and toxicity of the peptide. The peptide and the conjugate were synthesized using the solid phase peptide synthesis (SPPS). Circular dichroism assays in PBS showed that the RP1 peptide and its conjugate had a typical spectrum for disordered structures. The Fc-RP1 presented antiamastigote activity against Leishmania amazonensis (IC 50 = 0.25 μmol L -1 ). In comparison with amphotericin B, a second-line drug approved for leishmaniasis treatment, (IC 50 = 0.63 μmol L -1 ), Fc-RP1 was more active and showed a 2.5-fold higher selectivity index. The RP1 peptide presented a MIC of 4.3 μmol L -1 against S. agalactiae, whilst Fc-RP1 was four times more active (MIC = 0.96 μmol L -1 ), indicating that ferrocene improved the antimicrobial activity against Gram-positive bacteria. The Fc-RP1 peptide also decreased the minimum inhibitory concentration (MIC) in the assays against E. faecalis (MIC = 7.9 μmol L -1 ), E. coli (MIC = 3.9 μmol L -1 ) and S. aureus (MIC = 3.9 μmol L -1 ). The cytotoxicity of the compounds was tested against HaCaT cells, and no significant activity at the highest concentration tested (500 μg. mL -1 ) was observed, showing the high potential of this new compound as a possible new drug. The coupling of ferrocene also increased the vesicle permeabilization of the peptide, showing a direct relation between high peptide concentration and high carboxyfluorescein release, which indicates the action mechanism by pore formation on the vesicles. Several studies have shown that ferrocene destabilizes cell membranes through lipid peroxidation, leading to cell lysis. It is noteworthy that the Fc-RP1 peptide synthesized here PLOS ONE

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Section: Introductionmentioning

confidence: 99%

Antimicrobial activity of RP-1 peptide conjugate with ferrocene group

et al. 2020

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“…25 The efforts of organizations like the DNDi and Tres Cantos Open Lab Foundation have increased awareness about neglected parasitic diseases, and inspired many new trypanosomiasis drug discovery programs. Most campaigns have focused on either T. brucei 13,[26][27][28][29][30][31][32][33][34][35][36] or T. cruzi; [37][38][39][40][41][42] fewer have involved a concerted effort to discover leads that are effective against both pathogenic species, [43][44][45][46][47][48][49][50][51][52][53] despite the economies of broad-spectrum drug development, especially for neglected diseases.…”

Section: Introductionmentioning

confidence: 99%

Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides

et al. 2016

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The parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-(2-phenylthiazol-4-yl)ethyl)amides, carbamates, and ureas, which rapidly, selectively, and potently kill both species of trypanosome. The mode of action of these compounds is unknown but does not involve CYP51 inhibition. They do, however, exhibit clear structure-activity relationships, consistent across both trypanosome species. Favorable physicochemical parameters place the best compounds in CNS drug-like chemical space but, as a class, they exhibit poor metabolic stability. One of the best compounds (64a) cleared all signs of T. cruzi infection in mice when CYP metabolism was inhibited, with sterile cure achieved in one mouse. This family of compounds thus shows significant promise for trypanosomiasis drug discovery.

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“…Velasquez, et al . 87 cloned and sequenced the gene encoding the PRX enzyme in the Y strain of T . cruzi and confirmed its presence in the mitochondrial compartment.…”

Section: Discussionmentioning

confidence: 99%

Metabolic syndrome agravates cardiovascular, oxidative and inflammatory dysfunction during the acute phase of Trypanosoma cruzi infection in mice

Lucchetti

Boaretto

Lopes

et al. 2019

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We evaluated the influence of metabolic syndrome (MS) on acute Trypanosoma cruzi infection. Obese Swiss mice, 70 days of age, were subjected to intraperitoneal infection with 5 × 102 trypomastigotes of the Y strain. Cardiovascular, oxidative, inflammatory, and metabolic parameters were evaluated in infected and non-infected mice. We observed higher parasitaemia in the infected obese group (IOG) than in the infected control group (ICG) 13 and 15 days post-infection. All IOG animals died by 19 days post-infection (dpi), whereas 87.5% of the ICG survived to 30 days. Increased plasma nitrite levels in adipose tissue and the aorta were observed in the IOG. Higher INF-γ and MCP-1 concentrations and lower IL-10 concentrations were observed in the IOG compared to those in the ICG. Decreased insulin sensitivity was observed in obese animals, which was accentuated after infection. Higher parasitic loads were found in adipose and hepatic tissue, and increases in oxidative stress in cardiac, hepatic, and adipose tissues were characteristics of the IOG group. Thus, MS exacerbates experimental Chagas disease, resulting in greater damage and decreased survival in infected animals, and might be a warning sign that MS can influence other pathologies.

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Synthesis and tripanocidal activity of ferrocenyl and benzyl diamines against Trypanosoma brucei and Trypanosoma cruzi

Cited by 27 publications

References 38 publications

Antimicrobial activity of RP-1 peptide conjugate with ferrocene group

Antimicrobial activity of RP-1 peptide conjugate with ferrocene group

Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides

Metabolic syndrome agravates cardiovascular, oxidative and inflammatory dysfunction during the acute phase of Trypanosoma cruzi infection in mice

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