Differential lethal action of C17:2 and C17:0 anacardic acid derivatives in Trypanosoma cruzi – A mechanistic study

Umehara, Eric; Silva, Thais A. Costa; Mendes, Viviane M.; Guadagnin, Rafael C.; Sartorelli, Patrı́cia; Tempone, André G.; Lago, João Henrique G.

doi:10.1016/j.bioorg.2020.104068

Cited by 11 publications

(9 citation statements)

References 28 publications

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“…Differently of compound 2 and simplified derivative 5 , both inactives against intracellular amastigotes, compound 4 showed an EC 50 value of 48.2 μM. Based on these results, it is possible to suggest that the absence of the double bond at C‐7 in the simplified derivative 3 and hinokinin ( 1 ) showed to be crucial for the activity against both parasite forms [41] …”

Section: Resultsmentioning

confidence: 85%

“…Based on these results, it is possible to suggest that the absence of the double bond at C-7 in the simplified derivative 3 and hinokinin (1) showed to be crucial for the activity against both parasite forms. [41] Using the web-server SwissADME, in silico studies of compounds 1-5 (Table 2), suggested adequate 'drug-like' parameters associated to gastrointestinal absorption (GI) and oral bioavailability, according to ClogP and TPSA values. None of the tested compounds violated the Lipinski's rule, [42] supporting the use of compounds 1-5 as oral candidates.…”

Section: Compoundsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 85%

Section: Compoundsmentioning

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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“…Trypomastigotes (2 × 10 6 /well) were incubated with compounds 1 (230.2 µM) and 2 (32.06 µM) in HBSS medium supplemented with D-glucose (10 mM) for 3 h. Subsequently, JC-1 (10 µM) was added for 20 min and the fluorescence was monitored in a flow cytometer with excitation of 488 nm and emission of 530 (BL-1)/574 nm (BL-2). The mitochondrial membrane potential was analyzed by the ratio between channels BL-2 and BL-1 [ 17 ]. CCCP (100 µM) was employed as a positive control and untreated parasites as the negative control.…”

Section: Methodsmentioning

confidence: 99%

Synthetic Analogues of Gibbilimbol B Induce Bioenergetic Damage and Calcium Imbalance in Trypanosoma cruzi

Amaral

Varela

Kant

et al. 2023

Life

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Chagas disease is an endemic tropical disease caused by the protozoan Trypanosoma cruzi, which affects around 7 million people worldwide, mostly in development countries. The treatment relies on only two available drugs, with severe adverse effects and a limited efficacy. Therefore, the search for new therapies is a legitimate need. Within this context, our group reported the anti-Trypanosoma cruzi activity of gibbilimbol B, a natural alkylphenol isolated from the plant Piper malacophyllum. Two synthetic derivatives, LINS03018 (1) and LINS03024 (2), demonstrated a higher antiparasitic potency and were selected for mechanism of action investigations. Our studies revealed no alterations in the plasma membrane potential, but a rapid alkalinization of the acidocalcisomes. Nevertheless, compound 1 exhibit a pronounced effect in the bioenergetics metabolism, with a mitochondrial impairment and consequent decrease in ATP and reactive oxygen species (ROS) levels. Compound 2 only depolarized the mitochondrial membrane potential, with no interferences in the respiratory chain. Additionally, no macrophages response of nitric oxide (NO) was observed in both compounds. Noteworthy, simple structure modifications in these derivatives induced significant differences in their lethal effects. Thus, this work reinforces the importance of the mechanism of action investigations at the early phases of drug discovery and support further developments of the series.

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“…In particular, CNSL consists of anacardic acids ( 1 ) (60–65%), cardanols ( 2 ), and cardols ( 3 ) (Figure ). These phenolic derivatives bear a lipophilic C15 chain in meta position with respect to the hydroxyl function, which may be saturated, or mono-, di-, or triolefinic. , Interestingly, the bis-unsaturated anacardic acid 1 ( n = 2) isolated from leaves of Schinus terebinthifolius and its hydrogenated derivative 1 ( n = 0) were shown to possess activity against trypomastigote forms of T. cruzi with IC 50 values of 8.3 and 9.0 μM, respectively . More recently, further CNSL derivatives were developed in an effort to treat neurodegenerative and metabolic diseases.…”

mentioning

confidence: 99%

“…20,21 Interestingly, the bis-unsaturated anacardic acid 1 (n = 2) isolated from leaves of Schinus terebinthifolius and its hydrogenated derivative 1 (n = 0) were shown to possess activity against trypomastigote forms of T. cruzi with IC 50 values of 8.3 and 9.0 μM, respectively. 22 More recently, further CNSL derivatives were developed in an effort to treat neurodegenerative 23 and metabolic 24 diseases. Ether phospholipids are a class of compounds with wellestablished chemotherapeutic activity against Trypanosomatids.…”

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confidence: 99%

Valorizing Constituents of Cashew Nut Shell Liquid toward the Sustainable Development of New Drugs against Chagas Disease

et al. 2023

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Six new ether phospholipid analogues encompassing constituents from cashew nut shell liquid as the lipid portion were synthesized in an effort to valorize byproducts of the cashew industry toward the generation of potent compounds against Chagas disease. Anacardic acids, cardanols, and cardols were used as the lipid portions and choline as the polar headgroup. The compounds were evaluated for their in vitro antiparasitic activity against different developmental stages of Trypanosoma cruzi. Compounds 16 and 17 were found to be the most potent against T. cruzi epimastigotes, trypomastigotes, and intracellular amastigotes exhibiting selectivity indices against the latter 32-fold and 7-fold higher than current drug benznidazole, respectively. Hence, four out of six analogues can be considered as hit-compounds toward the sustainable development of new treatments for Chagas disease, based on inexpensive agro-waste material.

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Differential lethal action of C17:2 and C17:0 anacardic acid derivatives in Trypanosoma cruzi – A mechanistic study

Cited by 11 publications

References 28 publications

Simplified Derivatives of Dibenzylbutyrolactone Lignans from Hydrocotyle bonariensis as Antitrypanosomal Candidates

Simplified Derivatives of Dibenzylbutyrolactone Lignans from Hydrocotyle bonariensis as Antitrypanosomal Candidates

Synthetic Analogues of Gibbilimbol B Induce Bioenergetic Damage and Calcium Imbalance in Trypanosoma cruzi

Valorizing Constituents of Cashew Nut Shell Liquid toward the Sustainable Development of New Drugs against Chagas Disease

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