Letícia de Almeida

Synthesis and evaluation of novel prenylated chalcone derivatives as anti-leishmanial and anti-trypanosomal compounds

Chalcones form a class of compounds that belong to the flavonoid family and are widely distributed in plants. Their simple structure and the ease of preparation make chalcones attractive scaffolds for the synthesis of a large number of derivatives enabling the evaluation of the effects of different functional groups on biological activities. In this Letter, we report the successful synthesis of a series of novel prenylated chalcones via Claisen-Schmidt condensation and the evaluation of their effect on the viability of the Trypanosomatidae parasites Leishmania amazonensis, Leishmania infantum and Trypanosoma cruzi.

Leishmanicidal Activities of Novel Synthetic Furoxan and Benzofuroxan Derivatives

ABSTRACT A novel series of furoxan (1,2,5-oxadiazole 2-oxide) (compounds 3, 4a and -b, 13a and -b, and 14a to -f) and benzofuroxan (benzo[c][1,2,5]oxadiazole 1-oxide) (compounds 7 and 8a to -c) derivatives were synthesized, characterized, and evaluated for in vitro activity against promastigote and intracellular amastigote forms of Leishmania amazonensis. The furoxan derivatives exhibited the ability to generate nitric oxide at different levels (7.8% to 27.4%). The benzofuroxan derivative 8a was able to increase nitrite production in medium supernatant from murine macrophages infected with L. amazonensis at 0.75 mM after 48 h. Furoxan and benzofuroxan derivatives showed remarkable leishmanicidal activity against both promastigote and intracellular amastigote forms. Compounds 8a, 14a and -b, and 14d exerted selective leishmanicidal activities superior to those of amphotericin B and pentamidine. In vitro studies at pH 5.4 reveal that compound 8a is stable until 8 h and that compound 14a behaves as a prodrug, releasing the active aldehyde 13a. These compounds have emerged as promising novel drug candidates for the treatment of leishmaniasis.

The 2',4'-dihydroxychalcone could be explored to develop new inhibitors against the glycerol-3-phosphate dehydrogenase from Leishmania species

The enzyme glycerol-3-phosphate dehydrogenase (G3PDH) from Leishmania species is considered as an attractive target to design new antileishmanial drugs and a previous in silico study reported on the importance of chalcones to achieve its inhibition. Here, we report the identification of a synthetic chalcone in our in vitro assays with promastigote cells from Leishmania amazonensis, its biological activity in animal models, and docking followed by molecular dynamics simulation to investigate the molecular interactions and structural patterns that are crucial to achieve the inhibition complex between this compound and G3PDH. A molecular fragment of this natural product derivative can provide new inhibitors with increased potency and selectivity.

At-Home Bleaching: Color Alteration, Hydrogen Peroxide Diffusion and Cytotoxicity

This study evaluated the color change, cytotoxicity and hydrogen peroxide (HP) diffusion caused by different home bleaching protocols: 10% carbamide peroxide (CP) for 3 or 1.5 h, 6% hydrogen peroxide for 1.5 h or 45 min. To quantify the peroxide penetration, disks of bovine teeth were placed in artificial pulp chambers (APCs) containing acetate buffer, which was collected for evaluation in a spectrophotometer. For analysis of cytotoxicity, specimens were adapted in APCs containing culture medium, which subsequently was applied on MDPC-23 odontoblast-like cells for 1 h. Cellular metabolism was evaluated by methyl tetrazolium (MTT) assay and the color change of the specimens was analyzed using the CIE L * a * b * system. The data were submitted to ANOVA and Fisher test (α=5%). The treatment with 10% CP for 3 h was the most effective, and 6% HP for 45 min produced the lowest color change. The groups 10% CP for 1.5 h and 6% HP for 45 min had the lowest trans-enamel dentinal HP penetration, and the 6% HP for 1.5 h had the highest. None of the protocols affected cellular metabolism and morphology. In conclusion, reduced peroxide exposure time reduced the bleaching result; higher HP diffusion did not mean higher effectiveness.

Oleanonic acid from Lippia lupulina (Verbenaceae) shows strong in vitro antileishmanial and antitrypanosomal activity

Leishmaniasis and Chagas disease affect millions of people in tropical and subtropical regions. Drugs used currently to treat such diseases often present undesirable side effects and low efficiency. The aim of this work was to identify extracts and isolated compounds from the genus Lippia with leishmanicidal and trypanocidal activity. Fifteen extracts from different plant parts of Lippia species with partially known chemical compositions, four partition fractions, six compounds and a mixture of four interconverting flavanones previously isolated from Lippia salviaefolia and Lippia lupulina were assayed in vitro towards epimastigote forms of Trypanosoma cruzi and promastigote forms of Leishmania amazonensis. The root extract of L. lupulina had potent activity against T. cruzi and L. amazonensis (IC50 of 20.0 and 54.5 µg mL-1, respectively). The triterpenoid oleanonic acid showed the strongest activity against these protozoans (IC50 of 18.5 and 29.9 µM, respectively). Our results indicate that Lippia plants and their derivatives deserve further investigation in the search for new antiprotozoal drugs, particularly for the treatment of leishmaniasis and Chagas disease.

Effect of peroxide bleaching on the biaxial flexural strength and modulus of bovine dentin

Objective: This study evaluated the effects of carbamide peroxide and hydrogen peroxide on the biaxial flexural strength and flexural modulus of bovine dentin. Materials and Methods: Thirty coronal dentin disks (0.5 mm thick × 6.0 mm diameter) were prepared from bovine teeth. The disks were randomly divided into three groups (n=10): A control group (unbleached), a group bleached with 10% carbamide peroxide (8 h at 37°C), and a group bleached with 38% hydrogen peroxide (three 10 min applications at 37°C). The specimens were tested in a biaxial flexural apparatus held in a universal testing machine at 1.27 mm/min until failure occurred, and the biaxial mechanical properties were calculated. For each test parameter, the data were statistically analyzed by Fisher′s PLSD test (predetermined α = 0.05). Results: The group bleached with 38% hydrogen peroxide demonstrated significantly lower flexural strength than the unbleached control group. Hydrogen peroxide treatment resulted in a significantly lower flexural modulus compared with the control group and with carbamide peroxide bleaching. Conclusion: Exposure of dentin to hydrogen peroxide significantly reduced both the flexural strength and the flexural modulus compared with the no-treatment control, whereas exposure to carbamide peroxide did not significantly affect either parameter.

An in silico Study of Benzophenone Derivatives as Potential Non-Competitive Inhibitors of Trypanosoma cruzi and Leishmania Amazonensis Cysteine Proteinases

This study investigates the mechanisms of interaction between benzophenone derivatives and cruzain and Llacys1 (the protein expressed by cysteine protease gene isoform 1 of L. amazonensis) by homology modelling, docking and molecular dynamics simulation. The results predict that the same binding site in cruzain and Llacys1 is involved in complexes with benzophenone derivatives that cause non-competitive inhibition of the enzymes. The Gln residue is conserved among the enzymes, and is shown to be a key residue in the allosteric site of these cysteine proteases and in the interaction with benzophenone derivatives. The binding free energies highlight that the main energetic term contributing to the cruzainand Llacys1-benzophenone compound interactions is the van der Waals term. Experimental results showed that benzophenone derivatives are promising potential inhibitors of cysteine proteases. Moreover, we found that two benzophenone derivatives are the most effective inhibitors of cruzain and L. amazonensis cysteine protease.

Corrigendum to “The 2′,4′-dihydroxychalcone could be explored to develop new inhibitors against the glycerol-3-phosphate dehydrogenase from Leishmania species” [Bioorg. Med. Chem. Lett. 25 (2015) 3564–3568]

UNESP—School of Pharmaceutical Sciences Department of Clinical Analyses, Rodovia Araraquara-Jau, Km 01

In vivo antileishmanial activity and histopathological evaluation in Leishmania infantum infected hamsters after treatment with a furoxan derivative

N-oxide derivatives compounds such as furoxan and benzofuroxan are promising scaffolds for designing of new antileishmanial drugs. A series of furoxan (1,2,5-oxadiazole 2-N-oxide) (compounds 4a-b, and 14a-f) and benzofuroxan (benzo[c][1,2,5]oxadiazole1-N-oxide) (compounds 8a-c) derivatives were evaluated against in vitro cultured L. infantum promastigotes and amastigotes. The compounds exhibited activity against promastigote and intracellular amastigote forms with EC50 values ranging from 2.9 to 71.2μM and 2.1 to 18.2μM, respectively. The most promising compound, 14e, showed good antileishmanial activity (EC50=3.1μM) against intracellular amastigote forms of L. infantum with a selectivity index, based on murine macrophages (SI=66.4), almost 3-times superior to that presented by the standard drug amphotericin B (AmpB). The efficacy of 14e to eliminate the parasites in vivo was also demonstrated. Treatment of L. infantum-infected hamsters with compound 14e at 3.0mg/Kg/day led to a meaningful reduction of parasite load in spleen (49.9%) and liver (54.2%), respectively; these data were corroborated by histopathological analysis, which also revealed reduction in the number of inflammatory cells in the liver of the treated animals. Moreover, histological analysis of the spleen and kidney of treated animals did not reveal alterations suggestive of toxic effects. The parasite load reduction might be related to NO production, since this molecule is a NO-donor. We observed neither side effects nor elevation of hepatic/renal biomarker levels in the plasma. The data herein presented suggest that the compound should be considered in the development of new drugs for treatment of visceral leishmaniasis.