Reto Brun

Swiss Tropical and Public Health Institute, Bâle, Basel-City, Switzerland

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Publications (507)1899.68 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Several bicyclic compounds, 3-azabicyclo[3.2.2]nonanes, have been prepared. The new compounds were tested for their activities against one strain of the causative organism of Malaria tropica, Plasmodium falciparum K1, which is resistant against chloroquine and pyrimethamine. In addition, their cytotoxicity and their activity against the pathogen of the East African form of sleeping sickness, Trypanosoma brucei rhodesiense, were investigated. Structure-activity relationships are discussed considering data of readily prepared compounds. For the first time, a distinct in vivo activity was observed against Plasmodium berghei in a mouse model. The active compound was further investigated. Copyright © 2015 Elsevier Ltd. All rights reserved.
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    ABSTRACT: Acid-catalyzed transannular cyclization of the germacrene-type sesquiterpene lactone nobilin 1 was investigated with the aim of obtaining new anti-trypanosomal cadinane derivatives. The reaction was regiospecific in all tested reaction conditions. Compounds were fully characterized by spectroscopic and computational methods, and the anti-trypanosomal activity was evaluated and compared to nobilin (IC50 3.19±1.69μM). The tricyclic derivative 11 showed most potent in vitro activity against Trypanosoma brucei rhodesiense bloodstream forms (IC50 0.46±0.01μM). Acid-catalyzed transannular cyclization of natural cyclodecadienes is an efficient strategy to generate new natural product derivatives with anti-protozoal activity. Copyright © 2015. Published by Elsevier Ltd.
    Bioorganic & Medicinal Chemistry 02/2015; 23(7). DOI:10.1016/j.bmc.2015.02.005 · 2.95 Impact Factor
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    ABSTRACT: Human African trypanosomiasis (HAT, sleeping sickness) ranks among the most neglected tropical diseases based on limited availability of drugs that are safe and efficacious, particularly against the second stage (central nervous system [CNS]) of infection. In response to this largely unmet need for new treatments, the Consortium for Parasitic Drug Development developed novel parenteral diamidines and corresponding oral prodrugs that have shown cure of a murine model of second stage HAT. As a rationale for selection of one of these compounds for further development, the pharmacokinetics and efficacy of intramuscular (IM) active diamidine 2,5-bis(5-amidino-2-pyridyl)furan (DB829; CPD-0802) and oral prodrug2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868) were compared in the vervet monkey model of second stage HAT. Treatment was initiated 28 days post-infection of monkeys with T. b. rhodesiense KETRI 2537. Results showed that IM DB829 at 5 mg/kg/day for 5 consecutive days, 5 mg/kg/day every other day for 5 doses, or 2.5 mg/kg/day for 5 consecutive days cured all monkeys (5/5). Oral DB868 was less successful, with no cures (0/2) at 3 mg/kg/day for 10 days and cure rates of 1/4 at 10 mg/kg/day for 10 days and 20 mg/kg/day for 10 days; in total, only 2/10 monkeys were cured with DB868 dose regimens. The geometric mean plasma Cmax of IM DB829 at 5 mg/kg following the last of 5 doses was 25-fold greater than that after 10 daily oral doses of DB868 at 20 mg/kg. These data suggest that the active diamidine DB829, administered IM, should be considered for further development as a potential new treatment for second stage HAT.
    PLoS Neglected Tropical Diseases 02/2015; 9(2):e0003409. DOI:10.1371/journal.pntd.0003409 · 4.49 Impact Factor
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    ABSTRACT: In an in vitro screen of 206 extracts from South African plants, the CH2Cl2/MeOH (1:1) stem extract of Drypetes gerrardii Hutch. var gerrardii (Putranjivaceae) inhibited Plasmodium falciparum and Leishmania donovani (IC50s of 0.50 and 7.31 μg/ml, respectively). In addition, the CH2Cl2/MeOH (1:1) extract of the leaves showed activity against Trypanosoma brucei rhodesiense (IC50 of 12.1 μg/ml). The active constituents were tracked by HPLC-based activity profiling, and isolated by preparative and semi-preparative RP-HPLC chromatography. Their structures were established by HRESIMS, and 1D and 2D NMR (1H, 13C, COSY, HMBC, HSQC, and NOESY). From the stem extract, a new phenanthrenone derivative, drypetenone D (1), and a phenanthrenone heterodimer, drypetenone E (2), were isolated. Compound 1 showed potent in vitro activity against P. falciparum (IC50 of 0.9 μM) with a selectivity index (SI) of 71, as calculated from cytotoxicity data for L-6 cells. These data qualified 1 for in vivo assessment in the Plasmodium berghei mouse model, but the compound turned out to be inactive. Compound 2 also exhibited good in vitro antiplasmodial activity (IC50 of 2.0 μM) and selectivity (SI 31). From the leaf extract, the saponin putranoside A (3) was isolated and identified. Compound 3 showed weak in vitro trypanocidal activity, with an IC50 of 18.0 μM, and a SI of 4.
    Phytochemistry Letters 12/2014; 10. DOI:10.1016/j.phytol.2014.05.005 · 1.54 Impact Factor
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    ABSTRACT: A series of 14 (E)-cinnamic N-acylhydrazone derivatives, designed through molecular hybridization between the (E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(4-bromophenyl)prop-2-en-1-one and (E)-3-hydroxy-N'-((2-hydroxynaphthalen-1-yl)methylene)-7-methoxy-2-naphthohydrazide, were tested for in vitro antiparasitic activity upon axenic amastigote forms of Leishmania donovani and bloodstream forms of Trypamosoma brucei rhodesiense. The derivative (2E)-3-(4-hydroxy-3-methoxy-5-nitrophenyl)-N'-[(1E)-phenylmethylene]acrylohydrazide showed moderate antileishmanial activity (IC50 = 6.27 µM) when compared to miltefosine, the reference drug (IC50 = 0.348 µM). However, the elected compound showed an excellent selectivity index; in one case it was not cytotoxic against mammalian L-6 cells. The most active antitrypanosomal compound, the derivative (E)-N'-(3,4-dihydroxybenzylidene)cinnamohydrazide (IC50 = 1.93 µM), was cytotoxic against mammalian L-6 cells.
    Molecules 12/2014; 19(12):20374-81. DOI:10.3390/molecules191220374 · 2.10 Impact Factor
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    ABSTRACT: Some antimalarial agents in use typically bear basic side chains as ligands. Such ligands were attached to the amino substituent of a bridgehead atom of already antiprotozoal active 3-azabicyclo[3.2.2]nonanes. Structure verification was done by NMR measurements. The new compounds were tested for their antiplasmodial and antitrypanosomal activities against Plasmodium falciparum K 1 (multiresistant) and Trypanosoma brucei rhodesiense as well as for their cytotoxicity against L6 cells. Their activities are compared to those of already prepared compounds and structure-activity relationships are discussed.
    Archives of Pharmacal Research 11/2014; DOI:10.1007/s12272-014-0523-1 · 1.54 Impact Factor
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    ABSTRACT: A diverse array of 4-(1H)-quinolone derivatives bearing substituents at positions 1 and 2 were synthesized and evaluated for antiprotozoal activities against Plasmodium falciparum and Trypanosoma brucei rhodesiense, and cytotoxicity against L-6 cells in vitro. Furthermore, selectivity indices were also determined for both parasites. All compounds tested showed antimalarial activity at low micromolar concentrations, with varied degrees of selectivity against L-6 cells. Compound 5a was found to be the most active against P. falciparum, with an IC50 value of 90 nM and good selectivity for the malarial parasite compared to the L-6 cells. Compound 10a, on the other hand, showed a strong antitrypanosomal effect with an IC50 value of 1.25 µM. In this study side chain diversity was explored by varying the side chain length and substitution pattern on the aliphatic group at position-2 and a structure-antiprotozoal activity study revealed that the aromatic ring introduced at C-2 contributed significantly to the antiprotozoal activities.
    Molecules 09/2014; 19(9):14204-14220. DOI:10.3390/molecules190914204 · 2.10 Impact Factor
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    ABSTRACT: Ethnopharmacological relevance Leaf decoctions of Carica papaya have been traditionally used in some parts of Indonesia to treat and prevent malaria. Leaf extracts and fraction have been previously shown to possess antiplasmodial activity in vitro and in vivo. Materials and methods Antiplasmodial activity of extracts was confirmed and the active fractions in the extract were identified by HPLC-based activity profiling, a gradient HPLC fractionation of a single injection of the extract, followed by offline bioassay of the obtained microfractions. For preparative isolation of compounds, an alkaloidal fraction was obtained via adsorption on cationic ion exchange resin. Active compounds were purified by HPLC-MS and MPLC-ELSD. Structures were established by HR-ESI-MS and NMR spectroscopy. For compounds 5 and 7 absolute configuration was confirmed by comparison of experimental and calculated electronic circular dichroism (ECD) spectroscopy data, and by X-ray crystallography. Compounds were tested for bioactivity in vitro against four parasites (Trypanosoma brucei rhodensiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum), and in the Plasmodium berghei mouse model. Results Profiling indicated flavonoids and alkaloids in the active time windows. A total of nine compounds were isolated. Four were known flavonols manghaslin, clitorin, rutin, and nicotiflorin. Five compounds isolated from the alkaloidal fraction were piperidine alkaloids. Compounds 5 and 6 were inactive carpamic acid and methyl carpamate, while three alkaloids 7–9 showed high antiplasmodial activity and low cytotoxicity. When tested in the Plasmodium berghei mouse model, carpaine (7) did not increase survival time of animals. Conclusions The antiplasmodial activity of papaya leaves could be linked to alkaloids. Among these, carpaine was highly active and selective in vitro. The high in vitro activity could not be substantiated with the in vivo murine model. Further investigations are needed to clarify the divergence between our negative in vivo results for carpaine, and previous reports of in vivo activity with papaya leaf extracts.
    Journal of Ethnopharmacology 08/2014; DOI:10.1016/j.jep.2014.05.050 · 2.94 Impact Factor
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    ABSTRACT: This paper reports an evaluation of a melamine-nitroheterocycle, a potential lead for further development as an agent against human African trypanosomiasis (HAT). Studies on its efficacy, physicochemical and biopharmaceutical properties and potential for toxicity are described. The compound had previously been shown to possess exceptional activity against Trypanosoma brucei in in vitro assays, comparable to that of melarsoprol. Here, we demonstrate that the compound was also curative in the stringent acute mouse model T. b. rhodesiense STIB 900, when given intraperitoneally at 40 mg/kg. Nevertheless, activity was only moderate when the oral route was used and no cure was obtained when the compound was tested in a stage 2 rodent model of infection. Genotoxic profiling revealed that the compound induces DNA damage, in a mechanism apparently independent from nitro-reduction, and involving introduction of base-pair substitutions (Ames test), possibly caused by oxidative damage of the DNA (Comet test). No significant genotoxicity was observed at the chromosome level (micronucleus assay). The lack of suitable properties for oral and central nervous system uptake and the genotoxic liabilities prevent the progression of this melamine-nitroheterocycle as a drug candidate for HAT. Further modification of the compound is required to improve the pharmacokinetic properties of the molecule and to separate the trypanocidal activity from the toxic potential.
    Antimicrobial Agents and Chemotherapy 07/2014; 58(10). DOI:10.1128/AAC.01449-13 · 4.57 Impact Factor
  • Angewandte Chemie 07/2014; 126(27). DOI:10.1002/ange.201311162
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    ABSTRACT: The discovery of pyrrolopyrazines as potent antimalarial agents is presented, with the most effective compounds exhibiting EC50 values in the low nanomolar range against asexual blood stages of Plasmodium falciparum in human red blood cells, and Plasmodium berghei liver schizonts, with negligible HepG2 cytotoxicity. Their potential mode of action is uncovered by predicting macromolecular targets through avant-garde computer modeling. The consensus prediction method suggested a functional resemblance between ligand binding sites in non-homologous target proteins, linking the observed parasite elimination to IspD, an enzyme from the non-mevalonate pathway of isoprenoid biosynthesis, and multi-kinase inhibition. Further computational analysis suggested essential P. falciparum kinases as likely targets of our lead compound. The results obtained validate our methodology for ligand- and structure-based target prediction, expand the bioinformatics toolbox for proteome mining, and provide unique access to deciphering polypharmacological effects of bioactive chemical agents.
    Angewandte Chemie International Edition in English 07/2014; 53(27). DOI:10.1002/anie.201311162 · 13.45 Impact Factor
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    ABSTRACT: Fifteen novel bis-arylimidamide derivatives with various 6-membered (7a-c) and 5-membered (7d-o) heterocyclic rings replacing the terminal pyridyl rings of the lead compound DB766{(2,5-bis[2-i-propoxy-4-(2-pyridylimino)aminophenylfuran]}, were prepared and evaluated versus Trypanosoma cruzi, Leishmania amazonensis, Trypanosoma brucei rhodesiense and Plasmodium falciparum. Compound 7a with pyrimidine replacing the pyridine rings showed good activity versus T. cruzi, T. brucei rhodesiense and P. falciparum (IC50 = 200 nM, 32 nM and 8.5 nM, respectively). Three compounds (7g, 7i, 7j) with thiazole replacing the pyridine rings gave low micromolar (0.17-0.3 μM) IC50 values versus L. amazonensis, however only 7g exhibited an acceptable selectivity index (SI = 27). Compounds 7a, 7j and 7m exhibited potent activity against T. brucei rhodesiense (IC50 = 12-60 nM). Ten of the 15 compounds with pyrimidine, pyrrole, thiazole and imidazole terminal units were highly active against P. falciparum (IC50 = 9-87 nM). Both pyrimidine and pyridine terminal groups are advantageous for anti-T. cruzi activity and several different heterocyclic terminal units are effective versus P. falciparum, both findings merit further investigation.
    European Journal of Medicinal Chemistry 06/2014; 83C:167-173. DOI:10.1016/j.ejmech.2014.06.022 · 3.43 Impact Factor
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    ABSTRACT: The regioselective insertion of nitrogen in a bicyclic octanone skeleton is reported. The structure was established by a single crystal structure analysis. The antiprotozoal activities of lactames and their reduction products were determined and discussed. Graphical Abstract
    Monatshefte fuer Chemie/Chemical Monthly 06/2014; 46(1). DOI:10.1007/s00706-014-1243-4 · 1.35 Impact Factor
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    ABSTRACT: African sleeping sickness is a neglected tropical disease transmitted by tsetse flies. New and better drugs are still needed especially for its second stage, which is fatal if untreated. 28DAP010, a dipyridylbenzene analogue of DB829, is the second simple diamidine found to cure mice with central nervous system infections by a parenteral route of administration. 28DAP010 showed similar efficacy to DB829 in dose response studies in mouse models of first and second stage African sleeping sickness. The in vitro time to kill, determined by microcalorimetry and the parasite clearance time in mice, were shorter for 28DAP010 than for DB829. No cross-resistance was observed between 28DAP010 and pentamidine on the tested T. b. gambiense isolates from melarsoprol-refractory patients. 28DAP010 is the second promising preclinical candidate among the diamidines for the treatment of second stage African sleeping sickness.
    Antimicrobial Agents and Chemotherapy 05/2014; 58(8). DOI:10.1128/AAC.02309-13 · 4.45 Impact Factor
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    ABSTRACT: Human African trypanosomiasis (HAT), a neglected tropical disease, is fatal without treatment. Pentamidine, a cationic diamidine, has been used to treat first stage (hemolymphatic) HAT since the 1940s, but it is ineffective against second stage (meningoencephalitic or CNS) infection. Novel diamidines (DB75, DB820, and DB829) have shown promising efficacy in both mouse and monkey models of first stage HAT. However, only DB829 cured animals with second stage infection. In this study, we aimed to determine mechanisms underlying the differential efficacy of these diamidines against HAT by conducting a comprehensive pharmacokinetic characterization. This included the determination of metabolic stability in liver microsomes, permeability across MDCK and MDR1-MDCK cell monolayers, interaction with the efflux transporter MDR1 (P-glycoprotein 1 or P-gp), drug binding in plasma and brain, and plasma and brain concentration-time profiles after a single dose in mice. Results showed that DB829, an aza diamidine, had the highest systemic exposure and brain-to-plasma ratio, whereas pentamidine and DB75 were the lowest. None of these diamidines was a P-gp substrate and the binding of each to plasma proteins and brain differed greatly. The brain-to-plasma ratio best predicted the relative efficacy of these diamidines in mice with second stage infection. In conclusion, pharmacokinetics and CNS penetration influenced the in vivo efficacy of cationic diamidines against first and second stage HAT and should be considered when developing CNS-active antitrypanosomal diamidines.
    Antimicrobial Agents and Chemotherapy 05/2014; 58(7). DOI:10.1128/AAC.02605-14 · 4.57 Impact Factor
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    ABSTRACT: Buxus sempervirens L. (European Box, Buxaceae) has been used in ethnomedicine to treat malaria. In the course of our screening of plant extracts for antiprotozoal activity, a CH2Cl2 extract from leaves of B. sempervirens showed selective in vitro activity against Plasmodium falciparum (IC50 = 2.79 vs. 20.2 µg/mL for cytotoxicity against L6 rat cells). Separation of the extract by acid/base extraction into a basic and a neutral non-polar fraction led to a much more active and even more selective fraction with alkaloids while the fraction of non-polar neutral constituents was markedly less active than the crude extract. Thus, the activity of the crude extract could clearly be attributed to alkaloid constituents. Identification of the main triterpene-alkaloids and characterization of the complex pattern of this alkaloid fraction was performed by UHPLC/+ESI-QTOF-MS analyses. ESI-MS/MS target-guided larger scale preparative separation of the alkaloid fraction was performed by 'spiral coil-countercurrent chromatography'. From the most active subfraction, the cycloartane alkaloid O-tigloylcyclovirobuxeine-B was isolated and evaluated for antiplasmodial activity which yielded an IC50 of 0.455 µg/mL (cytotoxicity against L6 rat cells: IC50 = 9.38 µg/mL). O-tigloylcyclovirobuxeine-B is thus most significantly responsible for the high potency of the crude extract.
    Molecules 05/2014; 19(5):6184-6201. DOI:10.3390/molecules19056184 · 2.10 Impact Factor
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    ABSTRACT: In the course of our ongoing screening of plants of the family Asteraceae for antiprotozoal activity, a CH2Cl2-extract from the flowering aerial parts of Achillea ptarmica L. (sneezewort yarrow) was found to be active in vitro against Trypanosoma brucei rhodesiense (IC50 = 0.67 µg/mL) and Plasmodium falciparum (IC50 = 6.6 μg/mL). Bioassay guided fractionation led to the isolation and identification of five alkamides from the most active fractions. Pellitorine and 8,9-Z-dehyropellitorine are the main components of the extract. Beside these olefinic acid amides, four alkamides with diene-diyne structures were isolated. All alkamides were tested for antiprotozoal activity in vitro. Pellitorine was the most active compound so far within this study against P. falciparum (IC50 = 3.3 µg/mL), while 8,9-Z-dehydropellitorine was most active against T. b. rhodesiense (IC50 = 2.0 µg/mL). The activity of pure pellitorine against Plasmodium is higher than that of the crude extract and thus explains the activity of the latter. None of the isolated alkamides, however, was as active against T. b. rhodesiense as the crude extract whose antitrypanosomal activity must therfore be due to a synergistic effect of the isolated compounds or to more active yet to be identified constituents.
    Molecules 05/2014; 19(5):6428-38. DOI:10.3390/molecules19056428 · 2.10 Impact Factor
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    ABSTRACT: The causative agents of the parasitic disease human African trypanosomiasis belong to the family of trypanosomatids. These parasitic protozoa exhibit a unique thiol redox metabolism that is based on the flavoenzyme trypanothione reductase (TR). TR was identified as a potential drug target and features a large active site that allows a multitude of possible ligand orientations, which renders rational structure-based inhibitor design highly challenging. Herein we describe the synthesis, binding properties, and kinetic analysis of a new series of small-molecule inhibitors of TR. The conjunction of biological activities, mutation studies, and virtual ligand docking simulations led to the prediction of a binding mode that was confirmed by crystal structure analysis. The crystal structures revealed that the ligands bind to the hydrophobic wall of the so-called “mepacrine binding site”. The binding conformation and potency of the inhibitors varied for TR from Trypanosoma brucei and T. cruzi.
    ChemMedChem 04/2014; DOI:10.1002/cmdc.201402032 · 3.05 Impact Factor
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    ABSTRACT: In the present study, twenty one 1-aryl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline (THIQ) analogues were synthesized by based-catalyzed Pictet-Spengler reaction, and tested in vitro against P. falciparum using the [3H]hypoxanthine incorporation assay. Two compounds were found to be inactive while seventeen compounds displayed moderate antiplasmodial activity and two compounds were found to be highly active (IC50 < 0.2 μg/ml). The two highly active compounds, 1-(4-chlorophenyl)-6-hydroxyl-1,2,3,4-tetrahydroisoquinoline and 6-hydroxyspiro[1,2,3,4-tetrahydroisoquinoline-1:1’-cyclohexane], also displayed low cytotoxicity, against rat skeletal myoblast cells, with CC50 values of 257.6 and 174.2 μM respectively. These results justify further investigation of simple 1-aryl-1,2,3,4-tetrahydroisoquinolines as potential anti-malarial agents.
    RSC Advances 04/2014; 4:22856-22865. DOI:10.1039/C3RA46791K · 3.71 Impact Factor
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    ABSTRACT: SUMMARY Chagas disease (CD) is caused by the intracellular protozoan parasite Trypanosoma cruzi and affects more than 10 million people in poor areas of Latin America. There is an urgent need for alternative drugs with better safety, broader efficacy, lower costs and shorter time of administration. Thus the biological activity of viniconazole, a chloroaryl-substituted imidazole was investigated using in vitro and in vivo screening models of T. cruzi infection. Ultrastructural findings demonstrated that the most frequent cellular damage was associated with plasma membrane (blebs and shedding events), Golgi (swelling aspects) and the appearance of large numbers of vacuoles suggesting an autophagic process. Our data demonstrated that although this compound is effective against bloodstream and intracellular forms (16 and 24 μ m, respectively) in vitro, it does not present in vivo efficacy. Due to the urgent need for novel agents against T. cruzi, the screening of natural and synthetic products must be further supported with the aim of finding more selective and affordable drugs for CD.
    Parasitology 03/2014; 141(3):367-373. DOI:10.1017/S0031182013001601 · 2.36 Impact Factor

Publication Stats

10k Citations
1,899.68 Total Impact Points

Institutions

  • 1993–2015
    • Swiss Tropical and Public Health Institute
      • Department of Epidemiology and Public Health
      Bâle, Basel-City, Switzerland
    • Zhongshan University
      中山, Guangdong, China
  • 2014
    • University of Buea
      • Department of Chemistry
      Buea, South-West Province, Cameroon
  • 1999–2014
    • Universität Basel
      • • Group of Pharmaceutical Biology
      • • Swiss Tropical and Public Health Institute (Swiss TPH)
      Bâle, Basel-City, Switzerland
  • 2011
    • Shahid Beheshti University
      • Department of Phytochemistry
      Teheran, Tehrān, Iran
    • NorthShore University HealthSystem
      • Department of Radiation Medicine
      Chicago, Illinois, United States
  • 2007–2011
    • Karl-Franzens-Universität Graz
      • Institute of Pharmaceutical Sciences
      Gratz, Styria, Austria
    • Venezuelan Institute for Scientific Research
      • Laboratorio de Química Biológica
      Caracas, Distrito Federal, Venezuela
    • Centro Internacional de Entrenamiento e Investigaciones Médicas
      Santiago de Cali, Valle del Cauca, Colombia
    • University of Nebraska Medical Center
      • College of Pharmacy
      Omaha, Nebraska, United States
  • 2002–2011
    • Georgia State University
      • • Department of Chemistry
      • • Center for Biotechnology and Drug Design
      Atlanta, Georgia, United States
    • University of Botswana
      • Department of Chemistry
      Gaborone, South East District, Botswana
  • 2010
    • National Center for Genetic Engineering and Biotechnology (BIOTEC)
      Bang Kadi, Pathum Thani, Thailand
    • University of Wales
      Cardiff, Wales, United Kingdom
    • ETH Zurich
      • Institute of Pharmaceutical Sciences
      Zürich, Zurich, Switzerland
  • 2004–2010
    • University of North Carolina at Chapel Hill
      • Department of Pathology and Laboratory Medicine
      Chapel Hill, NC, United States
    • University of London
      • The School of Pharmacy
      Londinium, England, United Kingdom
    • Hacettepe University
      • Department of Biology
      Engüri, Ankara, Turkey
    • The Ohio State University
      • Division of Medicinal Chemistry and Pharmacognosy
      Columbus, OH, United States
  • 2000–2010
    • University of Wuerzburg
      • Institute of Organic Chemistry
      Würzburg, Bavaria, Germany
    • University of Peradeniya
      • Department of Chemistry
      Kandy, Central Province, Sri Lanka
  • 2009
    • Institute of Primate Research
      Nairoba, Nairobi Area, Kenya
    • Ijuí Charity Hospital
      Ijuhy, Rio Grande do Sul, Brazil
    • Hoshi University
      Edo, Tōkyō, Japan
    • Yale University
      • Department of Ecology and Evolutionary Biology
      New Haven, CT, United States
  • 2006–2009
    • London School of Hygiene and Tropical Medicine
      Londinium, England, United Kingdom
    • Spanish National Research Council
      • Instituto de Química Médica
      Madrid, Madrid, Spain
  • 2008
    • University of Milan
      Milano, Lombardy, Italy
    • Universidad de Panamá
      • Facultad de Farmacia
      Chitré, Provincia de Herrera, Panama
  • 2006–2007
    • University of Geneva
      • Department of Pharmaceutical Biochemistry
      Genève, GE, Switzerland
  • 2005–2007
    • Tohoku University
      • Graduate School of Pharmaceutical Sciences
      Miyagi, Japan
    • Julphar School of Pharmacy
      Louisiana, United States
    • Universidad de La Punta
      La Punta, San Luis, Argentina
    • University of Antwerp
      • Departement Farmaceutische Wetenschappen
      Antwerpen, VLG, Belgium
  • 2004–2007
    • University of Glasgow
      • • Institute of Infection, Immunity and Inflammation
      • • Wellcome Trust Centre for Molecular Parasitology
      Glasgow, Scotland, United Kingdom
  • 1999–2007
    • Cardiff University
      Cardiff, Wales, United Kingdom
  • 2003
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1996
    • Pace University
      • The Haskins Laboratories
      New York, New York, United States