1,721,206 research outputs found
Synthesis and evaluation of antiparasitic activities of new 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine derivatives
No full textA series of new 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine derivatives, prepared by two synthetic routes, were in vitro assayed against three Trypanosoma strains, Leishmania donovani, and Plasmodium falciparum K1. Seven out of 17 compounds showed moderate to very good activity against blood stage T. b. rhodesiense, with 10 and 17 exhibiting highest potency (IC 50 of 1.0 and 1.1 μM. respectively). Interestingly, the β-diketone precursors 1-3 had good antitrypanosomal activity toward the insect stage, with IC50 values of 1.0-3.4 μM. Among different compounds with moderate activity against T. cruzi, compound 17 showed the lowest IC50 value of 9.5 μM; thus, the series seemed to act selectively toward the different Trypanosoma parasites. Eight compounds were moderately active against L. donovani, with 2, 3, and 12 being the most promising ones (IC50 values of 2.3-5.2 μM), whereas compound 14 was the only derivative with good activity against P. falciparum (IC50 of 3.7 μM). © 2007 American Chemical Society
In pursuit of natural product leads: Synthesis and biological evaluation of 2-[3-hydroxy-2-[(3-hydroxypyridine-2-carbonyl)amino]phenyl]benzoxazole-4- carboxylic acid (A-33853) and its analogues: Discovery of N-(2-benzoxazol-2- ylphenyl)benzamides as novel antileishmanial chemotypes
No full textThe first synthesis and biological evaluation of antibiotic 31 (A-33853) and its analogues are reported. Initial screening for inhibition of L. donovani, T. b. rhodesiense, T. cruzi, and P. falciparum cultures followed by determination of IC50 in L. donovani and cytotoxicity on L6 cells revealed 31 to be 3-fold more active than miltefosine, a known antileishmanial drug. Compounds 14, 15, and 25 selectively inhibited L. donovani at nanomolar concentrations and showed much lower cytotoxicity. © 2008 American Chemical Society
Discovery of antiprotozoal compounds from medicinal plants
Full text linkTropical parasitic diseases such as malaria, human African trypanosomiasis, chagas disease, and leishmaniasis affect hundreds of millions of people worldwide and have devastating consequences. Current drugs available to treat these diseases have serious drawbacks. New drugs are urgently needed.
Natural products (NPs) play a dominant role in drug discovery for the treatment of human diseases. Particularly, quinine and artemisinin have their origin in nature and have inspired successful drugs for malaria treatment.
In a medium throughput screening, a total of 507 extracts from South African plants were assayed for their antiprotozoal activity against Plasmodium falciparum, Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania donovani. Extracts from Abrus precatorius L. ssp. africanus Verdc. (Fabaceae) and Drypetes gerrardii Hutch. var. gerrardii (Putranjivaceae) inhibited at least one of the parasites at a test concentration considered relevant. With the aim of identifying the compounds responsible for these activities, a HPLC-based activity profiling approach followed by dereplication was applied. Targeted isolation of promising compounds was achieved by a combination of chromatography techniques. Structure elucidation was achieved by HR-ESI-MS and NMR (1H, 13C, COSY, HMBC, HSQC, and NOESY spectroscopy). Absolute configuration was determined by comparison of electronic circular dichroism (ECD) spectra with calculated ECD data.
HPLC-based activity profiling of A. precatorius allowed the identification of abruquinones, as responsible for the trypanocidal activity of the crude extract. A total of ten abruquinones were isolated. Among these were five new compounds. Abruquinone B, I, A, D, K, and L showed remarkable inhibition (0.16 ± 0.060, 0.28 ± 0.051, 0.02 ± 0.003, 0.01 ± 0.001, 0.11 ± 0.053, and 0.02 ± 0.053, respectively) and notable selectivity, expressed as selectivity indices (SIs) which were calculated from cytotoxicity data in L-6 cells (51, 74, 1379, 668, 508, and 374, respectively). These results warrant in vivo assessment of abruquinones.
Abruquinones are promising hits due to their strong and selective in vitro inhibition of T. b. rhodesiense, their good compliance with Lipinski’s “rule-of-5” and other molecular properties, as well as their predicted low/moderate toxic potential.
Two different extracts of D. gerrardii showed antiprotozoal activity, and the active constituents were tracked and isolated by HPLC-based activity profiling. The CH2Cl2/MeOH (1:1) stems extract inhibited L. donovani and P. falciparum. The major compound, a new phenanthrenone, showed good in vitro activity (IC50 of 0.9 ? 0.3 mM) and selectivity (SI of 68) against P. falciparum. Based on these promising results, in-vivo studies were conducted. However, the compound was not able to reduce parasitemia in the P. berghei mouse model. A phenanthrenone heterodimer was also isolated and showed in vitro antiplasmodial activity (IC50 of 2.04 ? 0.15 mM and SI of 31). Furthermore, the CH2Cl2/MeOH (1:1) leaves extract displayed trypanocidal properties, and the known saponin putranoside A was isolated and tested against T. b. rhodesiense, (IC50 of 18.0 ? 3.8 mM and a SI of 4).
The phenanthrenone was the most active and selective in vitro inhibitor of P. falciparum, but showed no inhibition in vivo against P. berghei. However, the compound fulfilled Lipinski’s “rule-of-5” and other molecular properties, which indicates a potential to meet requirements of an ideal antimalarial drug such as, oral bioavailability and blood-brain barrier permeability. According to Medicines for Malaria Venture compound progressing criteria, the phenanthrenone complies with some of the features of a validated hit such as sufficient activity against P. falciparum in vitro (? 1 ?M).
Additionally, as part of a project aimed at investigating antiprotozoal European plants Chrysanthemum cynerariifolium (Trevir.) Vis. (Asteraceae), Laurus nobilis L. (Lauraceae), and Eupatorium cannabinum L. (Asteraceae) were studied. A hexane extract of C. cynerariifolium showed promising activity against P. falciparum. Pyrethrins (irregular monoterpenes) were the metabolites responsible for the antiplasmodial activities. Particularly, pyrethrin II and jasmolin II inhibited P. falciparum (IC50 4.0 ? 1.1 ?M and 5.0 ? 0.4 ?M, respectively and SI of 24 and 6, respectively) in vitro. Synthetic pyrethroids were also tested, but they did not show activity.
Finally, as a contribution to the structure activity relationship study of sesquiterpene lactones showing activity against T. b. rhodesiense, costunolide and zaluzanin D were isolated from Laurus nobilis L. (Lauraceae) and eupatoriopicrin from Eupatorium cannabinum L. (Asteraceae). Germacrolides, i.e. costunolide and eupatoriopicrin, showed a higher inhibition (IC50 of 1.3 ? 0.4 mM and 1.2 ± 0.2 mM, respectively) on the protozoon, than the guaianolide zaluzanin D (IC50 of 10.8 mM).
In brief, a total of 22 secondary metabolites were isolated from five species. Among them, seven new compounds were discovered. These compounds belong to the structural classes of isoflavonoids, phenanthrenones, and terpenes such as, sesquiterpene lactones, irregular monoterpenes and triterpenoid saponins. Most of them (15 compounds) exhibited in vitro antiprotozoal activity. The most promising compounds were the abruquinones and the phenanthrenone, which strongly and selectively inhibited T. b. rhodesiense and P. falciparum, respectively. Abruquinones and the phenanthrenone are drug-like compounds with a calculated toxic potential ranging from low to moderate.
ZUSAMMENFASSUNG
Tropische parasitäre Krankheiten wie Malaria, afrikanische Trypanosomiasis (Schlafkrankheit), Chagas-Krankheit und Leishmaniose betreffen Hunderte von Millionen Menschen weltweit und haben verheerenden Folgen. Aktuelle Medikamente, die zur Behandlung dieser Krankheiten zur Verfügung stehen, haben gravierende Nachteile. Neue Medikamente werden dringend benötigt.
Naturstoffe (NP) spielen eine dominierende Rolle in der Wirkstoffforschung für die Behandlung von menschlichen Erkrankungen. So haben Chinin und Artemisin ihren Ursprung in der Natur und führten zu erfolgreichen Medikamenten zur Malariabehandlung.
In einem mittleren Durchsatz-Screening wurden insgesamt 507 Extrakte von südafrikanischen Pflanzen auf ihre Aktivität gegen Protozoen - Plasmodium falciparum, Trypanosoma brucei rhodesiense, Trypanosoma cruzi und Leishmania donovani - getestet. Extrakte von Abrus precatorius L. ssp. africanus Verdc. (Fabaceae) und Drypetes gerrardii Hutch. var. gerrardii (Putranjivaceae) haben mindestens einen der Parasiten in einer als relevant bezeichneten Testkonzentration gehemmt.
Mit dem Ziel die für diese Aktivitäten verantwortlichen Verbindungen zu identifizieren wurde ein Ansatz bestehend aus HPLC-basiertes Aktivitäts-Profiling gefolgt von Dereplikation verwendet. Gezielte Isolierung der vielversprechenden Verbindungen erfolgte durch eine Kombination von Chromatographie-Techniken. Die Strukturaufklärung wurde durch HR-ESI-MS und NMR (1H, 13C, COSY, HMBC, HSQC, und NOESY Spektroskopie) durchgeführt. Die absolute Konfiguration wurde durch den Vergleich der elektronischen Zirkulardichroismus-(ECD)-Spektren mit berechneten ECD-Daten bestimmt.
HPLC-basiertes Aktivitäts-Profiling von A. precatorius ermöglichte die Identifizierung von Abruquinonen, als verantwortliche Substanzen für die trypanozide Aktivität des Rohextrakts. Es wurden insgesamt 10 Abruquinone isoliert, darunter fünf neue Verbindungen. Abruquinone B, I, A, D, K und L zeigten bemerkenswerte Hemmung (0.16 ± 0.060, 0.28 ± 0.051, 0.02 ± 0.003, 0.01 ± 0.001, 0.11 ± 0.053, und 0.02 ± 0.053) und beachtenswerte Selektivität, wiedergegeben als Selektivitätsindizes (SIs) die aus der Zytotoxizität in L-6 Zellen (51, 74, 1379, 668, 508, und 374) ermittelt wurden.
Wegen ihrer starken und selektiven in vitro Hemmung von T. b. rhodesiense, ihrer guten Übereinstimmung mit Lipinski’s „5er Regel“ und anderen molekularen Eigenschaften, sowie ihrem niederen/mässigen toxischen Potenzial sind Abruquinone vielversprechende Hits. Deshalb sind weitere Studien notwendig um botanische oder chemische Quellen sicherzustellen und die in-vivo Wirksamkeit dieser Verbindungen zu bestimmen.
Zwei verschiedene Extrakte von D. gerrardii zeigten Aktivität gegen Protozoen. Die aktiven Bestandteile wurden mit Hilfe vom HPLC-basiertem Aktivitäts-Profiling identifiziert und isoliert. Der CH2Cl2/MeOH (1:1) Extrakt aus den Stängeln hemmte L. donovani und P. falciparum. Die Hauptverbindung, ein neues Phenanthrenon, zeigte gute in vitro Aktivität (IC50 von 0.9 ? 0.3 mM) und Selektivität (SI von 68) gegen P. falciparum. Basierend auf diesen vielversprechenden Resultaten wurden in vivo Studien durchgeführt. Allerdings war diese Verbindung nicht in der Lage die Parasitenbelastung im P. berghei Mausmodell zu reduzieren. Es wurde ebenfalls ein Phenanthrenon-Heterodimer isoliert, der in vitro Aktivität gegen Plasmodien (IC50 von 2.04 ? 0.15 mM und SI von 31) aufwies. Ausserdem zeigte der CH2Cl2/MeOH (1:1) Blattextrakt ausgewiesene trypanozidale Eigenschaften. Aus diesem Extrakt wurde das bekannte Saponin Putranoside A isoliert und gegen T. b. rhodesiense, (IC50 von 18.0 ? 3.8 mM und SI von 4) getestet.
Das Phenanthrenon war der aktivste und selektivste in vitro Inhibitor von P. falciparum, zeigte jedoch keine Hemmung in vivo gegen P. berghei. Die Verbindung erfüllte jedoch Lipinski’s „5er Regel“ und andere molekulare Eigenschaften, wie orale Bioverfügbarkeit und Durchlässigkeit der Blut-Hirn-Schranke, was ein mögliches Potenzial aufzeigt den Anforderungen eines idealen Antimalariawirkstoffs gerecht zu werden. Nach „Medicines for Malaria Venture“-Kriterien für die weitere Entwicklung eines Wirkstoffs erfüllt das Phenanthrenon einige der Merkmale eines validierten Hits wie ausreichende in vitro Aktivität gegen P. falciparum (? 1 ?M).
Als weiterer Teil des Projekts wurde die Wirkung von europäischen Heilpflanzen Chrysanthemum cynerariifolium (Trevir.) Vis. (Asteraceae), Laurus nobilis L. (Lauraceae), und Eupatorium cannabinum L. (Asteraceae) gegen Protozoen studiert. Ein Hexan-Extrakt von C. cynerariifolium zeigte vielversprechende Aktivität gegen P. falciparum. Phyrethrine (unregelmässige Monoterpene) waren die Inhaltsstoffe verantwortlich für die antiplasmodiale Aktivität. Besonders Pyrethrin II und Jasmolin II hemmten P. falciparum (IC50 4.0 ? 1.1 ?M und 5.0 ? 0.4 ?M, und SI von 24 und 6) in vitro. Es wurden auch synthetische Pyrethroide getestet, sie zeigten aber keine Aktivität.
Schliesslich, als Beitrag zu den Struktur-Aktivitätsuntersuchungen von Sesquiterpenlactonen mit Aktivität gegen T. b. rhodesiense, wurden Costunolid und Zaluzanin D aus Laurus nobilis L. (Lauraceae) und Eupatoriopicrin aus Eupatorium cannabinum L. (Asteraceae) isoliert. Germacrolides, d.h. Costunolid und Eupatoriopicrin, zeigten eine höhere Hemmung (IC50 von 1.3 ? 0.4 mM und 1.2 ± 0.2 mM) auf Protozoen als das Guaianolid Zaluzanin D (IC50 von 10.8 mM).
Es wurden insgesamt 22 Sekundärmetaboliten aus fünf Arten isoliert, darunter sieben neue Verbindungen. Diese Substanzen gehören zu den Strukturklassen der Isoflavonoide, Phenanthrenone und Terpene einschliesslich Sesquiterpenelactone, unregelmässige Monoterpene und Triterpenoidsaponine. Die meisten von ihnen (15 Verbindungen) zeigten in vitro Aktivität gegen Protozoen. Die vielversprechendsten Verbindungen waren die Abruquinone und das Phenanthrenon, die starke und selektive Hemmung gegen T. b. rhodesiense und P. falciparum zeigten. Abruquinone und das Phenanthrenon sind drug-like Verbindungen mit einem rechnerischen toxischen Potential von gering bis mässig
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
New drugs against trypanosomatid parasites : rediscovery of fexinidazole
Full text linkNeglected tropical diseases (NTDs) are a group of communicable diseases mostly affecting people in developing countries. These diseases are responsible for a major part of the global morbidity, mortality and poverty. There is no doubt that the well-being of people in the developing world can only be improved if the NTDs are controlled. An important tool for disease control is the drug treatment. The few available drugs are unsatisfactory because of the limited efficacy, adverse effects and the high price. Chagas disease, leishmaniasis and human African trypanosomiasis belong to this group of NTDs. They are caused by infections with protozoa of the family Trypanosomatidae. For these three diseases new drugs are urgently needed.
By definition there is no commercial market for drugs against NTDs. Drug research and development (R&D) for NTDs is mainly driven by the public sector, the so-called product development partnerships (PDPs). Drug R&D is a very long (10-15 years), risky and therefore expensive process. Three different series of compounds (agrochemicals, marketed drugs and nitro-heterocyclic compounds) were tested for their antiparasitic effects, with the aim to identify new lead compounds or even clinical candidates against leishmaniasis, sleeping sickness, and Chagas disease.
Agrochemicals are used worldwide on a large scale in food production. They undergo a rigorous toxicological testing prior to launch. Over 600 compounds were screened for their antiparasitic activity. Agrochemicals are not optimized for use in mammals, yet a significant number of molecules were found with good and selective in vitro activity. Some of them showed also efficacy in the corresponding rodent model. These results indicate that agrochemicals can provide very interesting starting structures for drug research against parasitic diseases.
Drugs or drug-like compounds are an ideal starting point for antiparasitic drug discovery, because very often pharmacokinetic and toxicological data are available. A number of drugs, including antibiotics, antivirals, antifungals, and anti-psychotics were assayed for antiparasitic activity. Some of the drugs tested showed selective antiparasitic activity. These compounds can be regarded as new lead structures and should be further investigated.
Nitroheterocycles belong to a well- known class of compounds with the stigma of being mutagenic or genotoxic. Over 700 compounds, mainly nitroimidazoles, have been systematically tested for their antiparasitic activity, and their pharmacokinetics and mutagenicity was investigated. A number of effective, non-mutagenic and non- genotoxic compounds was identified. So fexinidazole was rediscovered, a drug that had been in clinical development already in the 70’s as a broad-spectrum antimicrobial drug. Fexinidazole is rapidly metabolized to fexinidazole-sulfoxide and -sulfone. The parent compound and the two principle metabolites showed in vitro trypanocidal activity against all (sensitive and resistant) tested T. brucei strains (IC50 of 0.2 - 0.9 ug / ml). Fexinidazole cured the first stage mouse model with a 4-day oral treatment of 100 mg/kg/day and the 2nd stage mouse model with a 5-day oral treatment of 200 mg/kg/day. The two metabolites are mainly responsible for the good efficacy in animal models. Both reach very high concentrations in blood and brain tissue. Fexinidazole has successfully completed preclinical development and Phase I clinical trials and is currently in a clinical phase II / III study.
With the approach of phenotypic screening of compounds that have been developed for other purposes, new leads for drug R&D against Chagas’ disease, leishmaniasis and human African trypanosomiasis were identified.
Fexinidazole is the first drug candidate in clinical Phase II / III trials since decades. It would be the first oral drug for the treatment of stage 1 and 2 of human African sleeping sickness. If fexinidazole overcomes all obstacles, this would be a major breakthrough in the fight against African sleeping sickness. With a well tolerated, orally active drug like Fexinidazole the elimination of sleeping sickness seems finally tangible
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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