Lieve Naesens

Universitair Psychiatrisch Centrum KU Leuven, Cortenberg, Flemish, Belgium

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Publications (153)581.99 Total impact

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    ABSTRACT: Influenza viruses cause considerable morbidity and mortality, whether in the context of annual epidemics, sporadic pandemics, or outbreaks of avian influenza virus. For hepatitis C virus (HCV), an estimated 170 million people are chronically infected worldwide. These individuals are at high risk of developing progressive liver injury or hepatocellular carcinoma. Since the efficacy of currently approved antiviral drugs is threatened by emerging viral resistance and the cost remains high, new antiviral drugs are still required. By utilizing a structure-based approach, novel substituted indole-flutimide heterocyclic derivatives (1,2-annulated indolediketopiperazines) were rationally designed, synthesized and evaluated as influenza PA endonuclease inhibitors. The compounds were also tested for their antiviral effect against HCV. All N-hydroxyimides were potent PA endonuclease inhibitors while displaying low cytotoxicity. Compound 6 proved to be the most active analogue, while the most favorable indole substitution was fluorine at position 8 (compound 18). The chloro-derivative 24 showed additional potent anti-HCV activity and exhibited remarkable selectivity (>19). In accordance with the SAR data, removal of the hydroxyl group from the imidic nitrogen (compound 26) caused a complete loss of activity against influenza PA as well as HCV.
    Medicinal Chemistry Communication 11/2015; DOI:10.1039/C5MD00439J · 2.50 Impact Factor
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    ABSTRACT: Alpha-carboxynucleoside phosphonates (α-CNPs) are novel viral DNA polymerase inhibitors that do not need metabolic conversion for enzyme inhibition. The prototype contains a cyclopentyl linker between nucleobase and α-carboxyphosphonate and preferentially (50- to 100-fold) inhibits HIV-1 RT compared with herpetic DNA polymerases. A synthesis methodology involving three steps has been developed for the synthesis of a series of novel α-CNPs, including a Rh(II)-catalyzed O-H insertion that connects the carboxyphosphonate group to a linker moiety and an attachment of a nucleobase to the other end of the linker by a Mitsunobu reaction followed by final deprotection. Replacing the cyclopentyl moiety in the prototype α-CNPs by a more flexible entity results in a selectivity shift of ∼100-fold in favor of the herpetic DNA polymerases when compared to selectivity for HIV-1 RT. The nature of the kinetic interaction of the acyclic α-CNPs against the herpetic DNA polymerases differs from the nature of the nucleobase-specific kinetic interaction of the cyclopentyl α-CNPs against HIV RT.
    Journal of Medicinal Chemistry 10/2015; 58(20). DOI:10.1021/acs.jmedchem.5b01180 · 5.45 Impact Factor
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    ABSTRACT: The influenza virus PA endonuclease is an attractive target for the development of novel anti-influenza virus therapeutics, which are urgently needed because of the emergence of drug-resistant viral strains. Reported PA inhibitors are assumed to chelate the divalent metal ion(s) (Mg2+ or Mn2+) in the enzyme’s catalytic site, which is located in the N-terminal part of PA (PA-Nter). In the present work, a series of salicylaldehyde thiosemicarbazone derivatives have been synthesized and evaluated for their ability to inhibit the PA-Nter catalytic activity. Compounds 1–6 have been evaluated against influenza virus, both in enzymatic assays with influenza virus PA-Nter and in virus yield assays in MDCK cells. In order to establish a structure–activity relationship, the hydrazone analogue of the most active thiosemicarbazone has also been evaluated. Since chelation may represent a mode of action of such class of molecules, we studied the interaction of two of them, one with and one without biological activity versus the PA enzyme, towards Mg2+, the ion that is probably involved in the endonuclease activity of the heterotrimeric influenza polymerase complex. The crystal structure of the magnesium complex of the o-vanillin thiosemicarbazone ligand 1 is also described. Moreover, docking studies of PA endonuclease with compounds 1 and 2 were performed, to further analyse the possible mechanism of action of this class of inhibitors.
    JBIC Journal of Biological Inorganic Chemistry 09/2015; DOI:10.1007/s00775-015-1292-0 · 2.54 Impact Factor
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    ABSTRACT: In order to promote attachment of the ristocetin aglycone molecule to the surface of the influenza virus, the aglycone was derivatized with a hemagglutinin ligand sialic acid moiety using a click reaction. The sialoristocetin derivative exhibited somewhat lower anti-influenza virus activity than ristocetin and aglycoristocetin.
    Chemical Papers 08/2015; 69(8). DOI:10.1515/chempap-2015-0116 · 1.47 Impact Factor
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    ABSTRACT: Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the human and Plasmodium falciparum 6-oxopurine phosphoribosyltransferases (PRTs), key enzymes of the purine salvage pathway. Chemical modifications, based on the crystal structures of several inhibitors in complex with the human PRTase, led to the design of a new class of inhibitors-the aza-ANPs. Because of the negative charges of the phosphonic acid moiety, their ability to cross cell membranes is, however, limited. Thus, phosphoramidate prodrugs of the aza-ANPs were prepared to improve permeability. These prodrugs arrest parasitemia with IC50 values in the micromolar range against Plasmodium falciparum-infected erythrocyte cultures (both chloroquine-sensitive and chloroquine-resistant Pf strains). The prodrugs exhibit low cytotoxicity in several human cell lines. Thus, they fulfill two essential criteria to qualify them as promising antimalarial drug leads. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Bioorganic & medicinal chemistry 07/2015; 23(17). DOI:10.1016/j.bmc.2015.07.038 · 2.79 Impact Factor
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    ABSTRACT: A series of alkylamino derivatives of N-benzylpyrazine-2-carboxamide was designed, synthesized and assayed in vitro for their antimycobacterial, antibacterial, antifungal as well as antiviral activities. Final structures were prepared from 6-chloro (1), 5-chloro (2) or 3-chloro (3) derivatives of N-benzylpyrazine-2-carboxamide by nucleophilic substitution of chlorine with n-alkylamines in the range from butylamine to octylamine (labelled a-e). Series 1a-e and 2a-e exerted higher activity against Mycobacterium tuberculosis H37Rv compared to the corresponding pattern compounds and the reference compound pyrazinamide. The most active derivatives reached an activity MIC = 4.6-10 μM (M. tbc H37Rv). More importantly, activity was also observed against other tested mycobacterial strains (including drug-resistant strains). Substitution of 3-chlorine was disadvantageous and led to completely inactive compounds 3a-e. Some compounds showed activity against Gram-positive bacterial strains (including MRSA) or influenza virus, but no antifungal activity was observed. This journal is
    Medicinal Chemistry Communication 07/2015; 6(7):1311-1317. DOI:10.1039/C5MD00178A · 2.50 Impact Factor
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    ABSTRACT: The influenza virus RNA-dependent RNA polymerase complex (RdRp), a heterotrimeric protein complex responsible for viral RNA transcription and replication, represents a primary target for antiviral drug development. One particularly attractive approach is interference with the endonucleolytic “cap-snatching” reaction by the RdRp subunit PA, more precisely by inhibiting its metal-dependent catalytic activity which resides in the N-terminal part of PA (PA-Nter). Almost all PA inhibitors (PAIs) thus far discovered bear pharmacophoric fragments with chelating motifs able to bind the bivalent metal ions in the catalytic core of PA-Nter. More recently, the availability of crystallographic structures of PA-Nter has enabled rational design of original PAIs with improved binding properties and antiviral potency. We here present a coupled pharmacophore/docking virtual screening approach that allowed us to identify PAIs with interesting inhibitory activity in a PA-Nter enzymatic assay. Moreover, antiviral activity in the low micromolar range was observed in cell-based influenza virus assays.
    ACS Medicinal Chemistry Letters 06/2015; 6(8):866-871. DOI:10.1021/acsmedchemlett.5b00109 · 3.12 Impact Factor
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    ABSTRACT: Acylhydrazones are very versatile ligands and their coordination properties can be easily tuned, giving rise to metal complexes with different nuclearities. In the last few years, we have been looking for new pharmacophores able to coordinate simultaneously two metal ions, because many enzymes have two metal ions in the active site and their coordination can be a successful strategy to inhibit the activity of the metalloenzyme. As a part of this ongoing research, we synthesized the acylhydrazone H2L and its complexes with Mg(II), Mn(II), Co(II), Ni(II), Cu(II) and Zn(II). Their characterization, both in solution - also by means of potentiometric studies - and in the solid state, evidenced the ability of the o-vanillin hydrazone scaffold to give rise to different types of metal complexes, depending on the metal and the reaction conditions. Furthermore, we evaluated both the free ligand and its metal complexes in in vitro studies against a panel of diverse DNA- and RNA-viruses. In particular, the Mg(II), Mn(II), Ni(II) and Zn(II) complexes had EC50 values in the low micromolar range, with a pronounced activity against vaccinia virus. Copyright © 2015 Elsevier Inc. All rights reserved.
    Journal of inorganic biochemistry 05/2015; 150. DOI:10.1016/j.jinorgbio.2015.05.013 · 3.44 Impact Factor
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    ABSTRACT: A series of N-alkyl-3-(alkylamino)pyrazine-2-carboxamides and their N-alkyl-3-chloropyrazine-2-carboxamide precursors were prepared. All compounds were characterized by analytical methods and tested for antimicrobial and antiviral activity. The antimycobacterial MIC values against Mycobacterium tuberculosis H37Rv of the most effective compounds, 3-(hexylamino)-, 3-(heptylamino)- and 3-(octylamino)-N-methyl-pyrazine-2-carboxamides 14‒16, was 25 μg/mL. The compounds inhibited photosystem 2 photosynthetic electron transport (PET) in spinach chloroplasts. This activity was strongly connected with the lipophilicity of the compounds. For effective PET inhibition longer alkyl chains in the 3-(alkylamino) substituent in the N-alkyl-3-(alkylamino)pyrazine-2-carboxamide molecule were more favourable than two shorter alkyl chains.
    Molecules 05/2015; 20(5):8687-711. DOI:10.3390/molecules20058687 · 2.42 Impact Factor
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    ABSTRACT: Human tuberculosis is a chronic infectious disease affecting millions of lives. Because of emerging resistance to current medications, new therapeutic drugs are needed. One potential new target is hypoxanthine-guanine phosphoribosyltransferase ( Mt HGPRT), a key enzyme of the purine salvage pathway. Here, newly synthesized acyclic nucleoside phosphonates (ANPs) have been shown to be competitive inhibitors of Mt HGPRT with K<sub>i</sub> values as low as 0.69 μM. Prodrugs of these compounds arrest the growth of a virulent strain of M. tuberculosis with MIC<sub>50</sub> values as low as 4.5 μM and possess low cytotoxicity in mammalian cells (CC<sub>50</sub> values as high as > 300 μM). In addition, the first crystal structures of MtHGPRT (2.03 - 2.76 Å resolution) have been determined, three of these in complex with novel ANPs and one with GMP and pyrophosphate. These data provide a solid foundation for the further development of ANPs as selective inhibitors of Mt HGPRT and as antituberculosis agents.</sub><sub>.
    Journal of Medicinal Chemistry 04/2015; 58(11). DOI:10.1021/acs.jmedchem.5b00611 · 5.45 Impact Factor
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    ABSTRACT: Two new polycyclic scaffolds were synthesized and evaluated as anti-influenza A compounds. The 5-azapentacyclo[,10).0(3,7).0(9,11)]dodecane derivatives were only active against the wild-type M2 channel in the low-micromolar range. However, some of the 14-azaheptacyclo[,5).0(3,11).0(4,9).0(6,17).0(12,16)]heptadecane derivatives were dual inhibitors of the wild-type and the V27A mutant M2 channels. The antiviral activity of these molecules was confirmed by cell culture assays. Their binding mode was analysed through molecular dynamics simulations, which showed the existence of distinct binding modes in the wild type M2 channel and its V27A variant. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    European Journal of Medicinal Chemistry 04/2015; 96. DOI:10.1016/j.ejmech.2015.04.030 · 3.45 Impact Factor
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    ABSTRACT: Two alternative syntheses of 2-oxaadamantan-5-amine, a novel analog of the clinically approved drug amantadine, are reported. The compound has been tested as an anti-influenza A virus agent and as an NMDA receptor antagonist. While the compound was not antivirally active, it displayed moderate activity as an NMDA receptor antagonist.
    Tetrahedron Letters 03/2015; 56(10). DOI:10.1016/j.tetlet.2015.01.160 · 2.38 Impact Factor
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    ABSTRACT: Polymerases have a structurally highly conserved negatively charged amino acid motif that is strictly required for Mg(2+) cation-dependent catalytic incorporation of (d)NTP nucleotides into nucleic acids. Based on these characteristics, a nucleoside monophosphonate scaffold, α-carboxy nucleoside phosphonate (α-CNP), was designed that is recognized by a variety of polymerases. Kinetic, biochemical, and crystallographic studies with HIV-1 reverse transcriptase revealed that α-CNPs mimic the dNTP binding through a carboxylate oxygen, two phosphonate oxygens, and base-pairing with the template. In particular, the carboxyl oxygen of the α-CNP acts as the potential equivalent of the α-phosphate oxygen of dNTPs and two oxygens of the phosphonate group of the α-CNP chelate Mg(2+), mimicking the chelation by the β- and γ-phosphate oxygens of dNTPs. α-CNPs (i) do not require metabolic activation (phosphorylation), (ii) bind directly to the substrate-binding site, (iii) chelate one of the two active site Mg(2+) ions, and (iv) reversibly inhibit the polymerase catalytic activity without being incorporated into nucleic acids. In addition, α-CNPs were also found to selectively interact with regulatory (i.e., allosteric) Mg(2+)-dNTP-binding sites of nucleos(t)ide-metabolizing enzymes susceptible to metabolic regulation. α-CNPs represent an entirely novel and broad technological platform for the development of specific substrate active- or regulatory-site inhibitors with therapeutic potential.
    Proceedings of the National Academy of Sciences 03/2015; 112(11). DOI:10.1073/pnas.1420233112 · 9.67 Impact Factor
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    ABSTRACT: Despite the close structural similarity between the heptapeptide cores of the glycopeptide antibiotics teicoplanin and ristocetin, synthetically modified derivatives of their aglycons show significantly different antibacterial and antiviral properties. The teicoplanin aglycon derivatives with one exception proved to be potent antibacterials but they did not exhibit anti-influenza virus activity. In contrast, the aglycoristocetin derivatives generally showed high anti-influenza virus activity and possessed moderate antibacterial activity. A systematic structure-activity relationship study has been carried out on ristocetin and teicoplanin aglycon derivatives, to explore which structural differences are responsible for these markedly different biological activities. According to electronic circular dichroism and in silico conformational studies, it was found that the differences in anti-influenza virus activity are mainly determined by the conformation of the heptapeptide core of the antibiotics controlled by the presence or absence of chloro substituents. Knowledge of the bioactive conformation will help to design new analogs with improved anti-influenza virus activity. For the teicoplanin derivatives, it was shown that derivatization to improve the antiviral efficacy was accompanied by a significant decrease in antibacterial activity. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    European Journal of Medicinal Chemistry 02/2015; 94C:73-86. DOI:10.1016/j.ejmech.2015.02.028 · 3.45 Impact Factor
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    ABSTRACT: This work presents synthesis and antimicrobial evaluation of nineteen 6-alkylamino-N-phenylpyrazine-2-carboxamides. Antimycobacterial activity was determined against Mycobacterium tuberculosis H37Rv, M. kansasii and two strains of M. avium. Generally, the antimycobacterial activity increased with prolongation of simple alkyl chain and culminated in compounds with heptylamino substitution (3e, 4e) with MIC = 5-10 μM against M. tuberculosis H3Rv. On the contrary, derivatives with modified alkyl chain (containing e.g. terminal methoxy or hydroxy group) as well as phenylalkylamino derivatives were mainly inactive. The most active compounds (with hexyl to octylamino substitution) were evaluated for their in vitro activity against drug-resistant strains of M. tuberculosis and possessed activity comparable to that of the reference drug isoniazid. None of the tested compounds were active against M. avium. Some derivatives exhibited activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (best MIC = 7.8 μM), while Gram negative strains as well as tested fungal strains were completely unsusceptible. Active compounds were tested for in vitro toxicity on various cell lines and in most cases were non-toxic up to 100 μM. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Chemical Biology &amp Drug Design 02/2015; 86(4). DOI:10.1111/cbdd.12536 · 2.49 Impact Factor
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    ABSTRACT: We have developed a series of N2-(1-(substituted-aryl)piperidin-4-yl)-N6-mesityl-9H-purine-2,6-diamine derivatives as potent antiviral agents. Preliminary biological evaluation indicated that nearly half of them possessed remarkable HIV inhibitory potencies in cellular assays. In particular, FZJ13 appeared to be the most notable one, which displayed anti-HIV-1 activity compared to 3TC. Moreover, an unexpected finding was that FZJ05 displayed significant potency against influenza A/H1N1 (strain A/PR/8/34) in MDCK cells with EC50 values much lower than those of ribavirin, amantadine and rimantadine. The results suggest that these novel purine derivatives have the potential to be further developed as new therapeutic agents against HIV-1 or influenza virus.This article is protected by copyright. All rights reserved.
    Chemical Biology &amp Drug Design 01/2015; 86(4). DOI:10.1111/cbdd.12520 · 2.49 Impact Factor
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    ABSTRACT: Hypoxanthine-guanine-[xanthine] phosphoribosyltransferase (HG[X]PRT) is considered an important target for anti-malarial chemotherapy as it is the only pathway for the synthesis of the purine nucleoside monophosphates required for DNA/RNA production. Thus, inhibition of this enzyme should result in cessation of replication. The aza-acyclic nucleoside phosphonates (aza-ANPs) are good inhibitors of Plasmodium falciparum HGXPRT (Pf HGXPRT) with Ki values as low as 0.08 μM and 0.01 μM for Plasmodium vivax HGPRT (PvHGPRT). Prodrugs of these aza-ANPs exhibit anti-malarial activity against Pf lines with IC 50 values (0.8-2.7 μM) and have low cytotoxicity against human cells. Crystal structures of six of these compounds in complex with human HGPRT have been determined. These suggest that the different affinities of these aza-ANPs could be due to the flexibility of the loops surrounding the active site as well as the flexibility of the inhibitors allowing them to adapt to fit into three binding pockets of the enzyme(s).
    Journal of Medicinal Chemistry 12/2014; 58(2). DOI:10.1021/jm501416t · 5.45 Impact Factor
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    ABSTRACT: The influenza virus PA endonuclease, which cleaves capped cellular pre-mRNAs to prime viral mRNA synthesis, is a promising target for novel anti-influenza virus therapeutics. The catalytic center of this enzyme resides in the N-terminal part of PA (PA-Nter) and contains two (or possibly one or three) Mg(2+) or Mn(2+) ions which are critical for its catalytic function. There is large interest in PA inhibitors that are optimally designed to occupy the active site and chelate the metal ions. We here focused on a series of β-diketo acid (DKA) and DKA-bioisosteric compounds containing different scaffolds, and determined their structure-activity relationship in an enzymatic assay with PA-Nter, to build a 3D pharmacophore model. Besides, we developed a molecular beacon (MB)-based PA-Nter assay which enables to compare the inhibition versus Mn(2+) or Mg(2+), the latter probably being the biologically relevant cofactor. This real-time MB assay allows to measure the enzyme kinetics of PA-Nter or perform high-throughput screening. Several DKA derivatives were found to cause strong inhibition of PA-Nter with IC50 values comparable to that of the prototype L-742,001 (i.e. below 2 μM). Among the different compounds tested, L-742,001 appeared unique in having equal activity against either Mg(2+) or Mn(2+). Three compounds ( 10: , with a pyrrole scaffold, and 40: and 41: , with an indole scaffold) exhibited moderate antiviral activity in cell culture (EC99 values: 64-95 μM), and were proven to affect viral RNA synthesis. Our approach to integrate complementary enzymatic, cellular and mechanistic assays should guide ongoing development of improved influenza virus PA inhibitors. The American Society for Pharmacology and Experimental Therapeutics.
    Molecular pharmacology 12/2014; 87(2). DOI:10.1124/mol.114.095588 · 4.13 Impact Factor
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    ABSTRACT: We report on the synthesis of novel conformationally locked nucleoside and nucleotide derivatives, which are structurally closely related to clinically used antivirals such as didanosine and abacavir. As a suitable conformationally rigid substitute of the sugar/pseudosugar ring allowing a permanent stabilization of the nucleoside in North conformation we employed bicyclo[2.2.1]heptane (norbornane) substituted in the bridgehead position with a hydroxymethyl group and in the C-3 position with a nucleobase. Prepared nucleoside derivatives were also converted into appropriate phosphoramidate prodrugs (ProTides) in order to increase delivery of the compounds in the cells. All target compounds were evaluated in a broad antiviral and cytostatic assay panel.
    Bioorganic & Medicinal Chemistry 11/2014; 23(1). DOI:10.1016/j.bmc.2014.11.011 · 2.79 Impact Factor
  • N. Pala · R. Dallocchio · A. Dessì · Cadoni · M. Carcelli · A.Stevaert · M. Sechi · L. Naesens ·

    2nd Innovative Approaches for Identification of Antiviral Agents Summer School, Cagliari, Sardinia, Italy,; 10/2014

Publication Stats

3k Citations
581.99 Total Impact Points


  • 2014-2015
    • Universitair Psychiatrisch Centrum KU Leuven
      Cortenberg, Flemish, Belgium
  • 1990-2014
    • University of Leuven
      • • Department of Microbiology and Immunology
      • • Department of Biomedical Kinesiology
      Louvain, Flemish, Belgium
  • 2012
    • University of Debrecen
      • Department of Pharmaceutical Chemistry
      Debreczyn, Hajdú-Bihar, Hungary
  • 2010
    • Istanbul University
      • Department of Pharmaceutical Chemistry
      İstanbul, Istanbul, Turkey
    • Universidad de Jaén
      • Department of Organic and Inorganic Chemistry
      Jaén, Andalusia, Spain
  • 2007
    • Friedrich Schiller University Jena
      • Institute of Virology and Antiviral Therapy
      Jena, Thuringia, Germany
    • Academy of Sciences of the Czech Republic
      • Výzkumné centrum Gilead Sciences a ÚOCHB
      Praha, Hlavni mesto Praha, Czech Republic
  • 2006
    • Ghent University
      • Faculty of Pharmaceutical Sciences
      Gand, Flanders, Belgium
  • 1996
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States