Acetylenic fatty acids from Porcelia macrocarpa (Annonaceae) against trypomastigotes of Trypanosoma cruzi: Effect of octadec-9-ynoic acid in plasma membrane electric potential

Londero, Vinicius S.; Costa-Silva, Thaís A.; Gomes, Kaio S.; Ferreira, Daiane Dias; Mesquita, Juliana Tonini; Tempone, André G.; Young, Maria Cláudia M.; Jerz, Gerold; Lago, João Henrique G.

doi:10.1016/j.bioorg.2018.03.025

Cited by 28 publications

(26 citation statements)

References 27 publications

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“…After 2 h of incubation at 37°C in a 5% CO 2 incubator, the cells were treated with compound 1 at different concentrations for 48 h. Benznidazole was used as the standard drug and the untreated cells as a negative control. Slides were stained with Giemsa, analyzed in a digital light microscope (EVOS M5000 Thermo Fisher, United States), and the IC 50 values were calculated by the infection index ( Londero et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

(-)-T-Cadinol—a Sesquiterpene Isolated From Casearia sylvestris (Salicaceae)—Displayed In Vitro Activity and Causes Hyperpolarization of the Membrane Potential of Trypanosoma cruzi

et al. 2021

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Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects 6–8 million people worldwide, mainly from developing countries. The treatment is limited to two approved nitro-derivatives, nifurtimox and benznidazole, with several side effects and reduced efficacy. Casearia sylvestris has been used in folk medicine as an antiseptic and cicatrizing in skin diseases. In the present work, the hexane phase from the MeOH extract from the leaves of Casearia sylvestris afforded a fraction composed by the sesquiterpene T-cadinol, which was chemically characterized by NMR and HRMS. The activity of T-cadinol was evaluated against T. cruzi, and IC50 values of 18 (trypomastigotes) and 15 (amastigotes) µM were established. The relation between the mammalian toxicity and the antiparasitic activity resulted in a selectivity index >12. Based on this promising activity, the mechanism of action was investigated by different approaches using fluorescent-based techniques such as plasma membrane permeability, plasma membrane electric potential, mitochondrial membrane electric potential, reactive oxygen species, and the intracellular calcium (Ca2+) levels. The obtained results demonstrated that T-cadinol affected neither the parasite plasma membrane nor the electric potential of the membrane. Nevertheless, this compound induced a mitochondrial impairment, resulting in a hyperpolarization of the membrane potential, with decreased levels of reactive oxygen species. No alterations in Ca2+ levels were observed, suggesting that T-cadinol may affect the single mitochondria of the parasite. This is the first report about the occurrence of T-cadinol in C. sylvestris, and our data suggest this sesquiterpene as an interesting hit compound for future optimizations in drug discovery studies for Chagas disease.

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Section: Methodsmentioning

confidence: 99%

(-)-T-Cadinol—a Sesquiterpene Isolated From Casearia sylvestris (Salicaceae)—Displayed In Vitro Activity and Causes Hyperpolarization of the Membrane Potential of Trypanosoma cruzi

et al. 2021

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“…At the end of the assay, slides were fixed with MeOH, stained with Giemsa, and counted using light microscopy. The IC 50 values were calculated as previously reported [ 30 ].…”

Section: Methodsmentioning

confidence: 99%

Discovery of New Hits as Antitrypanosomal Agents by In Silico and In Vitro Assays Using Neolignan-Inspired Natural Products from Nectandra leucantha

et al. 2021

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In the present study, the phytochemical study of the n-hexane extract from flowers of Nectandra leucantha (Lauraceae) afforded six known neolignans (1–6) as well as one new metabolite (7), which were characterized by analysis of NMR, IR, UV, and ESI-HRMS data. The new compound 7 exhibited potent activity against the clinically relevant intracellular forms of T. cruzi (amastigotes), with an IC50 value of 4.3 μM and no observed mammalian cytotoxicity in fibroblasts (CC50 > 200 μM). Based on the results obtained and our previous antitrypanosomal data of 50 natural and semi-synthetic related neolignans, 2D and 3D molecular modeling techniques were employed to help the design of new neolignan-based compounds with higher activity. The results obtained from the models were important to understand the main structural features related to the biological response of the neolignans and to aid in the design of new neolignan-based compounds with better biological activity. Therefore, the results acquired from phytochemical, biological, and in silico studies showed that the integration of experimental and computational techniques consists of a powerful tool for the discovery of new prototypes for development of new drugs to treat CD.

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“…Parasites were counted in a Neubauer hemocytometer, seeded at 1×10 6 cells/well (96‐well plates) and incubated with serial dilutions of the tested compounds (150–1.71 μM), during 24 h at 37 °C in a 5 % CO 2 ‐humidified incubator, with benznidazole as standard drug. The trypomastigote viability was evaluated by the resazurin (Sigma) assay and EC 50 values were calculated [47] …”

Section: Methodsmentioning

confidence: 99%

Simplified Derivatives of Dibenzylbutyrolactone Lignans from Hydrocotyle bonariensis as Antitrypanosomal Candidates

Souza

Costa-Silva

Morais

et al. 2021

Chemistry & Biodiversity

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The search for the pharmacophore of a bioactive compound, crucial for drug discovery studies, involves the adequate arrangement of different atoms in the molecule. As part of a continuous work aiming discovery of new drug candidates against the protozoan parasite Trypanosoma cruzi, the hexane extract of Hydrocotyle bonariensis was subjected to a bioactivity‐guided fractionation to afford two chemically related dibenzylbutyrolactone lignans – hinokinin (1) and hibalactone (2). Compounds 1 and 2 showed activity against trypomastigote with EC50 values of 17.0 and 69.4 μM, respectively. Compound 1 was also active against the clinically relevant form of the parasite, amastigotes, displaying an EC50 value of 34.4 μM. The structure‐activity relationship (SAR) indicated that the absence of the double bond at C‐7 is a crucial feature for the increment of the antiparasitic activity. The lethal action of the most potent compound 1 was investigated in the trypomastigotes. The fluorescent‐based assay with SYTOX Green demonstrated a significant alteration of the plasma membrane permeability of the parasite. Additionally, compound 1 demonstrated no significant hemolytic activity in mice erythrocytes at 200 μM. To search the pharmacophore, three different simplified compounds – 3,4‐methylenedioxydihydrocinnamic acid (3), 3,4‐methylenedioxydihydrocinnamic alcohol (4) and 3,4‐methylenedioxycinnamic acid (5) – were prepared and tested against T. cruzi. These derivatives displayed EC50 values of 37.2 (3), 25.8 (4) and 73.5 (5) μM against trypomastigotes, and 41.3 (3) and 48.2 (4) μM against amastigotes, whereas compound 5 was inactive. Except for compound 2, which resulted in a CC50 value of 114.5 μM, all compounds showed no mammalian cytotoxicity at 200 μM. An in silico ADMET study was performed and predicted values demonstrated an acceptable drug‐likeness profile for compounds 1–5. Despite the minor reduction in the potency, the simplified derivatives retained the antitrypanosomal activity against the intracellular amastigotes, even with 95 % reduction of their molecular weight. Additionally, in silico studies suggested them as more soluble compounds, making these simplified structures promising scaffolds for optimization studies in Chagas disease.

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Acetylenic fatty acids from Porcelia macrocarpa (Annonaceae) against trypomastigotes of Trypanosoma cruzi: Effect of octadec-9-ynoic acid in plasma membrane electric potential

Cited by 28 publications

References 27 publications

(-)-T-Cadinol—a Sesquiterpene Isolated From Casearia sylvestris (Salicaceae)—Displayed In Vitro Activity and Causes Hyperpolarization of the Membrane Potential of Trypanosoma cruzi

(-)-T-Cadinol—a Sesquiterpene Isolated From Casearia sylvestris (Salicaceae)—Displayed In Vitro Activity and Causes Hyperpolarization of the Membrane Potential of Trypanosoma cruzi

Discovery of New Hits as Antitrypanosomal Agents by In Silico and In Vitro Assays Using Neolignan-Inspired Natural Products from Nectandra leucantha

Simplified Derivatives of Dibenzylbutyrolactone Lignans from Hydrocotyle bonariensis as Antitrypanosomal Candidates

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