Reto Brun

University of Basel, Bâle, Basel-City, Switzerland

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Publications (570)2066.89 Total impact

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    ABSTRACT: Dehydroabietylamine (1) was used as a starting material to synthesize a small library of dehydroabietyl amides by simple and facile methods, and their activities against two disease-causing trypanosomatids, namely, Leishmania donovani and Trypanosoma cruzi, were assayed. The most potent compound, 10, an amide of dehydroabietylamine and acrylic acid, was found to be highly potent against these parasites, displaying an IC50 value of 0.37 μM against L. donovani axenic amastigotes and an outstanding selectivity index of 63. Moreover, compound 10 fully inhibited the growth of intracellular amastigotes in Leishmania donovani-infected human macrophages with a low IC50 value of 0.06 μM. This compound was also highly effective against T. cruzi amastigotes residing in L6 cells with an IC50 value of 0.6 μM and high selectivity index of 58, being 3.5 times more potent than the reference compound benznidazole. The potent activity of this compound and its relatively low cytotoxicity make it attractive for further development in pursuit of better drugs for patients suffering from leishmaniasis and Chagas disease.
    No preview · Article · Feb 2016 · Journal of Natural Products
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    ABSTRACT: Derivatives of dehydroabietic acid bearing different amino acids scaffolds have potent antiprotozoal activity against Leishmania donovani and Trypanosoma cruzi, with good to high selectivity, and can therefore be regarded as good models for further development into new drugs to fight leishmaniasis and Chagas disease. Several of the tested compounds were able to kill parasites residing inside cells, with IC50 values ranging from 2.3 to 9 μM (L. donovani) and 1.4 to 5.8 μM (T. cruzi), reflecting their ability to fight these infections at the relevant stage responsible for disease. One of the compounds, bearing a 3-pyridyl-D-alanine side chain, was 1.5-fold more potent against T. cruzi amastigotes residing in L6 cells than the reference compound benznidazole.
    Full-text · Article · Dec 2015 · Medicinal Chemistry Communication
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    Full-text · Article · Nov 2015 · Planta Medica
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    ABSTRACT: ω-Aminoacyl and -alkyl derivatives of 4-(dialkylamino)bicyclo[2.2.2]octan-2-amines and of 5-(dialkylamino)-2-azabicyclo[3.2.2]nonanes were prepared and their activities were examined in vitro against the multiresistant K1 strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900). The results of the biological tests of the newly synthesized compounds were compared with the activities of already synthesized compounds and of drugs in use. Lots of the newly synthesized compounds showed promising antiprotozoal properties and selectivity, some of them exhibited even higher antiplasmodial activity than chloroquine. Structure–activity relationships were discussed. Graphical abstract
    No preview · Article · Nov 2015 · Monatshefte fuer Chemie/Chemical Monthly
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    ABSTRACT: As part of our ongoing efforts to identify natural products with activity against pathogens causing neglected tropical diseases, we are currently performing an extensive screening of natural product (NP) databases against a multitude of protozoan parasite proteins. Within this project, we screened a database of NPs from a commercial supplier, AnalytiCon Discovery (Potsdam, Germany), against Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH), a glycolytic enzyme whose inhibition deprives the parasite of energy supply. NPs acting as potential inhibitors of the mentioned enzyme were identified using a pharmacophore-based virtual screening and subsequent docking of the identified hits into the active site of interest. In a set of 700 structures chosen for the screening, 13 (1.9%) were predicted to possess significant affinity towards the enzyme and were therefore tested in an in vitro enzyme assay using recombinant TbGAPDH. Nine of these in silico hits (69%) showed significant inhibitory activity at 50 µM, of which two geranylated benzophenone derivatives proved to be particularly active with IC50 values below 10 µM. These compounds also showed moderate in vitro activity against T. brucei rhodesiense and may thus represent interesting starting points for further optimization.
    Full-text · Article · Sep 2015 · Molecules
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    ABSTRACT: A screen of a focused kinase inhibitor library against Trypanosoma brucei rhodesiense led to the identification of seven series, totaling 121 compounds, which showed >50 % inhibition at 5 μM. Screening of these hits in a T. b. brucei proliferation assay highlighted three compounds with a 1H-imidazo[4,5-b]pyrazin-2(3H)-one scaffold that showed sub-micromolar activity and excellent selectivity against the MRC5 cell line. Subsequent rounds of optimisation led to the identification of compounds that exhibited good in vitro drug metabolism and pharmacokinetics (DMPK) properties, although in general this series suffered from poor solubility. A scaffold-hopping exercise led to the identification of a 1H-pyrazolo[3,4-b]pyridine scaffold, which retained potency. A number of examples were assessed in a T. b. brucei growth assay, which could differentiate static and cidal action. Compounds from the 1H-imidazo[4,5-b]pyrazin-2(3H)-one series were found to be either static or growth-slowing and not cidal. Compounds with the 1H-pyrazolo[3,4-b]pyridine scaffold were found to be cidal and showed an unusual biphasic nature in this assay, suggesting they act by at least two mechanisms.
    Full-text · Article · Sep 2015 · ChemMedChem
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    ABSTRACT: The human and veterinary disease complex known as African trypanosomiasis continues to inflict significant global morbidity, mortality and economic hardship. Drug resistance and toxic side effects of old drugs call for novel and unorthodox strategies towards new and safe treatment options. We designed methyltriazenyl purine prodrugs to be rapidly and selectively internalized by the parasite, after which they disintegrate into a non-toxic, naturally occurring purine nucleobase, a simple triazene-stabilizing group and the active toxin: a methyldiazonium cation capable of damaging DNA by alkylation. We identified 2-(3-acetyl-3-methyltriazen-1-yl)-6-hydroxypurine ( 1: ) as a new lead compound, which showed sub-micromolar potency against Trypanosoma brucei with a selectivity index of more than 500 and demonstrated a curative effect in animal models of acute trypanosomiasis. We investigated the mechanism of action of this lead compound and showed that this molecule has significantly higher affinity for parasite over mammalian nucleobase transporters and does not show cross-resistance with current first line drugs. Once selectively accumulated inside the parasite, the prodrug releases a DNA-damaging methyldiazonium cation. We propose that ensuing futile cycles of attempted mismatch repair then lead to G2/M phase arrest and eventually cell death, as evidenced by reduced efficacy of this purine analog against a mismatch repair-deficient (msh2(-/-)) trypanosome cell line. The observed absence of genotoxicity, hepatotoxicity and cytotoxicity against mammalian cells revitalizes the idea of pursuing parasite-selective DNA alkylators as a safe chemotherapeutic option for the treatment of human and animal trypanosomiasis.
    Full-text · Article · Aug 2015 · Antimicrobial Agents and Chemotherapy
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    ABSTRACT: Four new compounds, the monomeric dioncotetralones A (6 a) and B (6 b) and the dimeric compounds jozimine A3 (7) and jozimine A4 (9), were semi-synthesized from the natural product dioncophylline A (4) and its 5'-O-demethylated derivative (5), respectively, under phenol oxidative reaction conditions. Dioncotetralones A (6 a) and B (6 b) possess an unprecedented Z-configured double bond, in contrast to the classic biaryl axis that is present in the precursor dioncophylline A (4), and an additional stereogenic center at the C2' atom was generated due to the dearomatization. The resulting steric repulsion forced the expected planar double bond into a helical distorted conformation. The homocoupling of 5 yielded compounds 7 and 9, the latter of which is the first sp(3) -sp(2) coupled product of a monomeric naphthylisoquinoline with a reduced one and, thus, contains a newly generated stereogenic center. The full stereostructures of 6 a, 6 b, 7, and 9 were successfully elucidated by the interplay of spectroscopic methods (1D/2D NMR and electronic circular-dichroism spectroscopy) in combination with quantum-chemical calculations. In addition, compounds 6 a and 7 exhibited high antiplasmodial activities with excellent half-maximal inhibitory concentration values. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    No preview · Article · Aug 2015 · Chemistry - A European Journal
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    ABSTRACT: Neglected tropical diseases cause significant morbidity and mortality and are a source of poverty in endemic countries. Only a few drugs are available to treat diseases such as leish-maniasis, Chagas' disease, human African trypanosomiasis and malaria. Since drug development is lengthy and expensive, a drug repurposing strategy offers an attractive fast-track approach to speed up the process. A set of 100 registered drugs with drug repositioning potential for neglected diseases was assembled and tested in vitro against four protozoan parasites associated with the aforementioned diseases. Several drugs and drug classes showed in vitro activity in those screening assays. The results are critically reviewed and discussed in the perspective of a follow-up drug repositioning strategy where R&D has to be addressed with limited resources.
    Full-text · Article · Aug 2015 · PLoS ONE
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    ABSTRACT: Sleeping sickness, Chagas disease, Leishmaniasis, and Malaria are infectious diseases caused by unicellular eukaryotic parasites ("protozoans"). The three first mentioned are classified as Neglected Tropical Diseases (NTDs) by the World Health Organization and together threaten more than one billion lives worldwide. Due to the lack of research interest and the high increase of resistance against the existing treatments, the search for effective and safe new therapies is urgently required. In view of the large tradition of natural products as sources against infectious diseases [1,2], the aim of the present study is to investigate the potential of legally approved and marketed herbal medicinal products (HMPs) as antiprotozoal agents. Fifty-eight extracts from 53 HMPs on the German market were tested by a Multiple-Target-Screening (MTS) against parasites of the genera Leishmania, Trypanosoma, and Plasmodium. Sixteen HMPs showed in vitro activity against at least one of the pathogens (IC50 < 10 µg/mL). Six extracts from preparations of Salvia, Valeriana, Hypericum, Silybum, Arnica, and Curcuma exhibited high activity (IC50 < 2.5 µg/mL). They were analytically characterized by UHPLC/ESI-QqTOF-MSMS and the activity-guided fractionation of the extracts with the aim to isolate and identify the active compounds is in progress.
    Full-text · Article · Aug 2015 · Molecules
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    ABSTRACT: A small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives was initially developed to optimize the antitrypanosomatid profile of the multitarget hit compound B6 (1). The whole series was evaluated against the three most important human trypanosomatid pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani), and two compounds (14 and 21) showed good activity, despite a concomitant mammalian cytotoxicity. Furthermore, a subset also inhibited the glycolytic TbGAPDH enzyme in vitro. In light of these results and aware of the antitumor properties of quinones, the anticancer potential of some selected derivatives was investigated. Intriguingly, the tested compounds displayed antitumor activity, while being less toxic against non-cancerous cells. The observed cytotoxic potency was ascribed to a multitarget mechanism of action accounting for hGAPDH inhibition and mitochondrial toxicity. Overall, the development of further derivatives, able to finely modulate multiple pathways of cancer or parasite cell metabolism, might lead to more effective treatments against these devastating diseases.
    No preview · Article · Aug 2015 · Journal of Medicinal Chemistry
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    ABSTRACT: Several new tetrahydropyridinylidene ammonium salts were prepared by selective reduction. They were characterized using UV–Vis spectroscopy, FT-IR spectroscopy, and HRMS. Their structure was established by NMR spectroscopy and a single X-ray structure analysis. One compound shows a distinct antiplasmodial potency (IC50 = 0.34 μΜ) against the multiresistant K1-strain of Plasmodium falciparum and low cytotoxicity (IC50 = 199.8 μΜ) against L-6 cells (rat skeletal myoblasts). Graphical abstract
    No preview · Article · Aug 2015 · Monatshefte fuer Chemie/Chemical Monthly
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    ABSTRACT: Based on our previous finding that certain cembranoid diterpenes possess selective toxicity against protozoan pathogens of tropical diseases such as Trypanosoma and Plasmodium, we have subjected a series of 34 cembranes isolated from soft corals living in the Vietnamese sea to an in vitro screening for anti-protozoal activity against Trypanosoma brucei rhodesiense (Tbr), T. cruzi (Tc), Leishmania donovani (Ld), and Plasmodium falciparum (Pf). Twelve of the tested compounds displayed significant activity against at least one of the parasites. Specifically, 7S,8S-epoxy-1,3,11-cembratriene-16-oic methyl ester (1), (1R,4R,2E,7E,11E)-cembra-2,7,11-trien-4-ol (2), crassumol D (12), crassumol E (13), and (1S,2E,4S,6E,8S,11S)-2,6,12(20)-cembrantriene-4,8,11-triol (16) from Lobophytum crassum, L. laevigatum, and Sinularia maxima showed the highest level of inhibitory activity against T. b. rhodesiense, with IC50 values of about 1 µM or less. Lobocrasol A (6) and lobocrasol C (8) from L. crassum and L. laevigatum exhibited particularly significant inhibitory effects on L. donovani with IC50 values < 0.2 µM. The best antiplasmodial effect was exerted by laevigatol A (10), with an IC50 value of about 3.0 µM. The cytotoxicity of the active compounds on L6 rat skeletal myoblast cell was also assessed and found to be insignificant in all cases. This is the first report on anti-protozoal activity of these compounds, and points out the potential of the soft corals in discovery of new anti-protozoal lead compounds.
    Full-text · Article · Jul 2015 · Molecules
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    Full-text · Dataset · Jun 2015
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    ABSTRACT: Diverse solvent extracts of Artemisia indica leaves originating from the West Bengal region (India) were assessed for the content of artemisinin and characteristic Artemisia polymethoxyflavonoids, namely eupatin (1), casticin (2), chrysoplenetin (3), cirsilineol (4), chrysophenol-D (5), and artemetin (6). HPLC-DAD and HPLC-MS were used to investigate the extracts macerated by solvents of increasing polarity, i.e., petroleum ether, n-hexane, dichloromethane, acetone, MeOH, or EtOH (either 96, 80, or 60 % v/v), and hot water. Artemisinin was absent in all extracts. The acetone and EtOH extracts comprised the highest levels of polymethoxyflavonoids, whereas no flavonoid could be detected in the infusion. None of the remaining extracts contained chryosphenol-D (5) or artemetin (6), while chrysoplenetin (3) was found in all extracts. The essential oil of the plant was also obtained by hydrodistillation and analysed by gas chromatography and gas chromatography-mass spectrometry simultaneously. Of the 92 compounds detected in the oil, camphor (13.0 %) and caryophyllene oxide (10.87 %) were the major components. All solvent extracts and the volatile oil showed in vitro antimalarial activity, plus a potential malaria prophylactic effect by inhibiting at least two recombinant plasmodial fatty acid biosynthesis (PfFAS-II) enzymes. Except for the infusion, all extracts were also active against other parasitic protozoa and displayed low cytotoxicity against mammalian cells. This is the first detailed study investigating both artemisinin and polymethoxyflavonoid content as well as in vitro malaria prophylactic and detailed antiprotozoal potential of A. indica extracts against a panel of protozoan parasites. This is also the first report of antiparasitic activity of the essential oil of the plant. Georg Thieme Verlag KG Stuttgart · New York.
    Full-text · Article · Jun 2015 · Planta Medica
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    Full-text · Dataset · Jun 2015
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    Full-text · Dataset · Jun 2015
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    Full-text · Dataset · Jun 2015
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    Full-text · Dataset · Jun 2015
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    ABSTRACT: Naphthoquinones (NQs) occur naturally in a large variety of plants. Several NQs are highly active against protozoans, amongst them the causative pathogens of neglected tropical diseases such as human African trypanosomiasis (sleeping sickness), Chagas disease and leishmaniasis. Prominent NQ-producing plants can be found among Juglans spp. (Juglandaceae) with juglone derivatives as known constituents. In this study, 36 highly variable extracts were prepared from different plant parts of J. regia, J. cinerea and J. nigra. For all extracts, antiprotozoal activity was determined against the protozoans Trypanosoma cruzi, T. brucei rhodesiense and Leishmania donovani. In addition, an LC-MS fingerprint was recorded for each extract. With each extract's fingerprint and the data on in vitro growth inhibitory activity against T. brucei rhodesiense a Partial Least Squares (PLS) regression model was calculated in order to obtain an indication of compounds responsible for the differences in bioactivity between the 36 extracts. By means of PLS, hydrojuglone glucoside was predicted as an active compound against T. brucei and consequently isolated and tested in vitro. In fact, the pure compound showed activity against T. brucei at a significantly lower cytotoxicity towards mammalian cells than established antiprotozoal NQs such as lapachol.
    Full-text · Article · Jun 2015 · Molecules

Publication Stats

15k Citations
2,066.89 Total Impact Points


  • 1999-2015
    • University of Basel
      • • Group of Pharmaceutical Biology
      • • Swiss Tropical and Public Health Institute (Swiss TPH)
      Bâle, Basel-City, Switzerland
  • 1980-2015
    • Swiss Tropical and Public Health Institute
      • Department of Epidemiology and Public Health
      Bâle, Basel-City, Switzerland
  • 2014
    • University of Buea
      • Department of Chemistry
      Buea, South-West Province, Cameroon
  • 2012
    • Johannes Gutenberg-Universität Mainz
      Mayence, Rheinland-Pfalz, Germany
  • 2011
    • NorthShore University HealthSystem
      • Department of Radiation Medicine
      Chicago, Illinois, United States
    • Shahid Beheshti University
      • Department of Phytochemistry
      Teheran, Tehrān, Iran
  • 2009-2011
    • Georgia State University
      • • Department of Chemistry
      • • Center for Biotechnology and Drug Design
      Atlanta, Georgia, United States
    • Hoshi University
      • Institute of Medicinal Chemistry
      Edo, Tokyo, Japan
    • National Institute for Medical Research (NIMR)
      Dār es Salām, Dar es Salaam, Tanzania
    • Spanish National Research Council
      Madrid, Madrid, Spain
    • Institute of Primate Research
      Nairoba, Nairobi Area, Kenya
    • Università degli Studi di Siena
      • Department of Medicine, Surgery and Neuroscience
      Siena, Tuscany, Italy
  • 2003-2011
    • Karl-Franzens-Universität Graz
      • • Institute of Pharmaceutical Sciences
      • • Institute of Chemistry
      Gratz, Styria, Austria
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
  • 2010
    • University of Wales
      Cardiff, Wales, United Kingdom
    • ETH Zurich
      • Institute of Pharmaceutical Sciences
      Zürich, Zurich, Switzerland
    • National Center for Genetic Engineering and Biotechnology (BIOTEC)
      Bang Kadi, Pathum Thani, Thailand
  • 2006-2009
    • London School of Hygiene and Tropical Medicine
      Londinium, England, United Kingdom
    • Lafayette College
      • Department of Biology
      Easton, Pennsylvania, United States
  • 2008
    • University of Milan
      Milano, Lombardy, Italy
    • The Ohio State University
      • Division of Medicinal Chemistry and Pharmacognosy
      Columbus, Ohio, United States
    • Universidad de Panamá
      • Facultad de Farmacia
      Chitré, Provincia de Herrera, Panama
  • 2007
    • Venezuelan Institute for Scientific Research
      • Laboratorio de Química Biológica
      Caracas, Distrito Federal, Venezuela
  • 2004-2007
    • University of London
      • The School of Pharmacy
      Londinium, England, United Kingdom
  • 2001-2007
    • University of Glasgow
      • Institute of Infection, Immunity and Inflammation
      Glasgow, Scotland, United Kingdom
  • 2005
    • Julphar School of Pharmacy
      Louisiana, United States
    • Tohoku University
      • Graduate School of Pharmaceutical Sciences
      Sendai-shi, Miyagi-ken, Japan
    • Hacettepe University
      • Department of Pharmacognosy
      Engüri, Ankara, Turkey
  • 2002
    • Cardiff University
      Cardiff, Wales, United Kingdom
  • 2000-2001
    • University of Wuerzburg
      • Institute of Organic Chemistry
      Würzburg, Bavaria, Germany
    • University of Peradeniya
      • Department of Chemistry
      Kandy, Central Province, Sri Lanka
  • 1996
    • Pace University
      • The Haskins Laboratories
      New York, New York, United States
  • 1993
    • Zhongshan University
      中山, Guangdong, China