Publications by authors named "An Matheeussen"

35 Publications

Antiplasmodial Oleanane Triterpenoids from Root Bark.

J Nat Prod 2021 Mar 5;84(3):666-675. Epub 2021 Mar 5.

Natural Products & Food Research and Analysis (NatuRA), Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.

Phytochemical investigation of the -BuOH extract of the roots of Sc. Elliot (Combretaceae) led to the isolation and identification of 10 oleanane triterpenoids (-), among which six new compounds, i.e., albidanoside A (), albidic acid A (), albidinolic acid (), albidienic acid (), albidolic acid (), and albidiolic acid (), and two triterpenoid aglycones, i.e., albidic acid B () and albidic acid C (), were isolated here for the first time from a natural source, along with two known compounds. The structures of these constituents were established by means of 1D and 2D NMR spectroscopy and ESI mass spectrometry. The isolated compounds were evaluated for their antiplasmodial and antimicrobial activity against the chloroquine-resistant strain K1, , and . Compounds -, , , and showed moderate antiplasmodial activity with IC values between 5 and 15 μM. None of the tested compounds were active against or . These findings emphasize the potential of as a source for discovery of new antiplasmodial compounds.
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http://dx.doi.org/10.1021/acs.jnatprod.0c01119DOI Listing
March 2021

2-aminobenzimidazoles for leishmaniasis: From initial hit discovery to in vivo profiling.

PLoS Negl Trop Dis 2021 Feb 22;15(2):e0009196. Epub 2021 Feb 22.

Institute of Chemistry, University of Campinas (UNICAMP), Campinas-SP, Brazil.

Leishmaniasis is a major infectious disease with hundreds of thousands of new cases and over 20,000 deaths each year. The current drugs to treat this life-threatening infection have several drawbacks such as toxicity and long treatment regimens. A library of 1.8 million compounds, from which the hits reported here are publicly available, was screened against Leishmania infantum as part of an optimization program; a compound was found with a 2-aminobenzimidazole functionality presenting moderate potency, low metabolic stability and high lipophilicity. Several rounds of synthesis were performed to incorporate chemical groups capable of reducing lipophilicity and clearance, leading to the identification of compounds that are active against different parasite strains and have improved in vitro properties. As a result of this optimization program, a group of compounds was further tested in anticipation of in vivo evaluation. In vivo tests were carried out with compounds 29 (L. infantum IC50: 4.1 μM) and 39 (L. infantum IC50: 0.5 μM) in an acute L. infantum VL mouse model, which showed problems of poor exposure and lack of efficacy, despite the good in vitro potency.
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http://dx.doi.org/10.1371/journal.pntd.0009196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932521PMC
February 2021

Chemical and Pharmacological Potential of , an Endemic Endangered Plant from Cuba.

Molecules 2021 Feb 10;26(4). Epub 2021 Feb 10.

Natural Products & Food Research and Analysis (NatuRA), Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, BE-2610 Antwerp, Belgium.

Britton (Polygonaceae) is an endemic and critically endangered plant that only grows in Camagüey, a province of Cuba. In this study, a total of 13 compounds were identified in a methanolic leaf extract, employing a dereplication of the UHPLC-HRMS data by means of feature-based molecular networking (FBMN) analysis in the Global Natural Products Social Molecular Network (GNPS), together with the interpretation of the MS/MS data and comparison with the literature. The major constituents were glucuronides and glycosides of myricetin and quercetin, as well as epichatechin-3--gallate, catechin, epicatechin and gallic acid, all of them being reported for the first time in leaves. The leaf extract was also tested against various microorganisms, and it showed a strong antifungal effect against ATCC B59630 (azole-resistant) (IC 2.1 µg/mL) and ATCC B66663 (IC 4.1 µg/mL) with no cytotoxicity (CC > 64.0 µg/mL) on MRC-5 SV2 cells, determined by the resazurin assay. Additionally, the extract strongly inhibited COX-1 and COX-2 enzyme activity using a cell-free experiment in a dose-dependent manner, being significantly more active on COX-1 (IC 4.9 µg/mL) than on COX-2 (IC 10.4 µg/mL). The constituents identified as well as the pharmacological activities measured highlight the potential of leaves, increasing the interest in the implementation of conservation strategies for this species.
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http://dx.doi.org/10.3390/molecules26040935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916587PMC
February 2021

Phenols from L. and L. and their activity against carbonic anhydrase.

Nat Prod Res 2021 Feb 3:1-7. Epub 2021 Feb 3.

Laboratory of Pharmacognosy, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece.

spp. are lipophilic fungi that are part of the normal flora of the human skin and are the etiological agents of dandruff and seborrheic dermatitis. β-Carbonic Anhydrases (CAs; EC 4.2.1.1) expressed from the pathogenic fungi are an alternative/complementary drug target. Previous work by our groups demonstrated that flavonoids and depsides can effectively inhibit β-CA (MgCA). In continuation of this study herein we report the inhibitory activity of a variety of phenols from L. and L. against β-MgCA, among them I4-II7-di-carvacrol, a new natural product. Structure elucidation of the compounds was performed by 1 D, 2 D NMR and spectrometric analyses. Xanthomicrol and rosmarinic acid were active in the (sub)micromolar range (K 0.6 and 2.2 μM, respectively 40.0 μM of the standard inhibitor acetazolamide). Finally, the compounds were not cytotoxic, but showed no activity against .
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http://dx.doi.org/10.1080/14786419.2021.1880406DOI Listing
February 2021

Bioassay-guided isolation of antiplasmodial and antimicrobial constituents from the roots of Terminalia albida.

J Ethnopharmacol 2021 Mar 25;267:113624. Epub 2020 Nov 25.

Natural Products & Food Research and Analysis (NatuRA), Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.

Ethnopharmacological Relevance: Terminalia albida (Combretaceae), widely used in Guinean traditional medicine, showed promising activity against Plasmodium falciparum and Candida albicans in previous studies. Bioassay-guided fractionation was carried out in order to isolate the compounds responsible for these activities.

Materials And Methods: Fractionation and isolation were performed by flash chromatography, followed by semi-preparative HPLC-DAD-MS. The structural elucidation of the isolated compounds was carried out by 1D and 2D NMR as well as HR-ESI-MS. Isolated compounds were evaluated against Plasmodium falciparum, Candida albicans, Staphylococcus aureus and Escherichia coli, and their cytotoxicity against MRC-5 cells was determined.

Results: Bioassay-guided fractionation of Terminalia albida root resulted in the isolation of 14 compounds (1-14), and their antimicrobial properties were evaluated. Pantolactone (1) (IC 0.60 ± 0.03 μM) demonstrated significant activity against P. falciparum. Other compounds, including 3,4,3'-tri-O-methyl-ellagic acid (3), the triterpenes arjunolic acid (5), arjungenin (6), arjunic acid (7) and arjunglucoside II (10), and the phenol glycoside calophymembranside-B (14), were less active and showed IC values in the range 5-15 μM. None of the tested compound showed antibacterial or antifungal activity.

Conclusion: These results may explain at least in part the activity of the root extract of T. albida against P. falciparum.
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http://dx.doi.org/10.1016/j.jep.2020.113624DOI Listing
March 2021

Synthesis and Structure-Activity Relationships of Imidazopyridine/Pyrimidine- and Furopyridine-Based Anti-infective Agents against Trypanosomiases.

ChemMedChem 2021 Mar 11;16(6):966-975. Epub 2020 Nov 11.

QHeteM - Laboratório de Química Heterocíclica e Medicinal, School of Pharmaceutical Sciences of Ribeirão Preto - University of São Paulo, Ribeirão Preto, São Paulo, 14040-903, Brazil.

Neglected tropical diseases remain among the most critical public health concerns in Africa and South America. The drug treatments for these diseases are limited, which invariably leads to fatal cases. Hence, there is an urgent need for new antitrypanosomal drugs. To address this issue, a large number of diverse heterocyclic compounds were prepared. Straightforward synthetic approaches tolerated pre-functionalized structures, giving rise to a structurally diverse set of analogs. We report on a set of 57 heterocyclic compounds with selective activity potential against kinetoplastid parasites. In general, 29 and 19 compounds of the total set could be defined as active against Trypanosoma cruzi and T. brucei brucei, respectively (antitrypanosomal activities <10 μM). The present work discusses the structure-activity relationships of new fused-ring scaffolds based on imidazopyridine/pyrimidine and furopyridine cores. This library of compounds shows significant potential for anti-trypanosomiases drug discovery.
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http://dx.doi.org/10.1002/cmdc.202000616DOI Listing
March 2021

Antimicrobial investigation of ethnobotanically selected guinean plant species.

J Ethnopharmacol 2020 Dec 5;263:113232. Epub 2020 Aug 5.

Natural Products & Food Research and Analysis (NatuRA), Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.

Ethnopharmacological Relevance: In Guinea, medicinal plants play an important role in the management of infectious diseases including urinary disorders, skin diseases and oral diseases. This study was carried out to collect medicinal plant species employed for the treatment of these diseases and to investigate their antimicrobial potential.

Materials And Methods: Based on an ethnobotanical investigation carried out in three Guinean regions, 74 traditional healers and 28 herbalists were interviewed and medicinal plants were collected. The most quoted plant species were evaluated for their antimicrobial activities against Staphylococcus aureus, Escherichia coli, Candida albicans, and in addition against Plasmodium falciparum.

Results: A total of 112 plant species belonging to 102 genera distributed over 42 botanical families were inventoried. Among the selected plant species, promising activities against C. albicans were obtained for the methanolic extracts of the stem bark of Terminalia albida (IC 1.2 μg/ml), the leaves of Tetracera alnifolia (IC 1.6 μg/ml) and the root bark of Swartzia madagascariensis (IC 7.8 μg/ml). The highest activity against S. aureus was obtained for the dichloromethane extracts of the leaves of Pavetta crassipes (IC 8.5 μg/ml) and the root of Swartzia madagascariensis (IC 12.8 μg/ml). Twenty one extracts, obtained from twelve plant species, were strongly active against Plasmodium falciparum, including the dichloromethane extracts of the root and stem bark of Terminalia albida root (IC 0.6 and 0.8 μg/ml), the leaves of Landolphia heudelotii (IC 0.5 μg/ml), the stem bark of Combretum paniculatum (IC 0.4 μg/ml) and the leaves of Gardenia ternifolia (IC 1.3 μg/ml).

Conclusion: The present study provides a comprehensive overview of medicinal plants employed by Guinean traditional healers for the treatment of various microbial diseases, including urinary disorders, skin diseases and oral diseases. Some of the studied plant species showed promising antimicrobial activity and could be considered as a potential source for the development of new antifungal and/or antimalarial agents.
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http://dx.doi.org/10.1016/j.jep.2020.113232DOI Listing
December 2020

Lead Optimization of Phthalazinone Phosphodiesterase Inhibitors as Novel Antitrypanosomal Compounds.

J Med Chem 2020 04 26;63(7):3485-3507. Epub 2020 Mar 26.

Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.

Human African trypanosomiasis is causing thousands of deaths every year in the rural areas of Africa. In this manuscript we describe the optimization of a family of phtalazinone derivatives. Phosphodiesterases have emerged as attractive molecular targets for a novel treatment for a variety of neglected parasitic diseases. Compound resulted in being a potent TbrPDEB1 inhibitor with interesting activity against in a phenotypic screen. Derivative was studied in an acute mouse disease model but unfortunately showed no efficacy due to low metabolic stability. We report structural modifications to achieve compounds with an improved metabolic stability while maintaining high potency against TbrPDEB1 and . Compound presented a good microsomal stability in mouse and human microsomes and provides a good starting point for future efforts.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00985DOI Listing
April 2020

Bioactive Metabolites of Marine Origin Have Unusual Effects on Model Membrane Systems.

Mar Drugs 2020 Feb 19;18(2). Epub 2020 Feb 19.

Department of Biological Sciences, University of Bergen, Thormøhlensgate 55, NO-5006 Bergen, Norway.

Marine sponges and soft corals have yielded novel compounds with antineoplastic and antimicrobial activities. Their mechanisms of action are poorly understood, and in most cases, little relevant experimental evidence is available on this topic. In the present study, we investigated whether agelasine D (compound ) and three agelasine analogs (compound -) as well as malonganenone J (compound ), affect the physical properties of a simple lipid model system, consisting of dioleoylphospahtidylcholine and dioleoylphosphatidylethanolamine. The data indicated that all the tested compounds increased stored curvature elastic stress, and therefore, tend to deform the bilayer which occurs without a reduction in the packing stress of the hexagonal phase. Furthermore, lower concentrations (1%) appear to have a more pronounced effect than higher ones (5-10%). For compounds 4 and 5, this effect is also reflected in phospholipid headgroup mobility assessed using P chemical shift anisotropy (CSA) values of the lamellar phases. Among the compounds tested, compound 4 stands out with respect to its effects on the membrane model systems, which matches its efficacy against a broad spectrum of pathogens. Future work that aims to increase the pharmacological usefulness of these compounds could benefit from taking into account the compound effects on the fluid lamellar phase at low concentrations.
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http://dx.doi.org/10.3390/md18020125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073740PMC
February 2020

Evaluation of phthalazinone phosphodiesterase inhibitors with improved activity and selectivity against Trypanosoma cruzi.

J Antimicrob Chemother 2020 04;75(4):958-967

Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.

Background: Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, needs urgent alternative therapeutic options as the treatments currently available display severe limitations, mainly related to efficacy and toxicity.

Objectives: As phosphodiesterases (PDEs) have been claimed as novel targets against T. cruzi, our aim was to evaluate the biological aspects of 12 new phthalazinone PDE inhibitors against different T. cruzi strains and parasite forms relevant for human infection.

Methods: In vitro trypanocidal activity of the inhibitors was assessed alone and in combination with benznidazole. Their effects on parasite ultrastructural and cAMP levels were determined. PDE mRNA levels from the different T. cruzi forms were measured by quantitative reverse transcription PCR.

Results: Five TcrPDEs were found to be expressed in all parasite stages. Four compounds displayed strong effects against intracellular amastigotes. Against bloodstream trypomastigotes (BTs), three were at least as potent as benznidazole. In vitro combination therapy with one of the most active inhibitors on both parasite forms (NPD-040) plus benznidazole demonstrated a quite synergistic profile (xΣ FICI = 0.58) against intracellular amastigotes but no interaction (xΣ FICI = 1.27) when BTs were assayed. BTs treated with NPD-040 presented disrupted Golgi apparatus, a swollen flagellar pocket and signs of autophagy. cAMP measurements of untreated parasites showed that amastigotes have higher ability to efflux this second messenger than BTs. NPD-001 and NPD-040 increase the intracellular cAMP content in both BTs and amastigotes, which is also released into the extracellular milieu.

Conclusions: The findings demonstrate the potential of PDE inhibitors as anti-T. cruzi drug candidates.
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http://dx.doi.org/10.1093/jac/dkz516DOI Listing
April 2020

Identification of Phenylphthalazinones as a New Class of Leishmania infantum Inhibitors.

ChemMedChem 2020 01 9;15(2):219-227. Epub 2019 Dec 9.

Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.

Leishmaniasis is a neglected parasitic disease caused by over 20 different Leishmania species. Current treatments often rely on harsh regimes of pentavalent antimonials such as sodium stibogluconate, while more recent drugs suffer other shortcomings such as low stability and rapid emergence of treatment failure, amongst others. Furthermore, the effectiveness of drugs varies depending on the infecting Leishmania species, thus there is an urgent need for new and effective anti-leishmanial drugs. Screening of an in-house compound library identified the hexahydrophthalazinone NPD-2942 as a low micromolar hit with a pIC of 5.8 against L. infantum and a pIC of 4.6 for cytotoxicity against human MRC-5 fibroblasts. To derive structure-activity relationships, we modified the cyclohexyl ring of the hexahydrophthalazinone scaffold and 1,2,3-triazoles were attempted as replacement for the pyrazole ring, amongst others. Ultimately, the 2,3-pyrazole-substituted hexahydrophthalazinone NPD-1289 was identified as the most potent analogue in this series with a pIC of 6.3, although some cytotoxicity toward MRC-5 cells (pIC =5.1) was recorded as well. Replacement of the unsubstituted 2,3-pyrazole with 1,2,3-triazoles led to compounds with lower anti-leishmanial activity. The current scaffold is a valuable new starting point for optimization toward novel anti-leishmanial drugs.
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http://dx.doi.org/10.1002/cmdc.201900538DOI Listing
January 2020

Structure-activity relationship of 4-azaindole-2-piperidine derivatives as agents against Trypanosoma cruzi.

Bioorg Med Chem Lett 2020 01 31;30(1):126779. Epub 2019 Oct 31.

Institute of Chemistry, University of Campinas (UNICAMP), Rua Josué de Castro, S/N, Cidade Universitária, Campinas, SP 13083-861, Brazil. Electronic address:

The structure-activity relationship of a 4-Azaindole-2-piperidine compound selected from GlaxoSmithKline's recently disclosed open-resource "Chagas box" and possessing moderate activity against Trypanosoma cruzi, the parasite responsible for Chagas disease, is presented. Despite considerable medicinal chemistry efforts, a suitably potent and metabolically stable compound could not be identified to advance the series into in vivo studies. This research should be of interest to those in the area of neglected diseases and in particular anti-kinetoplastid drug discovery.
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http://dx.doi.org/10.1016/j.bmcl.2019.126779DOI Listing
January 2020

The synthesis and in vitro biological evaluation of novel fluorinated tetrahydrobenzo[j]phenanthridine-7,12-diones against Mycobacterium tuberculosis.

Eur J Med Chem 2019 Nov 19;181:111549. Epub 2019 Jul 19.

Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610, Wilrijk, Belgium.

Tuberculosis (TB) still has a major impact on public health. In order to efficiently eradicate this life-threatening disease, the exploration of novel anti-TB drugs is of paramount importance. As part of our program to design new 2-azaanthraquinones with anti-mycobacterial activity, various "out-of-plane" tetrahydro- and octahydrobenzo[j]phenanthridinediones were synthesized. In this study, the scaffold of the most promising hits was further optimized in an attempt to improve the bioactivity and to decrease enzymatic degradation. The rudiment bio-evaluation of a small library of fluorinated tetrahydrobenzo[j]phenanthridine-7,12-dione derivatives indicated no significant improvement of the bio-activity against intracellular and extracellular Mycobacterium tuberculosis (Mtb). Though, the derivatives showed an acceptable toxicity against J774A.1 macrophages and early signs of genotoxicity were absent. All derivatives showed to be metabolic stabile in the presence of both phase I and phase II murine or human microsomes. Finally, the onset of reactive oxygen species within Mtb after exposure to the derivatives was measured by electron paramagnetic resonance (EPR). Results showed that the most promising fluorinated derivative is still a possible candidate for the subversive inhibition of mycothione reductase.
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http://dx.doi.org/10.1016/j.ejmech.2019.07.052DOI Listing
November 2019

Identification of Phenylpyrazolone Dimers as a New Class of Anti-Trypanosoma cruzi Agents.

ChemMedChem 2019 09 23;14(18):1662-1668. Epub 2019 Aug 23.

Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.

Chagas disease is becoming a worldwide problem; it is currently estimated that over six million people are infected. The two drugs in current use, benznidazole and nifurtimox, require long treatment regimens, show limited efficacy in the chronic phase of infection, and are known to cause adverse effects. Phenotypic screening of an in-house library led to the identification of 2,2'-methylenebis(5-(4-bromophenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one), a phenyldihydropyrazolone dimer, which shows an in vitro pIC value of 5.4 against Trypanosoma cruzi. Initial optimization was done by varying substituents of the phenyl ring, after which attempts were made to replace the phenyl ring. Finally, the linker between the dimer units was varied, ultimately leading to 2,2'-methylenebis(5-(3-bromo-4-methoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (NPD-0228) as the most potent analogue. NPD-0228 has an in vitro pIC value of 6.4 against intracellular amastigotes of T. cruzi and no apparent toxicity against the human MRC-5 cell line and murine cardiac cells.
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http://dx.doi.org/10.1002/cmdc.201900370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771560PMC
September 2019

Synthesis and antimicrobial activities of N-hydroxyagelasine analogs and revision of the structure of ageloximes.

Bioorg Med Chem 2019 02 4;27(4):620-629. Epub 2019 Jan 4.

Department of Chemistry, University of Oslo, P.O.Box 1033, Blindern, 0315 Oslo, Norway. Electronic address:

(+)-N-Hydroxyagelasine D, the enantiomer of the proposed structure of (-)-ageloxime D, as well as N-hydroxyagelasine analogs were synthesized by selective N-7 alkylation of N-[tert-butyl(dimethyl)silyloxy]-9-methyl-9H-purin-6-amine in order to install the terpenoid side chain, followed by fluoride mediated removal of the TBDMS-protecting group. N-Hydroxyagelasine D and the analog carrying a geranylgeranyl side chain displayed profound antimicrobial activities against several pathogenic bacteria and protozoa and inhibited bacterial biofilm formation. However these compounds were also toxic towards mammalian fibroblast cells (MRC-5). The spectral data of N-hydroxyagelasine D did not match those reported for ageloxime D before. Hence, a revised structure of ageloxime D was proposed. Basic hydrolysis of agelasine D gave (+)-N-[4-amino-6-(methylamino)pyrimidin-5-yl]-N-copalylformamide, a compound with spectral data in full agreement with those reported for (-)-ageloxime D.
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http://dx.doi.org/10.1016/j.bmc.2019.01.002DOI Listing
February 2019

In vitro antiprotozoal activity of some medicinal plants against sleeping sickness, Chagas disease and leishmaniasis.

Future Med Chem 2018 Dec 4. Epub 2018 Dec 4.

Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Kasr El-Ainy Street, Cairo, 11562, Egypt.

Aim: Antiprotozoal activity of 36 medicinal plants was evaluated.

Materials & Methods: In vitro potency against Trypanosoma brucei brucei, T. b. rhodesiense, T. cruzi and Leishmania infantum beside cytotoxicity on MRC-5 fibroblasts were determined.

Results & Conclusion: Maytenus parviflora showed the highest activity against T. b. brucei (IC of 0.6 μg/ml) and T. b. rhodesiense (IC of 0.5 μg/ml) with low cytotoxicity (CC of 30 μg/ml). Saussurea costus and Commiphora wightii, showed pronounced potency against T. cruzi with an IC of 3.6 and 2.5 μg/ml, respectively. Jatropha pelargonifolia and Solanum villosum exhibited pronounced activity toward L. infantum with an IC of 3.2 and 2.0 μg/ml, respectively. M. parviflora, S. costus, C. wightii, J. pelargonifolia and S. villosum showed relevant selectivity.
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http://dx.doi.org/10.4155/fmc-2018-0180DOI Listing
December 2018

Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity.

J Med Chem 2018 05 1;61(9):3870-3888. Epub 2018 May 1.

Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems , Vrije Universiteit Amsterdam , 1081 HZ Amsterdam , The Netherlands.

Several trypanosomatid cyclic nucleotide phosphodiesterases (PDEs) possess a unique, parasite-specific cavity near the ligand-binding region that is referred to as the P-pocket. One of these enzymes, Trypanosoma brucei PDE B1 (TbrPDEB1), is considered a drug target for the treatment of African sleeping sickness. Here, we elucidate the molecular determinants of inhibitor binding and reveal that the P-pocket is amenable to directed design. By iterative cycles of design, synthesis, and pharmacological evaluation and by elucidating the structures of inhibitor-bound TbrPDEB1, hPDE4B, and hPDE4D complexes, we have developed 4a,5,8,8a-tetrahydrophthalazinones as the first selective TbrPDEB1 inhibitor series. Two of these, 8 (NPD-008) and 9 (NPD-039), were potent ( K = 100 nM) TbrPDEB1 inhibitors with antitrypanosomal effects (IC = 5.5 and 6.7 μM, respectively). Treatment of parasites with 8 caused an increase in intracellular cyclic adenosine monophosphate (cAMP) levels and severe disruption of T. brucei cellular organization, chemically validating trypanosomal PDEs as therapeutic targets in trypanosomiasis.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949723PMC
May 2018

Optimization of the pharmacokinetic properties of potent anti-trypanosomal triazine derivatives.

Eur J Med Chem 2018 May 23;151:18-26. Epub 2018 Mar 23.

Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium. Electronic address:

Human African trypanosomiasis is causing thousands of deaths every year in the rural areas of sub-saharan Africa. There is a high unmet medical need since the approved drugs are poorly efficacious, show considerable toxicity and are not easy to administer. This work describes the optimization of the pharmacokinetic properties of a previously published family of triazine lead compounds. One compound (35 (UAMC-03011)) with potent anti-trypanosomal activity and no cytotoxicity was selected for further study because of its good microsomal stability and high selectivity for Trypanosoma brucei over a panel including Trypanosoma cruzi, L.eishmania infantum, and Plasmodium falciparum. In vivo pharmacokinetic parameters were determined and the compound was studied in an acute in vivo mouse disease model. One of the important learnings of this study was that the rate of trypanocidal activity is an important parameter during the lead optimization process.
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http://dx.doi.org/10.1016/j.ejmech.2018.03.048DOI Listing
May 2018

UPLC/MS MS data of testosterone metabolites in human and zebrafish liver microsomes and whole zebrafish larval microsomes.

Data Brief 2018 Feb 6;16:644-648. Epub 2017 Dec 6.

Applied Veterinary Morphology, Department of Veterinary Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.

This article represents data regarding a study published in Toxicology in vitro entitled " in vitro CYP-mediated drug metabolism in the zebrafish (embryo) using human reference compounds" (Saad et al., 2017) [1]. Data were acquired with ultra-performance liquid chromatography - accurate mass mass spectrometry (UPLC-amMS). A full spectrum scan was conducted for the testosterone (TST) metabolites from the microsomal stability assay in zebrafish and humans. The microsomal proteins were extracted from adult zebrafish male (MLM) and female (FLM) livers, whole body homogenates of 96 h post fertilization larvae (EM) and a pool of human liver microsomes from 50 donors (HLM). Data are expressed as the abundance from the extracted ion chromatogram of the metabolites.
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http://dx.doi.org/10.1016/j.dib.2017.11.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847491PMC
February 2018

In vitro CYP-mediated drug metabolism in the zebrafish (embryo) using human reference compounds.

Toxicol In Vitro 2017 Aug 12;42:329-336. Epub 2017 May 12.

Applied Veterinary Morphology, Department of Veterinary Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium. Electronic address:

The increasing use of zebrafish embryos as an alternative model for toxicological and pharmacological studies necessitates a better understanding of xenobiotic biotransformation in this species. As cytochrome P450 enzymes (CYPs) play an essential role in this process, in vitro drug metabolism of four human CYP-specific substrates, i.e. dextromethorphan (DXM), diclofenac (DIC), testosterone (TST) and midazolam (MDZ) was investigated in adult male and female zebrafish, and in zebrafish embryos and larvae up to 120hours post-fertilization. Substrate depletion and production of their respective metabolites were measured using tandem quadrupole UPLC-MS/MS. Human liver microsomes were used as positive control. Adult zebrafish produced the two major human metabolites of DIC and DXM. For DIC the metabolite ratio was similar to that in man, whereas it was different for DXM. For TST, the major human metabolite could not be detected and MDZ was not metabolized. No sex-related differences were detected, except for the higher TST depletion rate in adult females. Zebrafish embryos and larvae showed no or only low biotransformation capacity. In conclusion, in vitro CYP-mediated drug metabolism in adult zebrafish shows differences compared to man and appears to be lacking in the early zebrafish life stages. As CYP-mediated drug metabolism in zebrafish may not be predictive for the one in man, we recommend including the zebrafish in metabolic stability testing of new compounds when considering non-clinical species for human risk assessment.
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http://dx.doi.org/10.1016/j.tiv.2017.05.009DOI Listing
August 2017

In vitro screening of 2-(1H-imidazol-1-yl)-1-phenylethanol derivatives as antiprotozoal agents and docking studies on Trypanosoma cruzi CYP51.

Eur J Med Chem 2016 May 15;113:28-33. Epub 2016 Feb 15.

Department of "Chimica e Tecnologie del Farmaco", Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185 Rome, Italy.

Sterol 14α-demethylase (CYP51) is a key enzyme involved in the survival and virulence of many parasite protozoa, such as Trypanosoma and Leishmania species, thus representing a valuable drug target for the treatment of Kinetoplastid diseases. A set of azole-based compounds selected from an in-house compound library was in vitro screened against different human protozoan parasites. Several compounds showed selective activity against Trypanosoma cruzi, with compound 7 being the most active (IC50 = 40 nM). Given the structural similarity between the compounds here reported and known CYP51 inhibitors, a molecular docking study was performed to assess their binding with protozoal target and to rationalize the biological activity data.
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http://dx.doi.org/10.1016/j.ejmech.2016.02.028DOI Listing
May 2016

Novel Amino-pyrazole Ureas with Potent In Vitro and In Vivo Antileishmanial Activity.

J Med Chem 2015 Dec 4;58(24):9615-24. Epub 2015 Dec 4.

Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp , S7, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium.

Visceral leishmaniasis is a severe parasitic disease that is one of the most neglected tropical diseases. Treatment options are limited, and there is an urgent need for new therapeutic agents. Following an HTS campaign and hit optimization, a novel series of amino-pyrazole ureas has been identified with potent in vitro antileishmanial activity. Furthermore, compound 26 shows high levels of in vivo efficacy (>90%) against Leishmania infantum, thus demonstrating proof of concept for this series.
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http://dx.doi.org/10.1021/acs.jmedchem.5b01456DOI Listing
December 2015

Synthesis and in vitro evaluation of tropane halogenated-derivatives against malaria, sleeping sickness, Chagas disease and leishmaniasis.

Med Chem 2014 ;10(8):753-8

School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest- Ansermet 30, CH-1211 Geneva 4, Switzerland.

A series of twelve analogs carrying fluoro, chloro, bromo and iodo halogens on the ortho, meta and para positions of a benzoyloxytropane skeleton were synthesized by a simple acylation of 8-methyl-8-aza-bicyclo[3.2.1]octan- 3α-ol by halogenobenzoyl chlorides. The compounds were evaluated in vitro against Plasmodium falciparum (P. f.), Trypanosoma brucei brucei (T. b. b.), Trypanosoma cruzi (T. c.) and Leishmania infantum (L. i.). This study shows that the presence of a halogenated atom and its position on the aromatic ring are important for in vitro activity. Compounds 4 (IC50 = 3.6 µM), 8 (IC50 = 6.7 µM), 5 (IC50 = 8.1 µM) and 7 (IC50 = 9.5 µM) were found the most active against P. f., whereas compounds 12 (IC50 = 5.1 µM), 11 (IC50 = 5.6 µM) and 9 (IC50 = 5.8 µM) exhibited the most pronounced activity against T. b. b. This series of compounds can be considered as non-toxic to the human cell line MRC-5.
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http://dx.doi.org/10.2174/1573406410666140507095430DOI Listing
June 2015

Assessment of antimicrobial and antiprotozoal activity of the olive oil macerate samples of Hypericum perforatum and their LC-DAD-MS analyses.

Food Chem 2013 Jun 20;138(2-3):870-5. Epub 2012 Nov 20.

Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey.

Twenty-one samples of traditionally-prepared (home-made) and ready-made (commercial) St. John's Wort olive oil macerates were profiled for their in vitro antimicrobial and antiprotozoal activity. Their cytotoxic potential was evaluated on MRC-5 fibroblasts. In the antiprotozoal assays, ten of the oils inhibited Trypanosoma brucei rhodesiense (IC(50) 15.9-64.5 μg/mL), while only one oil exerted antimicrobial activity towards Staphylococcus aureus (IC(50)=88.7 μg/mL). LC-DAD-MS data revealed the presence of pseudohypericin (0.135-3.280 μg/g) and hypericin (0.277-6.634 μg/g) in all the oils, whereas chlorogenic acid (1.063 μg/g) was detected only in one oil sample. Hyperforin was detected in four (0.977-2.399 μg/g) and adhyperforin in six samples (0.005-3.165 μg/g). Hypericin and pseudohypericin were common in the active oils, whereas hyperforin, adhyperforin, and chlorogenic acid were absent in these samples. Our results indicated that if the correct plant material is used, the infused oils from Hypericum perforatum may contain active components.
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http://dx.doi.org/10.1016/j.foodchem.2012.11.053DOI Listing
June 2013

Assessment of the in vitro antiprotozoal and cytotoxic potential of 20 selected medicinal plants from the island of Soqotra.

Molecules 2012 Dec 3;17(12):14349-60. Epub 2012 Dec 3.

Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

Malaria, leishmaniasis and human African trypanosomiasis continue to be major public health problems in need of new and more effective drugs. The aim of this study was to evaluate in vitro antiprotozoal activity of twenty endemic medicinal plants collected from the island of Soqotra in the Indian Ocean. The plant materials were extracted with methanol and tested for antiplasmodial activity against erythrocytic schizonts of Plasmodium falciparum, for antileishmanial activity against intracellular amastigotes of Leishmania infantum and for antitrypanosomal activity against intracellular amastigotes of Trypanosoma cruzi and free trypomastigotes of T. brucei. To assess selectivity, cytotoxicity was determined against MRC-5 fibroblasts. Selective activity was obtained for Punica protopunica against Plasmodium (IC₅₀ 2.2 µg/mL) while Eureiandra balfourii and Hypoestes pubescens displayed activity against the three kinetoplastid parasites (IC₅₀ < 10 µg/mL). Acridocarpus socotranus showed activity against T. brucei and T. cruzi (IC₅₀ 3.5 and 8.4 µg/mL). Ballochia atrovirgata, Dendrosicycos socotrana, Dracaena cinnabari and Euphorbia socotrana displayed non-specific inhibition of the parasites related to high cytotoxicity.
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http://dx.doi.org/10.3390/molecules171214349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6268263PMC
December 2012

Study of the in vitro antiplasmodial, antileishmanial and antitrypanosomal activities of medicinal plants from Saudi Arabia.

Molecules 2012 Sep 25;17(10):11379-90. Epub 2012 Sep 25.

Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

The present study investigated the in vitro antiprotozoal activity of sixteen selected medicinal plants. Plant materials were extracted with methanol and screened in vitro against erythrocytic schizonts of Plasmodium falciparum, intracellular amastigotes of Leishmania infantum and Trypanosoma cruzi and free trypomastigotes of T. brucei. Cytotoxic activity was determined against MRC-5 cells to assess selectivity. The criterion for activity was an IC₅₀ < 10 μg/mL (<5 μg/mL for T. brucei) and a selectivity index of ≥4. Antiplasmodial activity was found in the extracts of Prosopis juliflora and Punica granatum. Antileishmanial activity against L. infantum was demonstrated in Caralluma sinaica and Periploca aphylla. Amastigotes of T. cruzi were affected by the methanol extract of Albizia lebbeck pericarp, Caralluma sinaica, Periploca aphylla and Prosopius juliflora. Activity against T. brucei was obtained in Prosopis juliflora. Cytotoxicity (MRC-5 IC₅₀ < 10 μg/mL) and hence non-specific activities were observed for Conocarpus lancifolius.
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http://dx.doi.org/10.3390/molecules171011379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6268159PMC
September 2012

In vitro antiplasmodial, antileishmanial and antitrypanosomal activities of selected medicinal plants used in the traditional Arabian Peninsular region.

BMC Complement Altern Med 2012 Apr 20;12:49. Epub 2012 Apr 20.

Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Background: Worldwide particularly in developing countries, a large proportion of the population is at risk for tropical parasitic diseases. Several medicinal plants are still used traditionally against protozoal infections in Yemen and Saudi Arabia. Thus the present study investigated the in vitro antiprotozoal activity of twenty-five plants collected from the Arabian Peninsula.

Methods: Plant materials were extracted with methanol and screened in vitro against erythrocytic schizonts of Plasmodium falciparum, intracellular amastigotes of Leishmania infantum and Trypanosoma cruzi and free trypomastigotes of T. brucei. Cytotoxic activity was determined against MRC-5 cells to assess selectivity. The criterion for activity was an IC(50) < 10 μg/ml (<5 μg/ml for T. brucei) and selectivity index of >4.

Results: Antiplasmodial activity was found in the extracts of Chrozophora oblongifolia, Ficus ingens, Lavandula dentata and Plectranthus barbatus. Amastigotes of T. cruzi were affected by Grewia erythraea, L. dentata, Tagetes minuta and Vernonia leopoldii. Activity against T. brucei was obtained in G. erythraea, L. dentata, P. barbatus and T. minuta. No relevant activity was found against L. infantum. High levels of cytotoxicity (MRC-5 IC(50) < 10 μg/ml) and hence non-specific activities were noted in Cupressus sempervirens, Kanahia laniflora and Kniphofia sumarae.

Conclusion: The results endorse that medicinal plants can be promising sources of natural products with antiprotozoal activity potential. The results support to some extent the traditional uses of some plants for the treatment of parasitic protozoal diseases.
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http://dx.doi.org/10.1186/1472-6882-12-49DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493369PMC
April 2012

Integrated dataset of screening hits against multiple neglected disease pathogens.

PLoS Negl Trop Dis 2011 Dec 20;5(12):e1412. Epub 2011 Dec 20.

Special Programme for Research and Training in Tropical Diseases, World Health Organization, Geneva, Switzerland.

New chemical entities are desperately needed that overcome the limitations of existing drugs for neglected diseases. Screening a diverse library of 10,000 drug-like compounds against 7 neglected disease pathogens resulted in an integrated dataset of 744 hits. We discuss the prioritization of these hits for each pathogen and the strong correlation observed between compounds active against more than two pathogens and mammalian cell toxicity. Our work suggests that the efficiency of early drug discovery for neglected diseases can be enhanced through a collaborative, multi-pathogen approach.
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http://dx.doi.org/10.1371/journal.pntd.0001412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243694PMC
December 2011

Reverse fosmidomycin derivatives against the antimalarial drug target IspC (Dxr).

J Med Chem 2011 Oct 13;54(19):6796-802. Epub 2011 Sep 13.

Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität, Universitätsstrasse 1, 40225 Düsseldorf, Germany.

Reverse hydroxamate-based inhibitors of IspC, a key enzyme of the non-mevalonate pathway of isoprenoid biosynthesis and a validated antimalarial target, were synthesized and biologically evaluated. The binding mode of one derivative in complex with EcIspC and a divalent metal ion was clarified by X-ray analysis. Pilot experiments have demonstrated in vivo potential.
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http://dx.doi.org/10.1021/jm200694qDOI Listing
October 2011

Structure elucidation and NMR assignments of two new triterpenoids from the stems of Paragonia pyramidata (Bignoniaceae).

Magn Reson Chem 2011 Apr 9;49(4):184-9. Epub 2011 Mar 9.

Phytochemical investigation of dichloromethane (DCM) extract from the stems of Paragonia pyramidata var. pyramidata L. Rich. (Bur.) resulted in the isolation and characterization of two new triterpenoids 3β,19β-dihydroxylup-12, 20(29)-diene-28-oic acid (1) and 3β,19β-dihydroxylup-12-en-28-oic acid (2), three known triterpenoids lupeol (3), spinosic acid A (4) and oleanolic acid (5), together with four known steroids (20R)-22E-24-ethylcholesta-4,22-dien-3-one (6), (20R)-24-ethylcholest-4-en-3-one (7), stigmasterol (8) and β-sitosterol (9). HREIMS, GC-MS and NMR experiments including HSQC, HMBC, COSY and NOESY were used for the determination of the structures and NMR spectral assignments. This is the first report about the chemical constituents for this plant.
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http://dx.doi.org/10.1002/mrc.2726DOI Listing
April 2011