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

Abstract

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.

Activity of essential oils from leaves, flower buds and stems of Tetradenia riparia on Rhipicephalus (Boophilus) microplus larvae

“…The chemical components aromadendrene, valencene and caryophyllene oxide, extracted from the leaves of Eugenia langsdorffii, proved to be potent acaricides that led to mortality rates above 80%, as observed using the residual contact method (Moraes et al, 2012). Another sesquiterpene, T-cadinol, isolated from the EOs of Casearia sylvestris, was found to induce mitochondrial impairment of Trypanosoma cruzi, and thus demonstrated protozoicidal effects of importance with regard to formulating future drugs for combating Chagas disease (Santos et al, 2021). Because of this high biocidal power seen in relation to several groups of parasites, as confirmed through scientific evidence in the literature, it can be presumed that the larvicidal action seen in the present study was strongly associated with the large amounts of monoterpenes (both hydrocarbons and oxygenates) (17.42%, 17.90% and 12.30%) and sesquiterpenes (both hydrocarbons and oxygenates) (61.12%, Braz J Vet Parasitol 2023; 32(1): e013522 13/16…”

Larvicidal Activity and Phytochemical Profiling of Sweet Basil (Ocimum basilicum L.) Leaf Extract against Asian Tiger Mosquito (Aedes albopictus)

“…[59][60][61]. Several biological activities of cedrelanol have been reported in the literature, these include cytotoxic against human cancer cells, antibacterial, antifungal, antiparasitic, spasmolytic, and immunomodulatory activities [62][63][64][65]. Cedrelanol isolated from the bark of Swartzia polyphylla killed all the larvae of Cx.…”

Casearia Essential Oil: An Updated Review on the Chemistry and Pharmacological Activities

“…The (À )-T-cadinol eliminated the intracellular amastigotes (killing > 95 %) at 30 μM, while at 15 μM reduced 50 % of the amastigotes. [47] According to the Malebo et al, [57] the antitrypanosomal activity may be classified considering IC 50 values: strong < 1.0 μg/mL, moderate 1.0-5.0 μg/mL, mild 5.0-10.0 μg/mL, and inactive > 10.0 μg/mL. Therefore, the results indicated moderate activity against T. cruzi forms of the C. sylvestris EO component (À )-T-cadinol.…”

“…However, it did not inhibit edema induced by dextran, the Evans blue leakage into the rat peritoneal cavity induced by histamine, or the inflammation induced by inflammatory mediators (histamine and serotonin), besides not blocking the H 1 receptor induced by histamine. [47] The antiulcer activity of the EO from C. sylvestris at a concentration of 125 mg/kg was similar to that of cimetidine at 50 mg/kg, producing a decrease in the gastric secretion volume without modifying the pH in rats, which characterizes an improvement concerning H 2 receptor antagonists and proton pump inhibitors according to Esteves et al. [14] Ferreira et al [44] isolated α-zingiberene from the essential oil of C. sylvestris leaf and evaluated its effects on the inflammatory, angiogenic, and fibrotic components induced by subcutaneous sponge implants in mice.…”