In vivo antischistosomal efficacy of Porcelia ponderosa γ-lactones.

BACKGROUND: Schistosomiasis, caused by the parasitic blood fluke Schistosoma mansoni, is a significant global health concern, particularly in tropical and subtropical regions. The available chemotherapeutic drug is restricted to praziquantel with present problems related to efficacy, toxicity and resistance, justifying the search for new drugs. Different natural products, including γ-lactones, have demonstrated anthelmintic activity. Thus, in this study, new γ-lactones from Porcelia ponderosa were investigated for their anti-S. mansoni effects in vitro and in vivo. PURPOSE: To evaluate the therapeutical potential against S. mansoni of the mixture of γ-lactones 1 + 2 obtained from Porcelia ponderosa seeds. STUDY DESIGN AND METHODS: The precipitate formed during the concentration of CH2Cl2 extract from seeds of P. ponderosa showed to be composed by a mixture of the new γ-lactones 1 + 2 (in a ratio 77:23) which were chemically characterized using NMR and ESI-HRMS. This mixture was evaluated in vitro and in vivo against S. mansoni, using a murine model of schistosomiasis. Additionally, toxicity of the mixture of 1 + 2 (77:23) was determined using mammalian cell lines (in vitro) or the model organism Caenorhabditis elegans (in vivo). RESULTS: Seeds of P. ponderosa afforded a mixture of two unreported γ-lactones, 3­hydroxy-4-methylene-2-(tetracosa-17'Z,23'-diene-13',15'-diynyl)­but-2-enolide (1) and 3­hydroxy-4-methylene-2-(tetracos-17'Z-ene-13',15'-diynyl)­but-2-enolide (2). Initially, the antischistosomal activity of the mixture of 1 + 2 (77:23) was investigated in vitro, and obtained results demonstrate reduced activity against Schistosoma mansoni worms (EC50 of 83.3 µg/ml) in comparison to positive control praziquantel (EC50 of 1.5 µg/ml). However, when tested in vivo using oral administration at 400 mg kg-1, the standard dose used in the murine model of schistosomiasis, the mixture of 1 + 2 (77:23) revealed expressive reductions in both worm burden (65.7 %) and egg production (97.2 %), similar of those observed to praziquantel (89.7 % and 91.5 %, respectively). On the other hand, when treated using 200 and 100 mg kg-1, reductions in worm burden (25.7 and 12.4 %) and egg production (33.6 and 13.3 %) were also observed. Importantly, the mixture of 1 + 2 (77:23) exhibited no toxicity using mammalian cell lines (in vitro) or C. elegans (in vivo). CONCLUSION: Considering the promising in vivo activity of γ-lactones from P. ponderosa, the mixture of 1 + 2 (77:23) can be considered as promising candidate for the development of novel antischistosomal therapeutics, underscoring the importance of biodiversity exploration in the search for effective treatments against neglected tropical diseases.

Neolignans isolated from Saururus cernuus L. (Saururaceae) exhibit efficacy against Schistosoma mansoni.

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.

N-(4-Methoxyphenyl)Pentanamide, a Simplified Derivative of Albendazole, Displays Anthelmintic Properties against the Nematode Toxocara canis.

Infections caused by parasitic helminths have enormous health, social, and economic impacts worldwide. The treatment and control of these diseases have been dependent on a limited set of drugs, many of which have become less effective, necessitating the search for novel anthelmintic agents. In this study, a simplified compound, N-(4-methoxyphenyl)pentanamide (N4MP), based on the structure of the most widely used anthelmintic (albendazole), was chemically prepared using 4-anisidine and pentanoic acid. N-(4-Methoxyphenyl)pentanamide was evaluated in vitro against the nematode Toxocara canis, an ascarid roundworm of animals that can infect humans. Similar to albendazole, bioassays showed that N-(4-methoxyphenyl)pentanamide affected the viability of parasites in a time- and concentration-dependent manner. Interestingly, N-(4-methoxyphenyl)pentanamide showed a profile of lower cytotoxicity to human and animal cell lines than albendazole. Pharmacokinetic, drug-likeness, and medicinal chemistry friendliness studies demonstrated an excellent drug-likeness profile for N-(4-methoxyphenyl)pentanamide as well as an adherence to major pharmaceutical companies' filters. Collectively, the results of this study demonstrate that the molecular simplification of albendazole to give N-(4-methoxyphenyl)pentanamide may be an important pipeline in the discovery of novel anthelmintic agents. IMPORTANCE Infections caused by parasitic helminths have enormous health, social, and economic impacts worldwide. The treatment and control of these diseases have been dependent on a limited set of drugs, many of which have become less effective, necessitating the search for novel anthelmintic agents. Considering this scenario, the present study reports the preparation of N-(4-methoxyphenyl)pentanamide (N4MP), a simplified molecule based on the structure of the most widely used anthelmintic (albendazole). N4MP was evaluated in vitro against the nematode Toxocara canis, a common ascarid roundworm of domestic animals that can infect humans. Similar to albendazole, bioassays showed that N4MP affected the viability of parasites in a time- and concentration-dependent manner but displayed a profile of lower cytotoxicity to human and animal cell lines than albendazole. Therefore, this study demonstrates that the molecular simplification of albendazole to give N4MP may be an important pipeline in the discovery of novel anthelmintic agents.

Simplified Derivatives of Dibenzylbutyrolactone Lignans from Hydrocotyle bonariensis as Antitrypanosomal Candidates.

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.