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Background: Chagas disease and leishmaniasis affect a significant portion of the Latin American population and still lack efficient treatments. In this context, natural products emerge as promising compounds for developing more effective therapies, aiming to mitigate side effects and drug resistance. Notably, species from the Amaryllidaceae family emerge as potential reservoirs of antiparasitic agents due to the presence of diverse biologically active alkaloids., Purpose: To assess the anti-Trypanosoma cruzi and anti-Leishmania infantum activity of five isolated alkaloids from Hippeastrum aulicum Herb. (Amaryllidaceae) against different life stages of the parasites using in silico and in vitro assays. Furthermore, molecular docking was employed to evaluate the interaction of the most active alkaloids., Methods: Five natural isoquinoline alkaloids isolated in suitable quantities for in vitro testing underwent preliminary in silico analysis to predict their potential efficacy against Trypanosoma cruzi (amastigote and trypomastigote forms) and Leishmania infantum (amastigote and promastigote forms). The in vitro antiparasitic activity and mammalian cytotoxicity were investigated with a subsequent comparison of both analysis (in silico and in vitro) findings. Additionally, this study employed the molecular docking technique, utilizing cruzain (T. cruzi) and sterol 14α-demethylase (CYP51, L. infantum) as crucial biological targets for parasite survival, specifically focusing on compounds that exhibited promising activities against both parasites., Results: Through computational techniques, it was identified that the alkaloids haemanthamine (1) and lycorine (8) were the most active against T. cruzi (amastigote and trypomastigote) and L. infantum (amastigote and promastigote), while also revealing unprecedented activity of alkaloid 7‑methoxy-O-methyllycorenine (6). The in vitro analysis confirmed the in silico tests, in which compound 1 presented the best activities against the promastigote and amastigote forms of L. infantum with half-maximal inhibitory concentration (IC 50 ) 0.6 µM and 1.78 µM, respectively. Compound 8 exhibited significant activity against the amastigote form of T. cruzi (IC 50 7.70 µM), and compound 6 demonstrated activity against the trypomastigote forms of T. cruzi and amastigote of L. infantum, with IC 50 values of 89.55 and 86.12 µM, respectively. Molecular docking analyses indicated that alkaloids 1 and 8 exhibited superior interaction energies compared to the inhibitors., Conclusion: The hitherto unreported potential of compound 6 against T. cruzi trypomastigotes and L. infantum amastigotes is now brought to the forefront. Furthermore, the acquired dataset signifies that the isolated alkaloids 1 and 8 from H. aulicum might serve as prototypes for subsequent structural refinements aimed at the exploration of novel leads against both T. cruzi and L. infantum parasites., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

The steroidal glycoalkaloid α-tomatine (αTM) and its aglycone tomatidine (TD) are abundant in the skin of unripe green tomato and present in tomato leaves and flowers. They mainly serve as defensive agents to protect the plant against infections by insects, bacteria, parasites, viruses, and fungi. In addition, the two products display a range of pharmacological properties potentially useful to treat various human diseases. We have analyzed all known pharmacological activities of αTM and TD, and the corresponding molecular targets and pathways impacted by these two steroidal alkaloids. In experimental models, αTM displays anticancer effects, particularly strong against androgen-independent prostate cancer, as well as robust antifungal effects. αTM is a potent cholesterol binder, useful as a vaccine adjuvant to improve delivery of protein antigens or therapeutic oligonucleotides. TD is a much less cytotoxic compound, able to restrict the spread of certain viruses (such as dengue, chikungunya and porcine epidemic diarrhea viruses) and to provide cardio and neuro-protective effects toward human cells. Both αTM and TD exhibit marked anti-inflammatory activities. They proceed through multiple signaling pathways and protein targets, including the sterol C24 methyltransferase Erg6 and vitamin D receptor, both directly targeted by TD. αTM is a powerful regulator of the NFkB/ERK signaling pathway implicated in various diseases. Collectively, the analysis shed light on the multitargeted action of αTM/TD and their usefulness as chemo-preventive or chemotherapeutic agents. A novel medicinal application for αTM is proposed., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In this study, the essential oil (EO) from Laurelia sempervirens was analyzed by GC/MS and safrole ( 1 ) was identified as the major metabolite 1 , was subjected to direct reactions on the oxygenated groups in the aromatic ring and in the side chain, and eight compounds ( 4 to 12 ) were obtained by the process. EO and compounds 4 - 12 were subjected to biological assays on 24 strains of the genus Saprolegnia , specifically of the species 12 S.   parasitica and 12 S.   australis . EO showed a significant effect against Saprolegnia strains. Compound 6 presents the highest activity against two resistant strains, with minimum inhibitory concentration (MIC) and minimum oomyceticidal concentration (MOC) values of 25 to 100 and 75 to 125 µg/mL, respectively. The results show that compound 6 exhibited superior activities compared to the commercial controls bronopol and azoxystrobin used to combat these pathogens.

Propolis is a bee product that has been used in medicine since ancient times. Although its anti-inflammatory, antioxidant, antimicrobial, antitumor, and immunomodulatory activities have been investigated, its anti-parasitic properties remain poorly explored, especially regarding helminths. This review surveys the results obtained with propolis around the world against human parasites. Regarding protozoa, studies carried out with the protozoa Trypanosoma spp. and Leishmania spp. have demonstrated promising results in vitro and in vivo. However, there are fewer studies for Plasmodium spp., the etiological agent of malaria and less so for helminths, particularly for Fasciola spp. and Schistosoma spp. Despite the favorable in vitro results with propolis, helminth assays need to be further investigated. However, propolis has shown itself to be an excellent natural product for parasitology, thus opening new paths and approaches in its activity against protozoa and helminths., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

This work aimed to investigate, for the first time, the chemical composition, antioxidant, antiparasitic, cytotoxicity, and antimicrobial activities of the aromatic plant Limonium oleifolium Mill. essential oil (EO) and organic extracts. L. oleifolium aerial parts essential oil was analyzed by GC-FID and GC-MS, and 46 constituents representing 98.25±1.12 % of the oil were identified. γ-Muurolene (10.81±0.07 %), cis-caryophyllene (7.71±0.06 %), o-cymene (7.07±0.01 %) and α-copaene (5.02±0.05 %) were the essential oil main compounds. The antioxidant activity of L. oleifolium EO and organic extracts (MeOH, CHCl 3 , AcOEt, BuOH) was explored using 2,2-diphenyl-1-picrylhydrazyl (DPPH), ABTS, β-carotene/linoleic acid, cupric reducing antioxidant capacity (CUPRAC), and ferric reducing power assays. The results showed that L. oleifolium EO exhibit antioxidant capacity (IC 50 =17.40±1.32 μg/mL for DPPH assay, IC 50 =29.82±1.08 μg/mL for β-carotene assay, IC 50 =25.23±1.01 μg/mL for ABTS assay, IC 50 =9.11±0.08 μg/mL for CUPRAC assay and IC 50 =19.41±2.06 mg/mL for reducing power assay). Additionally, the EO showed significant activity against trophozoite form of Acanthamoeba castellanii (IC 50 =7.48±0.41 μg/mL) and promastigote form of Leishmania amazonensis (IC 50 =19.36±1.06 μg/mL) and low cytotoxicity on murine macrophages (LC 50  90.23±1.09 μg/mL), as well as good antimicrobial activity against Staphylococcus aureus, Escherichia coli, Klebsiella oxytoca, and Pseudomonas aeruginosa. These results suggest that L. oleifolium essential oil is a valuable source of bioactive compounds presenting antioxidant, antiparasitic, and antimicrobial activities. Furthermore, it is considered nontoxic., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

Ethnopharmacological Relevance: Folk medicine reports have described the use of Chenopodium ambrosioides as an anti-inflammatory, analgesic, and anthelmintic herb. These effects, including its activity against intestinal worms, are already scientifically observed. However, the immunological mechanisms of this species in the treatment of Schistosoma mansoni infection are unknown., Aim of the Study: To evaluate the immunological and anti-Schistosoma mansoni effects of a crude Chenopodium ambrosioides hydro-alcoholic extract (HCE)., Materials and Methods: For the in vitro analysis, cercariae and adult worms were exposed to different concentrations (0 to 10,000 μg/mL) of the HCE. For the in vivo evaluation, Swiss mice were infected with 50 cercariae of S. mansoni and separated into groups according to treatment as follows: a negative control (without treatment), a positive control (treated with Praziquantel®), HCE1 Group (treated with HCE during the cutaneous phase), HCE2 Group (treated with HCE during the lung phase), HCE3 Group (treated with HCE during the young worm phase), and HCE4 Group (treated with HCE during the adult worm phase). The animals treated with HCE received daily doses of 50 mg/kg, by gavage, for seven days, corresponding to the different developmental stages of S. mansoni. For comparison, a clean control group (uninfected and untreated) was also included. All animals were euthanized 60 days post-infection to allow the following assessments to be performed: a complete blood cells count, counts of eggs in the feces and liver, the quantification of cytokines and IgE levels, histopathological evaluations of the livers, and the analysis of inflammatory mediators., Results: HCE treatment increased the mortality of cercariae and adult worms in vitro. The HCE treatment in vivo reduced the eggs in feces and liver. The number and area of liver granulomas, independent of the phase of treatment, were also reduced. The treatment with HCE reduced the percentage of circulating eosinophils, IgE, IFN-γ, TNF-α, and IL-4. In contrast, the treatment with the HCE, dependent on the phase, increased IL-10 levels and the number of peritoneal and bone marrow cells, mainly of T lymphocytes, B lymphocytes, and macrophages. This effect could be due to secondary compounds presents in this extract, such as kaempferol, quercetin and derivatives., Conclusions: This study demonstrates that Chenopodium ambrosioides has antiparasitic and immunomodulatory activity against the different phases of schistosomiasis, reducing the granulomatous inflammatory profile caused by the infection and, consequently, improving the disease prognosis., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Propolis has been used in folk medicine for thousands of years and, in the past few decades, it has attracted renewed interest. Although propolis has been traditionally used in many communities worldwide against parasitic diseases, its effect against Schistosoma mansoni infection remains unclear., Aim of the Study: To demonstrate the effects of Brazilian red propolis on Schistosoma mansoni ex vivo and in an animal model of schistosomiasis., Materials and Methods: In vitro, we monitored phenotypic and tegumental changes as well as the effects of the crude extract of propolis on pairing and egg production. In a mouse infected with either immature (early infection) or adult (chronic infection) worms, propolis was administered by oral gavage and we studied the influence of this natural product on worm burden and egg production., Results: Propolis 25 μg/mL reduced motility and caused 100% mortality of adult parasites ex vivo. Further analysis revealed a pronounced reduction in oviposition after exposure to propolis at sub-lethal concentrations. In addition, scanning electron microscopy showed morphological alterations in the tegument of schistosomes. In the animal model, propolis markedly reduced worm burden and egg production in both early and chronic S. mansoni infection when compared to untreated control animals., Conclusions: The efficacy of Brazilian red propolis in both in vitro and in vivo studies suggests its potential anthelmintic properties against S. mansoni infection., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Pradimicins (PRMs) constitute an exceptional class of natural products that show Ca 2+ -dependent recognition of d-mannose (Man). In addition to therapeutic uses as antifungal drugs, the application of PRMs as lectin mimics for glycobiological research has been attracting considerable interest, since the emerging biological roles of Man-containing glycans have been highlighted. However, only a few attempts have been made to use PRMs for glycobiological purposes. The limited use of PRMs is primarily due to the early assumption that the readily modifiable carboxyl group of PRMs is involved in Ca 2+ binding, and thus, not available to prepare research tools. Recently, this assumption has been disproved by structural elucidation of the Ca 2+ complex of PRMs, which paves the way for designing carboxyl group modified derivatives of PRMs for research use. This article outlines studies related to Ca 2+ -mediated Man binding of PRMs and discusses their application for glycobiology., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Biogenic silver nanoparticles (AgNPs) continue captivating researchers in biomedicine field of research. Dicoma anomala Sond. plant, locally known as hloenya, hlonya, maagbossie, inyongwana, is widely recommended by South African traditional health practitioners (THPs) to treat against different health issues. The antiplasmodial effects of novel sesquiterpene molecules (C 30 H 36 O 7 ; MW: 509.25) isolated from D. anomala Sond. have been reported by us (Patent US 8,586,112 B2). The aim of the study was to determine the anticancer activity of AgNPs synthesized using D. anomala plant root extract and the antiparasitic potency of AgNP-conjugated sesquiterpene. Nanoparticles have been characterized using different methods. Anticancer activity of AgNPs was evaluated against the MCF-7. This study also revealed that the AgNP-conjugated sesquiterpene has shown better antiparasitic activity against Plasmodium falciparum NF54 strain. One-pot synthesized AgNPs using Dicoma anomala Sond. root extract caused oxidative damage in breast cancer cells. These findings indicate the need for more in-depth research in the use of the AgNPs and sesquiterpene for development into potential leads as an antimalarial candidates and to improve the bioavailability of these sesquiterpenes.

Giardia duodenalis, the most prevalent human intestinal parasite causes the disease, giardiasis. On an annual basis G. duodenalis infects ~1 billion people, of which ~280 million develop symptomatic disease. Giardiasis can be severe and chronic, causing malnutrition, stunted growth and poor cognitive development in children. Current treatment options rely on drugs with declining efficacy and side-effects. To improve the health and well-being of millions of people world-wide, new anti-Giardia drugs with different modes of action to currently used drugs are required. The Medicines for Malaria Venture's Pathogen Box, a collection of bio-active compounds specifically chosen to stimulate infectious disease drug discovery, represents an opportunity for the discovery of new anti-Giardia agents. While the anti-Giardia activity of Pathogen Box compounds has been reported, this work failed to identify known anti-Giardia controls within the compound set. It also reported the activity of compounds previously screened and shown to be inactive by others, suggesting data may be inaccurate. Given these concerns the anti-Giardia activity of Pathogen Box compounds was re-assessed in the current study. Data from this work identified thirteen compounds with anti-Giardia IC 50 values ≤2 μM. Five of these compounds were reference compounds (marketed drugs with known anti-microbial activity), or analogues of compounds with previously described anti-Giardia activity. However, eight, including MMV676358 and MMV028694, which demonstrated potent sub-μM IC 50 s against assemblage A, B and metronidazole resistant parasites (0.3 μM and 0.9 μM respectively), may represent new leads for future drug development. Interestingly, only four of these compounds were identified in the previously reported Pathogen Box screen highlighting the importance of assay selection and design when assessing compounds for activity against infectious agents., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction : Curcumin is an important bioactive compound present in Curcuma longa , and is well known for its bioactivities such as anti-inflammatory, anticancer, antimicrobial, antiparasitic and antioxidant activity. The use of curcumin is limited owing to its poor solubility in water, fast degradation, and low bioavailability. This problem can be solved by using nano-curcumin, which is soluble in water and enhances its activity against various microbial pathogens and parasites. Areas covered : We have reviewed curcumin, curcumin-loaded nanoparticles and their activities against various pathogenic microbes (antifungal, antiviral and antiprotozoal) and parasites, as curcumin has already demonstrated broad-spectrum antimicrobial activity. It has also inhibited biofilm formation by various bacteria including Pseudomonas aeruginosa . The antimicrobial activity of curcumin can be increased in the presence of light radiation due to its photo-excitation. Further, it has been found that the activity of curcumin nanoparticles is enhanced when used in combination with antibiotics. Finally, we discussed the toxicity and safety issues of curcumin. Expert opinion : Since many microbial pathogens have developed resistance to antibiotics, the combination of curcumin with different nanoparticles will prove to be a boon for their treatment. Moreover, curcumin and curcumin-loaded nanoparticles can also be used against various parasites.

Neolignan licarin A (1) was isolated from leaves of Nectandra oppositifolia (Lauraceae) and displayed activity against trypomastigote forms of the etiologic agent of American trypanosomiasis, Trypanosoma cruzi. Aiming for the establishment of SAR, five different compounds (1a - 1e) were prepared and tested against T. cruzi. The 2-allyl derivative of licarin A (1d) exhibited higher activity against trypomastigotes of T. cruzi (IC 50  = 5.0 μM and SI = 9.0), while its heterocyclic derivative 1e displayed IC 50 of 10.5 μM and reduced toxicity against NCTC cells (SI > 19.0). However, these compounds presented limited oral bioavailability estimation (<85%, Papp <1.0 × 10 -6  cm/s) in parallel artificial membrane permeability assays (PAMPA) due to excessive lipophilicity. Based on these results, different simplified structures of licarin A were designed: vanillin (2), vanillyl alcohol (3), isoeugenol (4), and eugenol (5), as well as its corresponding methyl (a), acetyl (b), O-allyl (c), and C-allyl (d) analogues. Vanillin (2) and its acetyl derivative (2b) displayed expressive activity against intracellular amastigotes of T. cruzi with IC 50 values of 5.5 and 5.6 μM, respectively, and reduced toxicity against NCTC cells (CC 50  > 200 μM). In addition, these simplified analogues showed a better permeability profile (Papp > 1.0 × 10 -6  cm/s) on PAMPA models, resulting in improved drug-likeness. Vanillyl alcohol acetyl derivative (3b) and isoeugenol methyl derivative (4a) displayed activity against the extracellular forms of T. cruzi (trypomastigotes) with IC 50 values of 5.1 and 8.8 μM respectively. Based on these results, compounds with higher selectivity index against extracellular forms of the parasite (1d, 1e, 3d, and 4a) were selected for a mechanism of action study. After a short incubation period (1 h) all compounds increased the reactive oxygen species (ROS) levels of trypomastigotes, suggesting cellular oxidative stress. The ATP levels were increased after two hours of incubation, possibly involving a high energy expenditure of the parasite to control the homeostasis. Except for compound 4a, all compounds induced hyperpolarization of mitochondrial membrane potential, demonstrating a mitochondrial imbalance. Considering the unique mitochondria apparatus of T. cruzi and the lethal alterations induced by structurally based on licarin A, these compounds are interesting hits for future drug discovery studies in Chagas disease.

Available treatments for Chagas' disease and visceral leishmaniasis are inadequate, and there is a pressing need for new therapeutics. Drug discovery efforts for both diseases principally rely upon phenotypic screening. However, the optimization of phenotypically active compounds is hindered by a lack of information regarding their molecular target(s). To combat this issue we initiate target deconvolution studies at an early stage. Here, we describe comprehensive genetic and biochemical studies to determine the targets of three unrelated phenotypically active compounds. All three structurally diverse compounds target the Q i active-site of cytochrome b , part of the cytochrome bc1 complex of the electron transport chain. Our studies go on to identify the Q i site as a promiscuous drug target in Leishmania donovani and Trypanosoma cruzi with a propensity to rapidly mutate. Strategies to rapidly identify compounds acting via this mechanism are discussed to ensure that drug discovery portfolios are not overwhelmed with inhibitors of a single target.

Background: The root-knot nematode Meloidogyne graminicola has become a serious threat to rice production as a result of the cultivation changes from transplanting to direct seeding. The nematicidal activity of Aspergillus welwitschiae have been investigated in vitro, and the disease control efficacy of the active compound has been evaluated under greenhouse and field conditions., Results: The active compound αβ-dehydrocurvularin (αβ-DC), isolated by nematicidal assay-directed fractionation, showed significant nematicidal activity against M. graminicola, with a median lethal concentration (LC 50 ) value of 122.2 μg mL - 1 . αβ-DC effectively decreased the attraction of rice roots to nematodes and the infection of nematodes and also suppressed the development of nematodes under greenhouse conditions. Moreover, αβ-DC efficiently reduced the root gall index under field conditions., Conclusions: To our knowledge, this is the first report to describe the nematicidal activity of αβ-DC against M. graminicola. The results obtained under greenhouse and field conditions provide a basis for developing commercial formulations from αβ-DC to control M. graminicola in the future.

Liposoluble molecules are a group of compounds that display potent biological and therapeutic properties. The present study aimed to identify liposoluble molecules produced by Ganoderma lipsiense grown in red rice medium using solid-state fermentation (SSF) techniques, and to investigate the antigiardial and antibacterial activities potential of extracts in vitro. Eighteen fatty acids and derivatives were identified by gas chromatograph-mass spectrometry (GC-MS) analysis in G. lipsense extract. Qualitative (Fourier transform infrared spectroscopy and nuclear magnetic resonance) characterizations identified the steroid ergosta-6,22-diene-3β,5α,8α-triol in purified hexane subfraction (HEXsf) F19 isolated from hexane fraction (HEXf) of crude extract (CE). Ergosta-6,22-diene-3β,5α,8α-triol exhibited significant inhibitory activity against Giardia duodenalis throphozoites (93.6%) in in vitro assays. CE and HEXf inhibited 95.38% and 92.74% of the G. duodenalis throphozoites in 100 µg mL -1 , whereas CE and their fractions dichloromethane (DCMf) and ethyl acetate (EAf) showed antibacterial activities against Pseudomonas aeruginosa and Staphylococcus aureus at 500 µg mL -1 . Importantly, some liposoluble compounds produced and identified in G. lipsiense are unpublished for this species. This is first report for the production of ergosta-6,22-diene-3β,5α,8α-triol by G. lipsiense and its antiparasitic activity., (© 2019 International Union of Biochemistry and Molecular Biology, Inc.)

Passive sampling is an attractive technique for the long-term monitoring of pharmaceuticals in the water environment. The reliability of the received results depends on the properly performed calibration, namely the determination of analyte sampling rates. This step can be the source of a systematic error, as the sampling rate values are dependent on the water donor phase parameters. This is especially important for pharmaceuticals, since their chemical characteristics and ionic form change with pH. In this study, the cross-effect of pH (3, 7, and 9) and salinity (0, 7, and 35 practical salinity unit, using artificial sea water) on the passive sampling of 21 pharmaceuticals (antiparasitics, beta-blockers, non-steroidal anti-inflammatory drugs, sulfonamides) was tested. The primarily determined parameter was the sampling rate. In addition, the extraction efficiency, partitioning coefficient, and the concentration of the analytes on the sorbent were calculated. Generally, for the non-steroidal anti-inflammatory drugs, beta-blockers, and antiparasitics, the change both in pH and salinity had a negligible impact on the mentioned experimental parameters. In contrast, the extraction of sulfonamides was impacted by both pH and salinity, while lipophilicity was not a decisive parameter., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Ivermectin is deployed in mass drug administration (MDA) campaigns to control parasitic diseases in the tropics, with billions of treatments having been administered in the last three decades. Simple blood sampling tools, like the dried blood spots (DBS) technique, are needed to monitor treatments in such challenging settings. Thus, we developed a fully automated method for the analysis of ivermectin in DBS microsamples, including a bioanalytical and clinical validation. Automated extraction was carried out using a DBS-MS 500 autosampler which was coupled to a LC-MS/MS system. DBS were extracted with 20 μL solvent and eluted on a C8 analytical column. Analysis was performed by multiple reaction monitoring in the positive mode. Automated DBS extraction resulted in consistent recoveries (62.8 ± 4.3%) and matrix effects (68.0 ± 8.1%) between different donors and concentration levels. Intra- and inter-day accuracy and precision deviations were ≤15%, while samples with hematocrits from 20 to 60% could be quantified reliably. The achieved sensitivity of 1 ng/mL in DBS samples is sufficient to analyze ivermectin at the dose given (single oral administration of 12 mg) over a period of at least 72 h post treatment. Importantly, DBS samples are stable after one-month storage at room temperature (accuracy: 88.8-96.2%), thus samples collected in the field must not be shipped on dry ice. Ivermectin concentrations in venous and capillary blood agreed strongly, with a mean difference of -4.8%. Moreover, the drying process of DBS did not alter the analysis and importantly plasma concentrations can be estimated from DBS data using the hematocrit and red blood cell partitioning as correction factor. Our method enables uncomplicated sample collection and shipment as well as automated analysis of large amounts of samples, which is key to surveying MDA campaigns in remote settings., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Rare actinomycetes are prolific in the marine environment; however, knowledge about their diversity, distribution and biochemistry is limited. Marine rare actinomycetes represent a rather untapped source of chemically diverse secondary metabolites and novel bioactive compounds. In this review, we aim to summarize the present knowledge on the isolation, diversity, distribution and natural product discovery of marine rare actinomycetes reported from mid-2013 to 2017. A total of 97 new species, representing 9 novel genera and belonging to 27 families of marine rare actinomycetes have been reported, with the highest numbers of novel isolates from the families Pseudonocardiaceae, Demequinaceae, Micromonosporaceae and Nocardioidaceae. Additionally, this study reviewed 167 new bioactive compounds produced by 58 different rare actinomycete species representing 24 genera. Most of the compounds produced by the marine rare actinomycetes present antibacterial, antifungal, antiparasitic, anticancer or antimalarial activities. The highest numbers of natural products were derived from the genera Nocardiopsis , Micromonospora , Salinispora and Pseudonocardia . Members of the genus Micromonospora were revealed to be the richest source of chemically diverse and unique bioactive natural products., Competing Interests: The authors declare no conflict of interest.

Essential oils (EOs) have gained increasing attention due to their pharmacological effectiveness, and they also constitute some of the most popular natural products. In this study, we present the chemical characterization of the EO from Phania matricarioides and the in vitro activity/selectivity against a wide panel of bacteria, fungi and parasitic protozoa. Forty-five compounds were identified in the studied EO, of which lavandulyl acetate (40.1%) and thymyl isobutyrate (13.9%) were the major components. The EO did not inhibit bacterial or fungal growth at the maximum concentration tested (64 µg/mL), although it displayed activity on all evaluated protozoa (IC 50 values ranging from 2.2 to 56.6 µg/mL). In parallel, the EO demonstrated a noteworthy cytotoxic activity against peritoneal macrophages (CC 50 values of 28.0 µg/mL). The most sensitive microorganism was Trypanosoma cruzi , which had a superior activity (IC 50 = 2.2 µg/mL) and selectivity (SI = 13) in respect to other parasitic protozoa and the reference drug ( p < 0.05). Further in vivo studies are needed to evaluate the potential use of this EO and the main compounds as antitrypanosomal agents. To our knowledge, this is the first report of chemical characterization and antimicrobial assessment of the EO from P. matricarioides .

The objective of this study was to investigate the biological activities of Algerian algae, Sargassum vulgare, Cladostephus hirsutus and Rissoella verruculosa. Antimicrobial activity of the crude extracts and their fractions was assessed using the disc diffusion assay, the minimum inhibitory concentration and the minimum bactericidal concentration. Antiparasitic activity was studied in vitro against the blood stream forms of Trypanosoma brucei brucei and the intraerythrocytic stages of Plasmodium falciparum. Ethyl acetate (EA) fractions of the three tested algae showed more potent antimicrobial activity against S. aureus (7-14.5 mm) and B. cereus (7-10.75 mm), MIC values ranged from 0.9375 to 7.5 mg mL -1 and MBC values > 15 mg mL -1 . Concerning the antiparasitic activity, EA factions of S. vulgare (IC 50  = 9.3 μg mL -1 ) and R. verruculosa (IC 50  = 11.0 μg mL -1 ) were found to be more effective against T. brucei brucei, whereas the three EA fractions were little active against P. falciparum.

To control the fish fungal pathogen Saprolegnia, the effects of the petroleum ether extracts of Magnolia officinalis were evaluated by a rapeseed (Brassicanapus) microplate method in vitro. By loading on an open silica gel column and eluting with petroleum ether-ethyl acetate-methanol, honokiol (C 18 H 18 O 2 ) and magnolol (C 18 H 18 O 2 ) were isolated from Magnolia officinalis. Saprolegnia parasitica growth was inhibited significantly when honokiol concentration was >8.0 mg/L, and magnolol concentration was >9.0 mg/L, with EC 50 values of 4.38 and 4.92 mg/L, respectively. Six honokiol and magnolol derivatives were designed, synthesized and evaluated for their anti-Saprolegnia activity. According to the results, double bond and hydroxyl played an important role in inhibiting Saprolegnia. Mechanistically, through the scanning electron microscope observation, honokiol and magnolol could cause the Saprolegnia parasitica mycelium tegumental damage including intensive wrinkles and nodular structures. Moreover, compared to traditional drugs kresoxim-methyl (LC 50  = 0.66 mg/L) and azoxystrobin (LC 50  = 2.71 mg/L), honokiol and magnolol showed a lower detrimental effect on zebrafish, with the LC 50 values of 6.00 and 7.28 mg/L at 48 h, respectively. Overall, honokiol and magnolol were promising lead compounds for the development of commercial drugs anti-Saprolegnia., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Functional and structural diversity of proteins of snake venoms is coupled with a wide repertoire of pharmacological effects. Snake venoms are targets of studies linked to searching molecules with biotechnological potential., Methods: A homologue phospholipase A2 (BmatTX-IV) was obtained using two chromatographic techniques. Mass spectrometry and two-dimensional gel electrophoresis were used to determine the molecular mass and isoelectric point, respectively. By means of Edman degradation chemistry, it was possible to obtain the partial sequence of amino acids that comprise the isolated toxin. Trypanocidal, leishmanicidal and cytoxic activity against Trypanosoma cruzi, Leishmania infantum and murine fibrobasts was determinated., Results: Combination of both chromatographic steps used in this study demonstrated efficacy to obtain the PLA2-Lys49. BmatTX-IV showed molecular mass and isoelectric point of 13.55 kDa and 9.3, respectively. Amino acid sequence of N-terminal region (51 residues) shows the presence of Lys49 residue at position 49, a distinctive trait of enzymatically inactive PLA2. Bothrops mattogrossensis snake venom showed IC50 values of 11.9 μg/mL against Leishmania infantum promastigotes and of 13.8 μg/mL against Trypanosoma cruzi epimastigotes, respectively. On the other hand, the venom showed a high cytotoxic activity (IC50 value of 16.7 μg/mL) against murine fibroblasts, whereas the BmatTX-IV showed IC50 value of 81.2 μg/mL., Conclusion: Physicochemical and biological characterization of snake venoms components is critically important, since these complex mixtures provide a source of molecules with antiparasitic potential, making further studies necessary to identify and characterize components with higher efficacy and selectivity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Plant-based systems continue to play an essential role in healthcare, and their use by different cultures has been extensively documented. Baccharis trimera, popularly known as carqueja, is a plant widely distributed in South America and has been traditionally used for treating several diseases particularly associated with hepatic and gastric disorders. The present study aimed to provide a general review of the available literature on phytochemical and biological data related to the species B. trimera as a potential source of new compounds with biological activity. Considering phytochemical studies, flavonoids, terpenes and chlorogenic acids were the main classes of compounds identified in aerial parts which were correlated with their biological activities such as antioxidant, anti-inflammatory, gastric and hepatic-protector, anti-microbial, anti-fungal, anti-parasitic and aid in weight loss., (Copyright © 2018. Published by Elsevier B.V.)

A new alkaloid paenidigyamycin A ( 1 ) was obtained from the novel Ghanaian Paenibacillus sp. isolated from the mangrove rhizosphere soils of the Pterocarpus santalinoides tree growing in the wetlands of the Digya National Park, Ghana. Compound 1 was isolated on HPLC at t R = 37.0 min and its structure determined by MS, 1D, and 2D-NMR data. When tested against L. major , 1 (IC 50 0.75 µM) was just as effective as amphotericin B (IC 50 0.31 µM). Against L. donovani , 1 (IC 50 7.02 µM) was twenty-two times less active than amphotericin B (IC 50 0.32 µM), reinforcing the unique effectiveness of 1 against L. major . For T. brucei brucei , 1 (IC 50 0.78 µM) was ten times more active than the laboratory standard Coptis japonica (IC 50 8.20 µM). The IC 50 of 9.08 µM for 1 against P. falciparum 3d7 compared to artesunate (IC 50 36 nM) was not strong, but this result suggests the possibility of using the paenidigyamycin scaffold for the development of potent antimalarial drugs. Against cercariae, 1 showed high anticercaricidal activity compared to artesunate. The minimal lethal concentration (MLC) and minimal effective concentration (MEC) of the compound were 25 and 6.25 µM, respectively, while artesunate was needed in higher quantities to produce such results. However, 1 (IC 50 > 100 µM) was not active against T. mobilensis .

The phytochemical study of Laelia marginata (Lindl.) L. O. Williams (Orchidaceae) led to the isolation of a new natural product named crispoic acid (1), together with six other known compounds (2-7). The new natural product was identified as a dimer of eucomic acid and was structurally characterised based upon 1D and 2D NMR and HRMS data. Biological assays with plant crude extract, fractions and isolated compounds were performed against two human cancer cell lines (Hela and Siha), and the tropical parasites Trypanosoma cruzi and Leishmania (Leishmania) amazonensis. The phenantrenoid 9,10-dihydro-4-methoxyphenanthren-2,7-diol 2 was active against Hela and Siha cells (CC 50 5.86 ± 0.19 and 20.78 ± 2.72 μg/mL, respectively). Sub-lethal concentrations of the flavone rhamnazin 4 were not able to rescue the viability of the Vero cells infected by Zika virus.

Focused on our interest to develop novel antiparasistic agents, the present study was aimed to evaluate the biological activity of an extract of Laurencia johnstonii collected in Baja California Sur, Mexico, against an Acantamoeba castellanii Neff strain. Bioassay-guided fractionation allowed us to identify the amoebicidal diastereoisomers α-bromocuparane ( 4 ) and α-isobromocuparane ( 5 ). Furthermore, bromination of the inactive laurinterol ( 1 ) and isolaurinterol ( 2 ) yielded four halogenated derivatives, ( 6 )⁻( 9 ), which improved the activity of the natural sesquiterpenes. Among them, the most active compound was 3α-bromojohnstane ( 7 ), a sesquiterpene derivative which possesses a novel carbon skeleton johnstane.

Antimicrobial peptides are molecules of natural origin, produced by organisms such as insects, which have focused attention as potential antiparasitic agents. They can cause the death of parasites such Leishmania by interacting with their membrane. In this study, additional information was obtained on how the anionic peptide 2 and cecropin D-like peptide derived from Galleria mellonella interact with liposomes that mimic the composition of the Leishmania membrane. In order to do this, lipid bilayers consisting of dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, dimyristoylphosphatidylserine, and dimyristoylphosphatidylglycerol were constructed. The effect of the peptides on these membranes was evaluated using calorimetry analysis and fluorescence spectroscopy. The results obtained using differential scanning calorimetry indicated a concentration-dependent effect on membranes composed of phosphatidylserine and phosphatidylglycerol, showing a preference of both peptides for anionic lipids. The binding of the peptides drastically reduced the transition enthalpy in the phosphatidylserine and phosphatidylglycerol liposomes. The results suggest that the mode of action of anionic peptide 2 and cecropin D-like peptide is different, with a higher effect of cecropin D-like on the anionic lipids, which led to changes in the main transition temperature and a complete solubilization of the vesicles. Interactions between peptides and phosphatidylcholine, which is the most abundant lipid on the surface of Leishmania cells, were evaluated using isothermal titration calorimetry and the anisotropy of fluorescence of DPH. The peptides had a slight effect on the gel phase of the phosphatidylcholine, with changes in the anisotropy correlated with that observed by DSC. The results showed a selectivity of these peptides toward some lipids, which will direct the study of the development of new drugs.

Ethnopharmacological Relevance: Worldwide, more than three billion cases of parasitic disease are reported yearly and it is likely that this figure is substantially under-estimated. Approximately one in six people globally are estimated to be infected with at least one parasite species annually. In South Africa, the prevalence of Schistosoma haematobium (bilharzia) and intestinal worms and helminths are particularly high, especially in children and in crowded or poorer rural communities with inadequate sanitation and nutrition. Despite alarmingly high estimates, medical research into parasitic diseases remains neglected and only malaria receives significant attention and funding. Traditional medicines have been used for centuries in Africa by multiple ethnic groups and many people rely on these healing systems as their primary healthcare modality. The traditional use of South African medicinal plants to treat parasite infestations is relatively well documented, and it is important to link these traditional uses to scientific evidence validating efficacy., Aim of the Study: To document the medicinal plants used for parasitic infections and critically review the literature on the anti-parasitic properties of South African plants against some neglected parasitic diseases., Materials and Methods: A review of the literature (ethnobotanical books and publications documenting traditional plant use) was undertaken related to specific medicinal use for parasitic infections in Southern Africa. Inclusion criteria focused on human use. Exclusion criteria included veterinary use and malaria due to the extensive nature of these subject matters. An in-depth analysis of previous studies was undertaken and future prospectives are considered., Results: In particular, bilharzia, gastrointestinal worms and helminths, ectoparasites, trichomoniasis, leishmaniasis and trypanosomiasis are reviewed with special emphasis on the gaps in research., Conclusions: Despite the availability of relatively extensive ethnobotanical records on the anti-parasitic properties of southern African medicinal plants, the antiparasitic properties of many plants have been poorly examined. There was in many instances a lack of evidence to support traditional use of many species towards some parasites and research is urgently needed in this area., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Ichthyophthirius multifiliis is a ciliated parasite that infests almost all freshwater fish species and causes great economic losses to the aquaculture industry. In this study, a compound with anti-I. multifiliis activity was isolated from Polygonum cuspidatum and identified as emodin. In vitro anti-I. multifiliis results showed that emodin at 1 mg/L killed all I. multifiliis theronts for 96.0 min, and at 0.5 mg/L or lower concentrations could not kill all I. multifiliis theronts, but could significantly reduce the infectivity of theronts after pretreatment with emodin at the low concentrations mentioned above for 2 h. Additionally, emodin at 1 mg/L and 2 mg/L completely terminated the reproduction of nonencysted and encysted tomonts, respectively. In vivo tests, emodin at 0.5 mg/L could cure infected grass carp and protect naive fish from I. multifiliis infection by continuous adding emodin for 10 days. The 96 h median lethal concentration (LC 50 ) of emodin to grass carp was 3.15 mg/L, which were approximately 18 and 7 times the median effective concentration (EC 50 ) of emodin for killing theronts (0.18 mg/L) and nonencysted tomonts (0.45 mg/L), respectively. On the basis of these results, emodin is an effective compound for the development of a new drug against I. multifiliis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A set of chemically engineered extracts enriched in compounds including N-N and N-O fragments in their structures was prepared. Bromodomain binding screening and bioguided fractionation led to the identification of one oxime hit that interacts with TcBDF3 with affinity in the submicromolar range and that shows interesting antiparasitic properties against the different life cycle stages of T. cruzi.

Objectives: Sterculia and Brachychiton are two related genera (Malvaceae) containing more than 300 species. Most of these species are ornamental trees that are native to Australia and widely cultivated in many countries. Different members of the two genera were used by various cultures for medicinal and economical purposes. This review sheds light on the medicinal values and chemical composition of various species of these two genera., Key Findings: Sterculia and Brachychiton species were used traditionally for the treatment of gastrointestinal disorders, microbial infection, skin diseases, inflammation and many other conditions. The seeds of various species were roasted and eaten by many traditional tribes. Plants from the two genera revealed their anti-inflammatory, antioxidant, antimicrobial, antidiabetic, antiulcer, insecticidal and analgesic activity. These activities may be attributed to the presence of a wide range of secondary metabolites as flavonoids, phenolic acids, coumarins, terpenoids particularly sesquiterpenes and triterpenes in addition to sterols and fatty acids. Moreover, the gummy exudates obtained from some members of these genera played an important role in different pharmaceutical dosage forms and drug-delivery systems., Conclusions: More research is recommended on other species of Sterculia and Brachychiton to discover new molecular entities with potential biological and economic values., (© 2018 Royal Pharmaceutical Society.)

Investigating new antimicrobial and antiparasitic components from Viperidae venoms represents an alternative therapeutic strategy. In this study, we report the characterization of a disintegrin isolated from Cerastes cerastes venom, exhibiting antiparasitic activity on Leishmania infantum promastigotes. Indeed, isolated disintegrin, referred to Disintegrin&#95;Cc, induced 84.75% of parasiticidal activity and deep morphological alterations on the parasites. SDS-PAGE analysis indicated that this disintegrin was homogenous. This dimeric disintegrin of 14,193.97 Da contains an RGD domain and four intramolecular disulfide bridges. It presents a high percentage of identity with other related snake disintegrins. Predicted 3D structure indicated that this peptide shares partial homology with well-known active antimicrobial peptides. Disintegrin&#95;Cc inhibited 80% of arachidonic acid-induced platelet aggregation. The obtained results suggest that the isolated molecule plays a dual role as a disintegrin and as an anti-leishmanial compound. This component could be useful as a drug in the treatment of leishmaniasis., (© 2017 Wiley Periodicals, Inc.)

Trichomonas vaginalis is a major non-viral sexually-transmitted infection resulted into serious obstetrical and gynecological troubles. The increasing resistance to nitroimidazole therapy and recurrence makes it crucial to develop new drugs against trichomoniasis. Over the past few years, a large number of research articles highlighting the synthetic and natural product research to combat Trichomonas vaginalis have been published. Electronic databases were searched to collect all data from the year 2006 through June 2017 for anti-Trichomonas activity potential of synthetic and natural products. This review article put together the synthetic and natural product research to find out an effective metronidazole alternative to cure trichomoniasis., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Chagas disease is a neglected tropical disease, caused by the protozoan parasite Trypanosoma cruzi, which affects more than eight million people in Tropical and Subtropical countries especially in Latin America. Current treatment is limited to nifurtimox and benznidazole, both with reduced effectiveness and high toxicity. In this work, the n-hexane extract from leaves of Nectandra leucantha (Lauraceae) displayed in vitro antitrypanosomal activity against T. cruzi. Using several chromatographic steps, four related neolignans were isolated and chemically characterized as dehydrodieugenol B (1), 1-(8-propenyl)-3-[3'-methoxy-1'-(8-propenyl)-phenoxy]-4,5-dimethoxybenzene (2), 1-[(7S)-hydroxy-8-propenyl]-3-[3'-methoxy-1'-(8'-propenyl)-phenoxy]-4-hydroxy-5-methoxybenzene (3), and 1-[(7S)-hydroxy-8-propenyl]-3-[3'-methoxy-1'-(8'-propenyl)-phenoxy]-4,5-dimethoxybenzene (4). These compounds were tested against intracellular amastigotes and extracellular trypomastigotes of T. cruzi and for mammalian cytotoxicity. Neolignan 4 showed the higher selectivity index (SI) against trypomastigotes (>5) and amastigotes (>13) of T. cruzi. The investigation of the mechanism of action demonstrated that neolignan 4 caused substantial alteration of the plasma membrane permeability, together with mitochondrial dysfunctions in trypomastigote forms. In silico studies of pharmacokinetics and toxicity (ADMET) properties predicted that all compounds were non-mutagenic, non-carcinogenic, non-genotoxic, weak hERG blockers, with acceptable volume of distribution (1.66-3.32 L/kg), and low rodent oral toxicity (LD 50 810-2200 mg/kg). Considering some clinical events of cerebral Chagas disease, the compounds also demonstrated favorable properties, such as blood-brain barrier penetration. Unfavorable properties were also predicted as high promiscuity for P450 isoforms, high plasma protein binding affinity (>91%), and moderate-to-low oral bioavailability. Finally, none of the isolated neolignans was predicted as interference compounds (PAINS). Considering the promising chemical and biological properties of the isolated neolignans, these compounds could be used as starting points to develop new lead compounds for Chagas disease., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The "rule of 5" has become a mainstay of decision-making in the pharmaceutical industry as well as in nonindustrial (academic and institutional) drug development. However the authors of the original paper never intended for "double cutoffs" to preclude development of new drug leads for parasitic diseases., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Chemical investigation of the ethyl acetate extract from the endophytic fungus Diaporthe phaseolorum-92C (92C) isolated from the roots of Combretum lanceolatum led to the isolation of 18-des-hydroxy Cytochalasin H (compound 1). The trypanocidal and schistosomicidal activity and cytotoxicity of the extract from 92C were evaluated. The schistosomicidal, leishmanicidal, antimicrobial, and antioxidant actions, as well as the antitumor activity against the breast cancer cells MDA-MB-231 and MCF-7, and the cytotoxicity towards normal human lung fibroblasts GM07492A of compound 1 was tested. The extract from 92C (20 μg/mL) exerted potent trypanocidal activity, reducing 82% of the number of amastigotes and trypomastigotes of Trypanosoma cruzi. Compound 1 at 50 μg/mL killed 50% of Schistosoma mansoni adult worms. Compound 1 reduced the viability of Leishmania amazonenses promastigotes (IC 50  = 9.2 μg/mL) and of the cancer cells MDA-MB-231 and MCF-7 (IC 50  = 17.5 and 8.88 μg/mL, respectively), presented moderate antioxidant activity, and gave IC 50 of 2049.7 ± 39.9 μg/mL for the cytotoxicity towards normal cells GM07492A. This knowledge is highly relevant to the search for new promising compounds for therapeutic purposes.

A family of 2,2-dimethyl-3-hydroxy-7-octynoic acid (Dhoya)-containing cyclic depsipeptides, named dudawalamides A-D (1-4), was isolated from a Papua New Guinean field collection of the cyanobacterium Moorea producens using bioassay-guided and spectroscopic approaches. The planar structures of dudawalamides A-D were determined by a combination of 1D and 2D NMR experiments and MS analysis, whereas the absolute configurations were determined by X-ray crystallography, modified Marfey's analysis, chiral-phase GCMS, and chiral-phase HPLC. Dudawalamides A-D possess a broad spectrum of antiparasitic activity with minimal mammalian cell cytotoxicity. Comparative analysis of the Dhoya-containing class of lipopeptides reveals intriguing structure-activity relationship features of these NRPS-PKS-derived metabolites and their derivatives.

Three new monoterpene indole alkaloids (1-3) have been isolated from the bark of Geissospermum laeve, together with the known alkaloids (-)-leuconolam (4), geissolosimine (5), and geissospermine (6). The structures of 1-3 were elucidated by analysis of their HRMS and NMR spectroscopic data. The absolute configuration of geissolaevine (1) was deduced from the comparison of experimental and theoretically calculated ECD spectra. The isolation workflow was guided by a molecular networking-based dereplication strategy using an in-house database of monoterpene indole alkaloids. In addition, five known compounds previously undescribed in the Geissospermum genus were dereplicated from the G. laeve alkaloid extract network and were assigned with various levels of identification confidence. The antiparasitic activities against Plasmodium falciparum and Leishmania donovani as well as the cytotoxic activity against the MRC-5 cell line were determined for compounds 1-5.

Chemical analysis, antimicrobial activity and cytotoxic effects of essential oils (EOs) from leaves of Piper aduncum var. ossanum from two localities Bauta (EO-B) and Ceiba (EO-C), Artemisa Province, Cuba, were determined. EOs were obtained by hydrodistillation and analyzed by gas chromatography/mass spectrometry. EO-B demonstrated higher activity against S. aureus and L. amazonensis; while a lower cytotoxicity on mammalian cells was observed. Both EOs displayed the same activity against Plasmodium falciparum, Trypanosoma cruzi, Trypanosoma brucei, and Leishmania infantum. Both EOs were inactive against Escherichia coli and Candida albicans., (© 2016 Wiley-VHCA AG, Zurich, Switzerland.)

Current scolicidal agents, which have been used for inactivation of protoscoleces during hydatid cyst surgery are associated with adverse side effects. This study aims to evaluate the in vitro scolicidal effects of Nectaroscordum tripedale L. leave extract against protoscoleces of hydatid cysts and its acute toxicity in mice model. Various concentrations of the extract (12.5-100 mg/mL) were used for 5 to 30 min. Viability of protoscoleces was confirmed using eosin exclusion test (0.1% eosin staining). In addition, the acute toxicity of N. tripedale extract was determined for 2 days in mice model. The results showed that the N. tripedale extract at the concentration of 100 mg/mL after 5 min of exposure killed 100% protoscoleces. Similarly, the mean of mortality rate of protoscoleces after 10 min of exposure to concentration of 50 mg/mL was 100%. The LD 50 values of intraperitoneal injection of the N. tripedale extract was 3.36 g/kg body wt. and the maximum nonfatal doses were 2.98 g/kg body wt. The results showed the potential of N. tripedale extract as a natural source for the production of new scolicidal agent for use in hydatid cyst surgery.

Context C-6-Geranylated flavonoids possess promising biological activities. These substances could be a source of lead compounds for the development of therapeutics. Objective The study was designed to evaluate their antibacterial and antileishmanial activity. Materials and methods C-6-Geranylated flavanones were tested in micromolar concentrations against promastigote forms of Leishmania brazilensis, L. donovani, L. infantum, and L. panamensis against methicillin-resistant Staphylococcus aureus (MRSA); and synergistic potential with antibiotics was analyzed. IC50 values (after 72 h) were calculated and compared with that of miltefosine. Flow cytometry and DNA fragmentation analysis were used the mechanism of the effect. Geranylated flavanones or epigallocatechin gallate were combined with oxacillin, tetracycline, and ciprofloxacin, and the effects of these two-component combinations were evaluated. Minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) were established (after 24 h), the synergy was measured by the checkerboard titration technique, and the sums of the fractional inhibitory concentrations (∑FICs) were computed. Results 3'-O-Methyl-5'-O-methyldiplacone and 3'-O-methyldiplacone showed good antileishmanial activities (IC50 8-42 μM). 3'-O-Methyl-5'-hydroxydiplacone activates the apoptotic death at leishmanias, the effect of 3'-O-methyl-5'-O-methyldiplacone has another mechanism. The test of the antibacterial activity showed good effects of 3'-O-methyldiplacol and mimulone against MRSA (MIC 2-16 μg/mL), and in six cases, the results showed synergistic effects when combined with oxacillin. Synergistic effects were also found for the combination of epigallocatechin gallate with tetracycline or oxacillin. Conclusion This work demonstrates anti-MRSA and antileishmanial potential of geranylated flavanones and uncovers their promising synergistic activities with antibiotics. In addition, the mechanism of antileishmanial effect is proposed.

Psychotria is a genus of ca. 1500 species in the family Rubiaceae. Up to now, 41 species of the Psychotria genus have been chemically investigated, and 159 compounds, including alkaloids of indole, quinoline and benzoquinolizidine type, terpenoids, steroids, phenolics and aliphatic compounds have been isolated. These compounds show potent bioactivities, such as antimicrobial, antiviral, and antiparasitic activities., (© 2016 Wiley-VHCA AG, Zürich.)

Drug development for neglected diseases has been historically hampered due to lack of market incentives. The advent of public domain resources containing chemical information from high throughput screenings is changing the landscape of drug discovery for these diseases. In this work we took advantage of data from extensively studied organisms like human, mouse, E. coli and yeast, among others, to develop a novel integrative network model to prioritize and identify candidate drug targets in neglected pathogen proteomes, and bioactive drug-like molecules. We modeled genomic (proteins) and chemical (bioactive compounds) data as a multilayer weighted network graph that takes advantage of bioactivity data across 221 species, chemical similarities between 1.7 105 compounds and several functional relations among 1.67 105 proteins. These relations comprised orthology, sharing of protein domains, and shared participation in defined biochemical pathways. We showcase the application of this network graph to the problem of prioritization of new candidate targets, based on the information available in the graph for known compound-target associations. We validated this strategy by performing a cross validation procedure for known mouse and Trypanosoma cruzi targets and showed that our approach outperforms classic alignment-based approaches. Moreover, our model provides additional flexibility as two different network definitions could be considered, finding in both cases qualitatively different but sensible candidate targets. We also showcase the application of the network to suggest targets for orphan compounds that are active against Plasmodium falciparum in high-throughput screens. In this case our approach provided a reduced prioritization list of target proteins for the query molecules and showed the ability to propose new testable hypotheses for each compound. Moreover, we found that some predictions highlighted by our network model were supported by independent experimental validations as found post-facto in the literature.

Background: Leishmaniasis is a neglected disease that affects 15 million people around the world. Many limitations are associated to the treatment as high cost and toxicity. Several classes of natural substances with proven leishmanicidal activity were reported in the literature. Phytochemsitry study of Anaxagorea dolichocarpa (Annonacea) reported the isolation of aporphine alkaloids., Methods: In this study, we evaluate the potential activity of the azaphenanthrene alkaloids eupolaramine, imbiline 1, imbiline 4, sampangine, 3-metoxisampangine and 4- metoxisampangine, isolated from A. dolichocarpa, together with a homemade databank of 142 aporphynic alkaloids isolated from Annonaceae, through ligand-based and structurebased virtual screening (VS) against Leishmania donovani. A diverse set selected from CHEMBL databank of 1397 structures, with tested antileishmanial activity against promastigote L. donovani, were classified according pIC50 values in order to generate and validate Random Forest model that show higher statistical indices values. The structure of six different L. donovani enzymes were downloaded from PDB databank and alkaloids structures were submitted to molecular docking., Results: From the six azaphenanthrene alkaloids, sampangine, 3-methoxy, and 4-methoxy were indicated as potential actives by the RF model. Docking results gave similar values for all six azaphenanthrene alkaloids. So, we performed in vitro tests with sampangine, imbiline 1, imbiline 4, and eupolaramine, which are available in our laboratory, and that show significant values of pIC50 (> 5.26)., Conclusion: Combined approach of VS allowed us to select that aporphynic alkaloid xyloguyelline as potential multitarget compound for leishmanial treatment, presenting activity against five strategic enzymes to treatment with probability of activity over 60% by RF model.

This work describes the use of Colubrina greggii as a model to investigate the use of chemometric analysis combined with data from a leishmanicidal bioassay, using Principal Component Analysis (PCA) and Orthogonal Projections to Latent Structures (O-PLS), to detect biologically active natural products in crude extracts from plants having little or no phytochemical information. A first analysis of the HPLC-UV profiles of the extract and its semi-purified fractions using both Principal Component Analysis (PCA) and Orthogonal Partial Least Squares (O-PLS) indicated that the components at tR 48.2, 48.7, 51.8min correlated with the variation in bioactivity. However, a further O-PLS analysis of the HPLC-UV profiles of fractions obtained through a final semi-preparative HPLC purification showed two components at tR 48.7 and 49.5min which correlated with the variation of the bioactivity in a high performance predictive model, with high determination coefficient, high correlation coefficient values (R(2) and Q(2)=0.99) and a low root mean square error (RMSE=0.018). This study demonstrates that the association of chemometric analysis with bioassay results can be an excellent strategy for the detection and isolation of bioactive metabolites from phytochemically unknown plant crude extracts., (Copyright © 2015. Published by Elsevier B.V.)

Nosemosis is one of the most common and widespread diseases of adult honeybees. The causative agents, Nosema apis and Nosema ceranae, belong to microsporidia some obligate intracellular eukaryotic parasites. In this study, 10 sulphated polysaccharides from algae were evaluated for their antimicrosporidian activity. They were first shown to inhibit the in vitro growth of the mammal microsporidian model, Encephalitozoon cuniculi. The most efficient polysaccharides were then tested for their ability to inhibit the growth of Nosema ceranae in experimentally-infected adult honeybees. Two polysaccharides extracted from Porphyridium spp. did not show any toxicity in honeybees and one of them allowed a decrease of both parasite load and mortality rate due to N. ceranae infection. A decrease in parasite abundance but not in mortality rate was also observed with an iota carrageenan. Our results are promising and suggest that algal sulphated polysaccharides could be used to prevent and/or control bee nosemosis., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

This study describes the biochemical and functional characterization of a new metalloproteinase named BbMP-1, isolated from Bothrops brazili venom. BbMP-1 was homogeneous on SDS-PAGE, presented molecular mass of 22,933Da and pI 6.4. The primary structure was partially elucidated with high identity with others metalloproteinases from Viperidae venoms. The enzymatic activity on azocasein was evaluated in different experimental conditions (pH, temperature). A significant reduction in enzyme activity after exposure to chelators of divalent cations (EDTA), reducing agents (DTT), pH less than 5.0 or temperatures higher than 45 °C was observed. BbMP-1 showed activity on fibrinogen degrading Aα chain quickly and to a lesser extent the Bβ chain. Also demostrated to be weakly hemorrhagic, presenting however, significant myotoxic and edematogenic activity. The in vitro activity of BbMP-1 against Plasmodium falciparum showed an IC50 of 3.2 ± 2.0 μg/mL. This study may help to understand the pathophysiological effects induced by this group of toxin and their participation in the symptoms observed in cases of snake envenomation. Moreover, this result is representative for this group of proteins and shows the biotechnological potential of BbMP-1 by the demonstration of its antiplasmodial activity., (Copyright © 2015 Elsevier Ltd. All rights reserved.)