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This study identified the isoindolone ring as a scaffold for novel agents against Trypanosoma brucei rhodesiense and explored the structure‐activity relationships of various aromatic ring substitutions. The compounds were evaluated in an integrated in vitro screen. Eight compounds exhibited selective activity against T. b. rhodesiense (IC50<2.2 μm) with no detectable side activity against T. cruzi and Leishmania infantum. Compound 20 showed low nanomolar potency against T. b. rhodesiense (IC50=40 nm) and no toxicity against MRC‐5 and PMM cell lines and may be regarded as a new lead template for agents against T. b. rhodesiense. The isoindolone‐based compounds have the potential to progress into lead optimization in view of their highly selective in vitro potency, absence of cytotoxicity and acceptable metabolic stability. However, the solubility of the compounds represents a limiting factor that should be addressed to improve the physicochemical properties that are required to proceed further in the development of in vivo‐active derivatives. [ABSTRACT FROM AUTHOR]

A series of polymeric silver(I) complexes with Schiff base ligands containing pyridine and 3,5‐halogen substituted phenol moieties were synthesized and characterized by spectroscopic methods and in the case of Ag6 also by X‐ray crystallography. All silver(I) complexes (Ag1–Ag8) were evaluated for their biological activity against a panel of pathogens including the protozoa Trypanosoma cruzi, T. brucei, T. rhodesiense and Leishmania infantum; the bacteria Staphylococcus aureus, Escherichia coli, Mycobacterium tuberculosis H37Ra and the yeast Candida albicans. Cytotoxicity evaluation was carried out on human lung fibroblasts (MRC‐5) and on primary peritoneal mouse macrophages. The most relevant result reveals antileishmanial activity potential with all complexes demonstrating higher potency than the reference drug miltefosine. Complexes with the best antiprotozoal profile (i.e., Ag2 and Ag7) were selected for incorporation into poly (lactic acid) nanoparticles (PLA NPs) with the aim to enhance selectivity. PLA/Ag2 NPs and PLA/Ag7 NPs exhibited adequate physicochemical properties, that is, average size of 263 ± 60 nm and 225 ± 6 nm, respectively, good entrapment efficiency (69% and 63%), loading content (6.2% and 5.7%) and stability. The cytotoxicity of PLA/Ag2 NPs and PLA/Ag7 NPs on MRC‐5 cells was reduced with respect to the "free" metal complexes by ~2‐fold and ~6‐fold, respectively. [ABSTRACT FROM AUTHOR]

Chemotherapy is currently the only effective approach to treat all forms of leishmaniasis. However, its effectiveness is severely limited due to high toxicity, long treatment length, drug resistance, or inadequate mode of administration. As a consequence, there is a need to identify new molecular scaffolds and targets as potential therapeutics for the treatment of this disease. We report a small series of 1,2‐substituted‐1H‐benzo[d]imidazole derivatives (9a–d) showing affinity in the submicromolar range (Ki = 0.15–0.69 μM) toward Leishmania mexicanaCPB2.8ΔCTE, one of the more promising targets for antileishmanial drug design. The compounds confirmed activity in vitro against intracellular amastigotes of Leishmania infantum with the best result being obtained with derivative 9d (IC50 = 6.8 μM), although with some degree of cytotoxicity (CC50 = 8.0 μM on PMM and CC50 = 32.0 μM on MCR‐5). In silico molecular docking studies and ADME‐Tox properties prediction were performed to validate the hypothesis of the interaction with the intended target and to assess the drug‐likeness of these derivatives. [ABSTRACT FROM AUTHOR]

In an effort to identify novel molecular warheads able to inhibit Leishmania mexicana cysteine protease CPB2.8ΔCTE, fused benzo[b]thiophenes and β,βʹ‐triketones emerged as covalent inhibitors binding the active site cysteine residue. Enzymatic screening showed a moderate‐to‐excellent activity (12%–90% inhibition of the target enzyme at 20 μ m). The most promising compounds were selected for further profiling including in vitro cell‐based assays and docking studies. Computational data suggest that benzo[b]thiophenes act immediately as non‐covalent inhibitors and then as irreversible covalent inhibitors, whereas a reversible covalent mechanism emerged for the 1,3,3ʹ‐triketones with a Y‐topology. Based on the predicted physicochemical and ADME–Tox properties, compound 2b has been identified as a new drug‐like, non‐mutagen, non‐carcinogen, and non‐neurotoxic lead candidate. [ABSTRACT FROM AUTHOR]

The diverse pharmacological properties of the diaryltriazenes have sparked the interest to investigate their potential to be repurposed as antitubercular drug candidates. In an attempt to improve the antitubercular activity of a previously constructed diaryltriazene library, eight new halogenated nitroaromatic triazenides were synthesized and underwent biological evaluation. The potency of the series was confirmed against the Mycobacterium tuberculosis lab strain H37Ra, and for the most potent derivative, we observed a minimal inhibitory concentration of 0.85 μ m. The potency of the triazenide derivatives against M. tuberculosis H37Ra was found to be highly dependent on the nature of the halogenated phenyl substituent and less dependent on cationic species used for the preparation of the salts. Although the inhibitory concentration against J774A.1 macrophages was observed at 3.08 μ m, the cellular toxicity was not mediated by the generation of nitroxide intermediate as confirmed by electron paramagnetic resonance spectroscopy, whereas no in vitro mutagenicity could be observed for the new halogenated nitroaromatic triazenides when a trifluoromethyl substituent was present on both the aryl moieties. [ABSTRACT FROM AUTHOR]

Nymphoides indica (L.) Kuntze (Menyanthaceae) is traditionally used in the Indian subcontinent. However, scientific data reporting its constituents are poor. This study aimed at evaluating its phytochemical constituents and various biological activities. Phytochemical investigations of the extracts and fractions resulted in the isolation of 5 lipophilic compounds, i.e. azelaic (nonanedioic) acid (1) and 4-methyl-heptanedioic acid (3), hexadecanoic (2) and stearic acid (5) and the fatty alcohol hexadecanol (4); 3 seco-iridoids, i.e. 7-epiexaltoside (6), 6″,7″-dihydro-7-epiexaltoside (7) and menthiafolin (8); 3 flavonoids, i.e. 3,7-di-O-methylquercetin-4'-O-β-glucoside (9), 3-O-methylquercetin-7-O-β-glucoside (10) and 3,7-di-O-methylquercetin (11); scopoletin (12) and ferulic acid (13); and the monoterpenoids foliamenthoic acid (14) and 6,7-dihydrofoliamenthoic acid methyl ester (15). Compounds 1-5 showed moderate antimicrobial activities, whereas compound 9 presented mild antiprotozoal activities against Trypanosoma brucei (IC50 8 μM), Leishmania infantum (IC50 32 μM) and Trypanosoma cruzi (IC50 30 μM). Antiglycation activity was shown by compounds 7 (IC50 0.36 mM), 10 (IC50 0.42 mM) and 15 (IC50 0.61 mM). Finally α-glucosidase inhibition was shown by compounds 7, 9, 11 and 13-15. It could be concluded that N. indica leaf extracts possess mild to moderate antimicrobial, antiprotozoal, antioxidant and antidiabetic activities. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Many topical commercial products are currently available for the treatment of onychomycosis. However, limited data are available concerning their antifungal activity. Using an in vitro onychomycosis model, the daily application of seven nail formulations was compared to the antifungal reference drug amorolfine (Loceryl®) and evaluated for inhibitory activity against Trichophyton mentagrophytes using an agar diffusion test. Of all commercial nail formulations, only Excilor® and Nailner® demonstrated inhibitory activity, which was much lower compared to the daily application of Loceryl®. However, Excilor® showed similar efficacy compared to the conventional weekly application of Loceryl®. These results suggest a role for organic acids in the antifungal effect of Excilor® (acetic acid, ethyl lactate) and Nailner® (lactic acid, citric acid, ethyl lactate) as all tested formulations without organic acids were inactive. [ABSTRACT FROM AUTHOR]

The Calophyllum genus is well-known for its antimicrobial and cytotoxic activities, and therefore, we analyzed these biological activities for resins of Calophyllum antillanum and Calophyllum inophyllum growing in Cuba. C. antillanum resins showed a potent activity against Plasmodium falciparum (IC50  = 0.3 ± 0.1 µg/mL), while its cytotoxicity against MRC-5 cells was much lower (IC50  = 21.6 ± 1.1 µg/mL). In contrary, the resin of C. inophyllum showed an unspecific activity. The presence of apetalic acid, isoapetalic acid, calolongic acid, pinetoric acid I, pinetoric acid II, isocalolongic acid, pinetoric acid III, and isopinetoric acid III in C. antillanum resins was also confirmed. These results demonstrated for the first time the potential activity of C. antillanum resins against P. falciparum. [ABSTRACT FROM AUTHOR]

Invasive aspergillosis (IA) has become increasingly common and is characterised by high morbidity and mortality. Upcoming resistance threatens treatment with azoles and highlights the continuous need for novel therapeutics. This laboratory study investigated the in vitro and in vivo potential of the alkylphospholipid oleylphosphocholine (Ol PC) against Aspergillus. In vitro activities of Ol PC, miltefosine, posaconazole and voriconazole were determined for Aspergillus fumigatus, A. niger, A. terreus and A. flavus. In vivo efficacy of Ol PC was evaluated in a systemic A. fumigatus mouse model, adopting a short-term and long-term oral or intraperitoneal dosing regimen. Ol PC showed good in vitro activity against A. fumigatus ( IC50 = 1.04 μmol l−1). Intraperitoneal administration of 50 mg kg−1 day−1 Ol PC significantly reduced the fungal organ burdens at 4 days post-infection (dpi). Although 5- and 10-day Ol PC treatment improved survival, organ burdens were not affected at 10 and 15 dpi. While this study showed excellent in vitro activity of Ol PC against Aspergillus spp., its therapeutic efficacy in an acute mouse model for IA was less convincing. Given the limited therapeutic options in the current antifungal market for invasive infections, Ol PC activity should be assessed in a less stringent in vivo model, potentially in combination treatment with other already marketed antifungal drugs. [ABSTRACT FROM AUTHOR]

Propolis is a beehive product with a very complex chemical composition, used since ancient times in several therapeutic treatments. As a contribution to the improvement of drugs against several tropical diseases caused by protozoa, we screened Portuguese propolis and its potential floral sources Populus x Canadensis and Cistus ladanifer against Plasmodium falciparum, Leishmania infantum, Trypanosoma brucei and Trypanosoma cruzi. The toxicity against MRC-5 fibroblast cells was evaluated to assess selectivity. The in vitro assays were performed following the recommendations of WHO Special Programme for Research and Training in Tropical Diseases (TDR) and revealed moderate activity, with the propolis extracts presenting the relatively highest inhibitory effect against T. brucei. Additionally, the antimicrobial activity against Staphylococcus aureus, Candida albicans, Trichophyton rubrum and Aspergillus fumigatus was also verified with the better results observed against T. rubrum. The quality of the extracts was controlled by evaluating the phenolic content and antioxidant activity. The observed biological activity variations are associated with the variable chemical composition of the propolis and the potential floral sources under study. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The use of electrogenerated acetonitrile anion allows the alkylation of N-Boc-4-aminopyridine in very high yields, under mild conditions andwithout by-products. The high reactivity of this base is due to its large tetraethylammoniumcounterion, which leaves the acetonitrile anion "naked."The deprotection of the obtained compounds led to high yields in N-alkylated 4-aminopyridines. Nonsymmetrically dialkylated 4-aminopyridines were obtained by subsequent reaction of monoalkylated ones with t-BuOK and alkyl halides, while symmetrically dialkylated 4-aminopyridineswere obtained by direct reaction of 4-aminopyridinewith an excess of t-BuOK and alkyl halides. Some mono- and dialkyl-4-aminopyridines were selected to evaluate antifungal and antiprotozoal activity; the dialkylated 4-aminopyridines 3ac, 3ae and 3ff showed antifungal towards Cryptococcus neoformans; whereas 3cc, 3ee and 3ff showed antiprotozoal activity towards Leishmania infantum and Plasmodium falciparum. [ABSTRACT FROM AUTHOR]

Background: The interest in non-antibiotic therapies for Helicobacter pylori infections in man has considerably grown because increasing numbers of antibiotic-resistant strains are being reported. Intervention at the stage of bacterial attachment to the gastric mucosa could be an approach to improve the control/eradication rate of this infection. Materials and Methods: Fractions of purified milk fat globule membrane glycoproteins were tested in vitro for their cytotoxic and direct antibacterial effect. The anti-adhesive effect on H. pylori was determined first in a cell model using the mucus-producing gastric epithelial cell line NCI-N87 and next in the C57BL/6 mouse model after dosing at 400 mg/kg protein once or twice daily from day −2 to day 4 post-infection. Bacterial loads were determined by using quantitative real-time PCR and the standard plate count method. Results: The milk fat globule membrane fractions did not show in vitro cytotoxicity, and a marginal antibacterial effect was demonstrated for defatted milk fat globule membrane at 256 μg/mL. In the anti-adhesion assay, the results varied from 56.0 ± 5.3% inhibition for 0.3% crude milk fat globule membrane to 79.3 ± 3.5% for defatted milk fat globule membrane. Quite surprisingly, in vivo administration of the same milk fat globule membrane fractions did not confirm the anti-adhesive effects and even caused an increase in bacterial load in the stomach. Conclusions: The promising anti-adhesion in vitro results could not be confirmed in the mouse model, even after the highest attainable exposure. It is concluded that raw or defatted milk fat globule membrane fractions do not have any prophylactic or therapeutic potential against Helicobacter infection. [ABSTRACT FROM AUTHOR]

Despite the high sensitivity and specificity of PCR, detection of Helicobacter pylori DNA in feces is still challenging. Fecal samples contain inhibitory molecules that can prevent amplification of the target DNA. Even by using specific DNA extraction kits for stools, monitoring of infection by analyzing stool samples remains problematic and endorses the need for improved diagnostic methods. The newly proposed method uses selective hybridization of target DNA with biotin-labeled probes, followed by DNA isolation with streptavidin-coated magnetic beads. After three washing steps, the purified DNA can be amplified immediately using conventional or quantitative PCR. In order to test this technique on biological samples, Mongolian gerbils were infected with H. pylori ATCC 43504 and fecal samples were analyzed on days 1, 4, and 10 post infection. A detection limit of one bacterial cell per 100 mg stool sample was established, but only after removal of the magnetic beads from the target DNA by heating. This resulted in a 10-fold increase of sensitivity compared to a commercially available stool DNA extraction kit. Analysis of fecal samples from infected gerbils demonstrated the presence of H. pylori DNA on each time point, while the uninfected animal remained negative. The proposed technique allows detection of very low quantities of H. pylori DNA in biological samples. In laboratory animal models, detailed monitoring of infection and complete clearance of infection can be demonstrated thanks to the low detection limit. [ABSTRACT FROM AUTHOR]

The methanol extract from the stem bark of Diospyros sanza-minika as well as five norbergenin derivatives isolated from this crude extract were evaluated for their in vitro activity against Plasmodium falciparum K1 and cytotoxicity on MRC-5 cells. 4- O-(3′-methylgalloyl)norbergenin was found to be the most potent compound (IC50 0.6 μg/mL; CC50 24.7 μg/mL), followed by 4- O-galloylnorbergenin (IC50 3.9 μg/mL; CC50 > 64 μg/mL) and 11- O- p-hydroxy-benzoyl-norbergenin (IC50 4.9 μg/mL; CC50 > 64 μg/mL). Norbergenin and 4- O-syringoylnorbergenin were inactive (IC50 > 32 μg/mL; CC50 > 64 μg/mL). The antimalarial activity of the pure constituents and of the methanol extract from the stem bark of Diospyros sanza-minika is reported for the first time. The results provide interesting baseline information for the potential use of the crude extract well as some of the isolated compounds in the search for novel antimalarial compounds. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The in vitro activity of the methanol extracts of 51 plants randomly collected from the Kingdom of Saudi Arabia and some of their fractions (petroleum ether, chloroform, ethyl acetate and aqueous) were evaluated against Plasmodium falciparum, Trypanosoma brucei brucei, T. cruzi and Leishmania infantum, as well as toxicity against MRC-5 fibroblast cells. Ten crude methanolic extracts that demonstrated potent and adequately selective antiprotozoal activity were subjected to solvent fractionation using petroleum ether, ethyl acetate and chloroform. Only three samples showed promising antiprotozoal activity. Argemone ochroleuca (CHCl3 fraction) showed pronounced activity against P. falciparumGHA (IC50 0.32 μg/mL) and T. cruzi (IC50 0.30 μg/mL) with low cytotoxicity against MRC-5 cells (CC50 11.6 μg/mL). Capparis spinosa (EtOAc fraction) showed pronounced activity against P. falciparumGHA with an IC50 0.50 μg/mL in the absence of toxicity against MRC-5 cell line (CC50 > 30 μg/mL). Heliotropium curassavicum (CHCl3 fraction) showed similar activity against P. falciparum (IC50 0.65 μg/mL; MRC-5 CC50 > 30 μg /mL). These three extracts will be subjected for further extensive studies to isolate and identify their active constituents. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Sixty-three extracts obtained from 18 plants traditionally used in the South Pacific archipelago Vanuatu for the treatment of infectious diseases were screened for antimicrobial and antiprotozoal activities. In addition, the extracts were subjected to a detailed analysis on cytotoxic effects toward a panel of human cancer cell lines, designed as a smaller version of the NCI60 screen. Intriguingly, 15 plant extracts exhibited strong cytotoxic effects specific for only one cancer cell line. Extracts of the leaves of Acalypha grandis B enth. significantly affected Plasmodium falciparum without showing obvious effects against the other protozoa tested. The leaves of Gyrocarpus americanus J acq. displayed significant activity against Trypanosoma b. brucei and the leaves of Tabernaemontana pandacaqui L am. I as well as the stems of Macropiper latifolium (L. f.) against Trypanosoma cruzi. In contrast none of the extracts showed relevant antibacterial or antifungal activity. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Maesa saponins with the 13,28-epoxy-oleanane triterpene core skeleton were described recently to possess strong and selective in vitro and in vivo antileishmania activity. In the absence of direct chemical derivatization possibilities, a structure-based literature search was carried out to explore a structure-activity relationship. Crude alcohol extracts from several plant species of Myrsinaceae, Primulaceae, Aceraceae and Icacinaceae were evaluated for in vitro activity against Leishmania infantum intracellular amastigotes and cytotoxicity on MRC-5SV2 cells, while the saponin content was evaluated qualitatively by TLC. A clear correlation was found between the presence of close analogue 13,28-epoxy-oleanane triterpene saponins and potent and selective antileishmania activity. This was most striking in Maesa species, except for M. macrosepala. Interesting activities were also found in extracts that did not exactly match the TLC characteristics of the Maesa saponin references, as was the case for Ardisia angusta, A. amherstiana, A. caudata, A. gigantifolia, A. roseiflora, Myrsine affinis, Acer brevipes and A. laurinum var. petelotii. This study indicates that the 13,28-epoxy-oleanane triterpene moiety is essential for selective antileishmania potential and that several other plant species could still be explored for antileishmania drug discovery. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]