Schistosomiasis, a parasitic disease caused by the blood fluke of the genus Schistosoma, affects over 230 million people, especially in developing countries. Despite the significant economic and public health consequences, only one drug is currently available for treatment of schistosomiasis, praziquantel. Thus, there is an urgent demand for new anthelmintic agents. Based on our continuous studies involving the chemical prospection of floristic biodiversity aiming to discover new bioactive compounds, this work reports the in vitro antiparasitic activity against Schistosoma mansoni adult worms of neolignans threo-austrobailignan-6 and verrucosin, both isolated from Saururus cernuus L. (Saururaceae). These neolignans showed a significant in vitro schistosomicidal activity, with EC50 values of 12.6–28.1 µM. Further analysis revealed a pronounced reduction in the number of S. mansoni eggs. Scanning electron microscopy analysis revealed morphological alterations when schistosomes were exposed to either threo-austrobailignan-6 or verrucosin. These relevant antischistosomal properties were accompanied by low cytotoxicity potential against the animal (Vero) and human (HaCaT) cell lines, resulting in a high selectivity index. Considering the promising chemical and biological properties of threo-austrobailignan-6 and verrucosin, this research should be of interest to those in the area of neglected diseases and in particular antischistosomal drug discovery.
Objective This work describes the isolation of anti-Leishmania amazonensis metabolites from Saururus cernuus (Saururaceae). Additionally, ultrastructural changes in promastigotes were evidenced by electron microscopy. Methods The MeOH extract from the leaves of S. cernuus was subjected to bioactivity-guided fractionation. Anti-L. amazonensis activity of purified compounds was performed in vitro against promastigote and amastigote forms. Key findings Bioactivity-guided fractionation of the MeOH extract from the leaves of S. cernuus afforded two related tetrahydrofuran dineolignans: threo, threo-manassantin A (1) and threo,erythro-manassantin A (2). Compounds 1 and 2 displayed activity against promastigotes (EC 50 of 35.4 AE 7.7 and 17.6 AE 4.2 lM, respectively) and amastigotes (EC 50 of 20.4 AE 1.9 and 16.0 AE 1.1 lM, respectively), superior to that determined for the positive control miltefosine (EC 50 of 28.7 AE 3.5 lM). Reduced cytotoxicity for host cells was observed for both compounds. Additionally, ultrastructural changes in promastigotes leading to an alteration of structural morphology were observed, as evidenced by electron microscopy. Furthermore, these compounds altered the morphology and physiology of the plasmatic membrane of L. amazonensis. Conclusions The obtained results indicated that dineolignans 1 and 2 could be considered as a scaffold for the design of novel and selective drug candidates for the treatment of leishmaniasis.
In the present work, dried leaves of Saururus cernuus (Saururaceae) were subjected to extraction using an ionic liquid (1-butyl-3-methylimidazolium bromide -BMImBr) in the microwave assisted extraction (MAE). The obtained extract was partitioned using n-hexane and cytotoxicity activity of this organic phase against murine melanoma cell line (B16F10-Nex2) was evaluated in vitro. Since this extract displayed activity (100% of cell death at 200 µg mL -1 ) it was subjected to a bioactivity-guided fractionation to afford four related neolignans: threo-austrobailignan-5 (1), threo-austrobailignan-6 (2), threo-dihydroguaiaretic acid (3) and saucernetin (4). Their chemical structures were established based on NMR and MS spectral analysis. Among the isolated neolignans, compound 2 exhibited the highest cytotoxic activity against HeLa (human cervical melanoma) cells with IC 50 of 28.3 ± 3.9 µg mL ). The obtained results provide important data for the selection of bioactive neolignans with promising cytotoxic potential using a simple and fast method employing a green solvent as 1-butyl-3-methylimidazolium bromide (BMImBr).
The Brazilian savanna known as "Cerrado" is very rich in medicinal plants that are used by the local population for treatment of several illnesses. The herpesvirus is a serious problem worldwide, and affects both animal and human health. This work aimed to study the antiviral activity of eight extracts from plants natives of "Cerrado" region against human (HSV-1), equine (EqHV-1) and swine herpesviruses (SuHV-1). The results showed that all plant extracts: Banisteriopsis variabilis, Byrsonima intermedia, Campomanesia xanthocarpa, Erythroxilum deciduum, Lacistema hasslerianum, Ocotea pulchella, Stryphodendron adstringens and Xylopia aromatica presented antiviral activity against at least one herpesvirus. Furthermore, it was observed a direct anti-herpes effect of extracts from B. variabilis and B. intermedia in non-toxic concentrations against all herpesviruses. B. intermedia crude aqueous extract showed the most promising results with selective index values of the 41.76 ± 0.04; 4.12 ± 0.1 and 193.97 ± 0.09 respectively against HSV-1, EqHV-1 and SuHV-1. Due to this, B. intermedia extract was also analyzed by HPLC/MS allowing for the identification of gallic acid and quercetin as main compounds.
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.
In this study, five neolignans were isolated from Saururus cernuus—threo‐dihydroguaiaretic acid (1), threo‐austrobailignan‐6 (2), threo‐austrobailignan‐5 (3), verrucosin (4), and saucernetin (5)—and have their cytotoxic effects evaluated in prostate cancer cell lines (PC3 and DU145). Initially, using an in silico approach, tested compounds were predicted to be absorbed by the gastrointestinal tract, be able to permeate the blood–brain barrier and did not show any alert in PAINS (pan‐assay structures interference). In vitro assays showed that compounds 2, 4, and 5 reduced cell viability of DU145 cell line at 100 μmol/L after 48 h while compounds 1 and 3 showed to be inactive at the same conditions. Furthermore, compounds 4 and 5 reduced cell number as early as in 24 h at 50 μmol/L and compound 2 showed effects at 100 μmol/L in 24 h against both cancer cell lines PC3 and DU145. Studies using flow cytometry were conducted and indicated that compound 4 induced strong necrosis and apoptosis whereas compound 5 induced strong necrosis. Otherwise, less active compound 2 did not show evidence of induction of apoptosis or necrosis, suggesting that its mechanism of action involves inhibition of cell proliferation. In conclusion, compounds 4 and 5 have been shown to be promising cytotoxic agents against prostate cancer cell lines and can be used as a starting point for the development of new drugs for the treatment of prostate cancer.
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