CISTIM Leuven Vzw

Leuven, Belgium

CISTIM Leuven Vzw

Leuven, Belgium
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Saudi M.,Rega Institute for Medical Research | Zmurko J.,Rega Institute for Medical Research | Kaptein S.,Rega Institute for Medical Research | Rozenski J.,Rega Institute for Medical Research | And 5 more authors.
European journal of medicinal chemistry | Year: 2016

High-throughput screening of a subset of the CD3 chemical library (Centre for Drug Design and Discovery; KU Leuven) provided us with a lead compound 1, displaying low micromolar potency against dengue virus and yellow fever virus. Within a project aimed at discovering new inhibitors of flaviviruses, substitution of its central imidazole ring led to synthesis of variably substituted pyrazine dicarboxylamides and phthalic diamides, which were evaluated in cell-based assays for cytotoxicity and antiviral activity against the dengue virus (DENV) and yellow fever virus (YFV). Fourteen compounds inhibited DENV replication (EC50 ranging between 0.5 and 3.4 μM), with compounds 6b and 6d being the most potent inhibitors (EC50 0.5 μM) with selectivity indices (SI) > 235. Compound 7a likewise exhibited anti-DENV activity with an EC50 of 0.5 μM and an SI of >235. In addition, good antiviral activity of seven compounds in the series was also noted against the YFV with EC50 values ranging between 0.4 and 3.3 μM, with compound 6n being the most potent for this series with an EC50 0.4 μM and a selectivity index of >34. Finally, reversal of one of the central amide bonds as in series 13 proved deleterious to the inhibitory activity. Copyright © 2016 The Authors. Published by Elsevier Masson SAS.. All rights reserved.


Abu El Asrar R.,Rega Institute for Medical Research | Margamuljana L.,Rega Institute for Medical Research | Klaassen H.,CISTIM Leuven vzw | Nijs M.,CISTIM Leuven vzw | And 9 more authors.
Biochemical Pharmacology | Year: 2017

Tuberculosis (TB), mainly caused by Mycobacterium tuberculosis (Mtb), is an infection that is responsible for roughly 1.5 million deaths per year. The situation is further complicated by the wide-spread resistance to the existing first- and second-line drugs. As a result of this, it is urgent to develop new drugs to combat the resistant bacteria as well as have lower side effects, which can promote adherence to the treatment regimens. Targeting the de novo synthesis of thymidylate (dTMP) is an important pathway to develop drugs for TB. Although Mtb carries genes for two families of thymidylate synthases (TS), ThyA and ThyX, only ThyX is essential for its normal growth. Both enzymes catalyze the conversion of uridylate (dUMP) to dTMP but employ a different catalytic approach and have different structures. Also, ThyA is the only TS found in humans. This is the rationale for identifying selective inhibitors against ThyX. We exploited the NADPH oxidation to NADP+ step, catalyzed by ThyX, to develop a spectrophotometric biochemical assay. Success of the assay was demonstrated by its effectiveness (average Z'=0.77) and identification of selective ThyX inhibitors. The most potent compound is a tight-binding inhibitor with an IC50 of 710nM. Its mechanism of inhibition is analyzed in relation to the latest findings of ThyX mechanism and substrate and cofactor binding order. © 2017.


Liebens V.,Catholic University of Leuven | Defraine V.,Catholic University of Leuven | Knapen W.,Catholic University of Leuven | Swings T.,Catholic University of Leuven | And 9 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2017

Antibiotics typically fail to completely eradicate a bacterial population, leaving a small fraction of transiently antibiotic-tolerant persister cells intact. Persisters are therefore seen to be a major cause of treatment failure and greatly contribute to the recalcitrant nature of chronic infections. The current study focused on Pseudomonas aeruginosa, a Gram-negative pathogen belonging to the notorious ESKAPE group of pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) and, due to increasing resistance against most conventional antibiotics, posing a serious threat to human health. Greatly contributing to the difficult treatment of P. aeruginosa infections is the presence of persister cells, and elimination of these cells would therefore significantly improve patient outcomes. In this study, a small-molecule library was screened for compounds that, in combination with the fluoroquinolone antibiotic ofloxacin, reduced the number of P. aeruginosa persisters compared to the number achieved with treatment with the antibiotic alone. Based on the early structure-activity relationship, 1-((2,4-dichlorophenethyl)amino)-3-phenoxypropan-2-ol (SPI009) was selected for further characterization. Combination of SPI009 with mechanistically distinct classes of antibiotics reduced the number of persisters up to 106-fold in both lab strains and clinical isolates of P. aeruginosa. Further characterization of the compound revealed a direct and efficient killing of persister cells. SPI009 caused no erythrocyte damage and demonstrated minor cytotoxicity. In conclusion, we identified a novel antipersister compound active against P. aeruginosa with promising applications for the design of novel, case-specific combination therapies in the fight against chronic infections. Copyright © 2017 American Society for Microbiology. All Rights Reserved.


Bardiot D.,Cistim Leuven Vzw | Thevissen K.,Catholic University of Leuven | De Brucker K.,Catholic University of Leuven | Peeters A.,Catholic University of Leuven | And 8 more authors.
Journal of Medicinal Chemistry | Year: 2015

From a fungicidal screen, we identified 2-(2-oxo-morpholin-3-yl)-acetamide derivatives as fungicidal agents against Candida species, additionally characterized by antifungal activity against Aspergillus species. However, development of this series was hampered by low plasmatic stability. Introduction of a gem-dimethyl on the 6-position of the morpholin-2-one core led to considerable improvement in plasmatic stability while maintaining in vitro antifungal activity. Further optimization of the series resulted in the discovery of N-(biphenyl-3-ylmethyl)-2-(4-ethyl-6,6-dimethyl-2-oxomorpholin-3-yl)acetamide (87), which, in addition to fungicidal activity against Candida species, shows promising and broad antifungal in vitro activity against various fungi species, such as molds and dermatophytes. In vivo efficacy was also demonstrated in a murine model of systemic Candida albicans infection with a significant fungal load reduction in kidneys. © 2015 American Chemical Society.


PubMed | Catholic University of Leuven, Bio Imaging Core and Center for the Biology of Disease, French National Center for Scientific Research and Cistim Leuven vzw
Type: Journal Article | Journal: Oncotarget | Year: 2016

The development of cancer is often accompanied by a loss of the primary cilium, a microtubule-based cellular protrusion that functions as a cellular antenna and that puts a break on cell proliferation. Hence, restoration of the primary cilium in cancer cells may represent a novel promising approach to attenuate tumor growth. Using a high content analysis-based approach we screened a library of clinically evaluated compounds and marketed drugs for their ability to restore primary cilium expression in pancreatic ductal cancer cells. A diverse set of 118 compounds stimulating cilium expression was identified. These included glucocorticoids, fibrates and other nuclear receptor modulators, neurotransmitter regulators, ion channel modulators, tyrosine kinase inhibitors, DNA gyrase/topoisomerase inhibitors, antibacterial compounds, protein inhibitors, microtubule modulators, and COX inhibitors. Certain compounds also dramatically affected the length of the cilium. For a selection of compounds (Clofibrate, Gefitinib, Sirolimus, Imexon and Dexamethasone) their ability to restore ciliogenesis was confirmed in a panel of human cancer cell line models representing different cancer types (pancreas, lung, kidney, breast). Most compounds attenuated cell proliferation, at least in part through induction of the primary cilium, as demonstrated by cilium removal using chloral hydrate. These findings reveal that several commonly used drugs restore ciliogenesis in cancer cells, and warrant further investigation of their antineoplastic properties.


Delattin N.,Catholic University of Leuven | Bardiot D.,CISTIM Leuven Vzw | Marchand A.,CISTIM Leuven Vzw | Chaltin P.,CISTIM Leuven Vzw | And 4 more authors.
Molecules | Year: 2012

We have identified two subseries of 2,6-disubstituted quinolines, consisting of 6-amide and 6-urea derivatives, which are characterized by fungicidal activity against Candida albicans with minimal fungicidal concentration (MFC) values < 15 μ M. The 6-amide derivatives displayed the highest fungicidal activity against C. albicans, in particular compounds 1, 5 and 6 characterized by MFC values of 6.25-12.5 μ M. Compounds 1 and 5 of this series displayed fungicidal activity against the emerging pathogen Candida glabrata (MFC < 50 μ M). The 6-amide derivatives 1, 2, 5, and 6 and the 6-urea derivatives 10, 12, 13 and 15 could also eradicate C. albicans biofilms. We found that the 6-urea derivatives 10, 13, and 15 induced accumulation of endogenous reactive oxygen species in Candida albicans biofilms. © 2012 by the authors; licensee MDPI, Basel, Switzerland.


Saudi M.,Rega Institute for Medical Research | Zmurko J.,Rega Institute for Medical Research | Kaptein S.,Rega Institute for Medical Research | Rozenski J.,Rega Institute for Medical Research | And 6 more authors.
European Journal of Medicinal Chemistry | Year: 2016

High-Throughput screening of a subset of the CD3 chemical library (Centre for Drug Design and Discovery; KU Leuven) provided us with a lead compound 1, displaying low micromolar potency against dengue virus and yellow fever virus. Within a project aimed at discovering new inhibitors of flaviviruses, substitution of its central imidazole ring led to synthesis of variably substituted pyrazine dicarboxylamides and phthalic diamides, which were evaluated in cell-based assays for cytotoxicity and antiviral activity against the dengue virus (DENV) and yellow fever virus (YFV). Fourteen compounds inhibited DENV replication (EC50 ranging between 0.5 and 3.4 1/4M), with compounds 6b and 6d being the most potent inhibitors (EC50 0.5 1/4M) with selectivity indices (SI) > 235. Compound 7a likewise exhibited anti-DENV activity with an EC50 of 0.5 1/4M and an SI of >235. In addition, good antiviral activity of seven compounds in the series was also noted against the YFV with EC50 values ranging between 0.4 and 3.3 1/4M, with compound 6n being the most potent for this series with an EC50 0.4 1/4M and a selectivity index of >34. Finally, reversal of one of the central amide bonds as in series 13 proved deleterious to the inhibitory activity. © 2016 The Authors.


PubMed | CISTIM Leuven vzw, Center for Drug Design and Discovery 3 and Rega Institute for Medical Research
Type: | Journal: European journal of medicinal chemistry | Year: 2016

High-throughput screening of a subset of the CD3 chemical library (Centre for Drug Design and Discovery; KU Leuven) provided us with a lead compound 1, displaying low micromolar potency against dengue virus and yellow fever virus. Within a project aimed at discovering new inhibitors of flaviviruses, substitution of its central imidazole ring led to synthesis of variably substituted pyrazine dicarboxylamides and phthalic diamides, which were evaluated in cell-based assays for cytotoxicity and antiviral activity against the dengue virus (DENV) and yellow fever virus (YFV). Fourteen compounds inhibited DENV replication (EC50 ranging between 0.5 and 3.4M), with compounds 6b and 6d being the most potent inhibitors (EC50 0.5M) with selectivity indices (SI)>235. Compound 7a likewise exhibited anti-DENV activity with an EC50 of 0.5M and an SI of >235. In addition, good antiviral activity of seven compounds in the series was also noted against the YFV with EC50 values ranging between 0.4 and 3.3M, with compound 6n being the most potent for this series with an EC50 0.4M and a selectivity index of >34. Finally, reversal of one of the central amide bonds as in series 13 proved deleterious to the inhibitory activity.


Draoui N.,Institute Of Recherche Experimentale Et Clinique Irec | Draoui N.,Reactivity | Schicke O.,Reactivity | Fernandes A.,Reactivity | And 13 more authors.
Bioorganic and Medicinal Chemistry | Year: 2013

Under hypoxia, cancer cells consume glucose and release lactate at a high rate. Lactate was recently documented to be recaptured by oxygenated cancer cells to fuel the TCA cycle and thereby to support tumor growth. Monocarboxylate transporters (MCT) are the main lactate carriers and therefore represent potential therapeutic targets to limit cancer progression. In this study, we have developed and implemented a stepwise in vitro screening procedure on human cancer cells to identify new potent MCT inhibitors. Various 7-substituted carboxycoumarins and quinolinone derivatives were synthesized and pharmacologically evaluated. Most active compounds were obtained using a palladium-catalyzed Buchwald-Hartwig type coupling reaction, which proved to be a quick and efficient method to obtain aminocarboxycoumarin derivatives. Inhibition of lactate flux revealed that the most active compound 19 (IC 50 11 nM) was three log orders more active than the CHC reference compound. Comparison with warfarin, a conventional anticoagulant coumarin, further showed that compound 19 did not influence the prothrombin time which, together with a good in vitro ADME profile, supports the potential of this new family of compounds to act as anticancer drugs through inhibition of lactate flux. © 2013 Elsevier Ltd. All rights reserved.


Delattin N.,Catholic University of Leuven | De brucker K.,Catholic University of Leuven | Vandamme K.,Health Science University | Meert E.,Catholic University of Leuven | And 5 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2014

Objectives: Biofilms of Candida species, often formed on medical devices, are generally resistant to currently available antifungal drugs. The aim of this study was to identify compounds that increase the activity of amphotericin B and caspofungin, commonly used antifungal agents, against Candida biofilms. Methods: A library containing off-patent drugs was screened for compounds, termed enhancers, that increase the in vitro activity of amphotericin B against Candida albicans biofilms. Biofilms were grown in 96-well plates and growth was determined by the cell titre blue assay. Synergy between identified enhancers and antifungal agents was further characterized in vitro using fractional inhibitory concentration index (FICI) values and in vivo using a worm biofilm infection model. In light of the application of these enhancers onto implants, their possible effect on the growth potential of MG63 osteoblast-like cells was assessed. Results: Pre-incubation of C. albicans biofilms with subinhibitory concentrations of the enhancers drospirenone, perhexiline maleate or toremifene citrate significantly increased the activity of amphotericin B or caspofungin (FICI < 0.5) against C. albicans and Candida glabrata biofilms. Moreover, these enhancers did not affect the growth potential of osteoblasts. Interestingly, toremifene citrate also enhanced the in vitro activity of caspofungin in a mixed biofilm consisting of C. albicans and Staphylococcus epidermidis. Furthermore, we demonstrate synergy between toremifene citrate and caspofungin in an in vivo worm C. albicans biofilm infection model. Conclusions: Our data demonstrate an in vitro and in vivo enhancement of the antibiofilm activity of caspofungin by toremifene citrate. Furthermore, our results pave the way for implant-related applications of the identified enhancers. © The Author 2013. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

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