References of "Pirotte, Bernard"
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See detailPolyhydroxybenzoic acid derivatives as potential new antimalarial agents
Degotte, Gilles ULiege; Pirotte, Bernard ULiege; Frederich, Michel ULiege et al

in Archiv der Pharmazie und Berichte der Deutschen Pharmazeutischen Gesellschaft (in press)

With more than 200 million cases and 400,000 related deaths, malaria remains one of the deadliest infectious diseases of 2021. Unfortunately, despite the availability of efficient treatments, we have ... [more ▼]

With more than 200 million cases and 400,000 related deaths, malaria remains one of the deadliest infectious diseases of 2021. Unfortunately, despite the availability of efficient treatments, we have observed an increase in people infected with malaria since 2015 (from 211 million in 2015 to 229 million in 2019). This trend could partially be due to the development of resistance to all the current drugs. Therefore, there is an urgent need for new alternatives. We have, thus, selected common natural scaffolds, polyhydroxybenzoic acids, and synthesized a library of derivatives to better under- stand the structure–activity relationships explaining their antiplasmodial effect. Only gallic acid derivatives showed a noticeable potential for furtherQ3 developments. Indeed, they showed a selective inhibitory effect on Plasmodium (IC50 ~20 μM, SI > 5) often associated with interesting water solubility. Moreover, this has confirmed the critical importance of free phenolic functions (pyrogallol moiety) for the antimalarial effect. Methyl 4-benzoxy-3,5-dihydroxybenzoate (39) has, for the first time, been recognized as a potential lead for future research because of its marked inhibitory activity against Plasmodium falciparum and its significant hydrosolubility (3.72 mM). [less ▲]

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See detailDevelopment of Thiochroman Dioxide Analogues of Benzothiadiazine Dioxides as New Positive Allosteric Modulators of α-Amino-3- hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors
Etse, Koffi Senam ULiege; Dorosz, Jerzy; Mc Lain Christensen et al

in ACS Chemical Neurosciences (in press)

Based on the activity of 1,2,4-benzothiadiazine 1,1-dioxides as AMPAR-PAMs, thiochroman 1,1-dioxides were designed apply- ing the isosteric replacement concept. The new compounds expressed a strong ... [more ▼]

Based on the activity of 1,2,4-benzothiadiazine 1,1-dioxides as AMPAR-PAMs, thiochroman 1,1-dioxides were designed apply- ing the isosteric replacement concept. The new compounds expressed a strong modulatory activity on AMPARs in vitro, although lower than their corresponding benzothiadiazine analogues. The pharmacokinetic profile of three thiochroman 1,1-dioxides (12a, 12b, 12e) was exam- ined in vivo after oral administration, showing that these compounds freely cross the blood-brain barrier. Structural analysis was achieved using X-ray crystallography after cocrystallisation of the racemic compound 12b in complex with GluA2-LBD (L504Y/N775S). Interestingly, both enantiomers of 12b were found to interact with the GluA2-LBD dimer interface, almost identically to its benzothiadiazine analogue, BPAM344 (4). The interactions of the two enantiomers in the cocrystal were further analyzed (mapping Hirshfeld surfaces and 2D finger- print) and compared to those of 4. Taken together, these data explain the lower affinity on AMPARs of thiochroman 1,1-dioxides compared to their corresponding 1,2,4-benzothiadiazine 1,1-dioxides. [less ▲]

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See detailOverview of natural antiplasmodials from the last decade to inspire medicinal chemistry
Degotte, Gilles ULiege; Pirotte, Bernard ULiege; Francotte, Pierre ULiege et al

in Current Medicinal Chemistry (2021)

Background: Despite the major advances in the fight against this parasitic disease, malaria remains a major cause of concerns in 2020. This infection, mainly due to Plasmodium falciparum, causes every ... [more ▼]

Background: Despite the major advances in the fight against this parasitic disease, malaria remains a major cause of concerns in 2020. This infection, mainly due to Plasmodium falciparum, causes every year more than 200 million of cases and hundreds of thousands of deaths in developing regions, mostly in Africa. The last statistics show an increase of cases for the third consecutive year, from 211 million in 2015, it has reached 229 million in 2019. This trend could be partially explained by the appearance of resistances to all the used antimalarials, even to artemisinin. Thus, the design of new anti-Plasmodium compounds is an urgent need. For thousands of years, nature has offered to humans the medicines to cure their diseases or the inspiration for development of new active principles. It seems then logical to explore the natural sources to find new molecules to treat this parasitosis. Method: Therefore, this review reports and analyzes the extracts (plants, bacteria, sponges, fungi) and the corresponding isolated compounds showing antiplasmodial properties between 2013 and 2019. Results & Conclusion: Nature remains a major source of active compounds. Indeed, 648 molecules from various origins, mostly plants, have been reported for their inhibitory effect on Plasmodium falciparum. Among them, 188 scaffolds were defined as highly active with IC50 ≤ 5 µM and have been reported here in details. Moreover, the most active compounds showed a large variety of structures: flavonoids, triterpenes, alkaloids... Therefore, these compounds could be an interesting source of inspiration for medicinal chemists. May-be several of these molecules should become the next leads for malaria treatment. [less ▲]

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See detailGPR101 drives growth hormone hypersecretion and gigantism in mice via constitutive activation of Gs and Gq/11
Abboud, Dayana ULiege; Daly, Adrian ULiege; Dupuis, Nadine ULiege et al

in Nature Communications (2020), 11(1), 4752

Growth hormone (GH) is a key modulator of growth and GH over-secretion can lead to gigantism. One form is X-linked acrogigantism (X-LAG), in which infants develop GH-secreting pituitary tumors over ... [more ▼]

Growth hormone (GH) is a key modulator of growth and GH over-secretion can lead to gigantism. One form is X-linked acrogigantism (X-LAG), in which infants develop GH-secreting pituitary tumors over-expressing the orphan G-protein coupled receptor, GPR101. The role of GPR101 in GH secretion remains obscure. We studied GPR101 signaling pathways and their effects in HEK293 and rat pituitary GH3 cell lines, human tumors and in transgenic mice with elevated somatotrope Gpr101 expression driven by the rat Ghrhr promoter (GhrhrGpr101). Here, we report that Gpr101 causes elevated GH/prolactin secretion in transgenic GhrhrGpr101 mice but without hyperplasia/tumorigenesis. We show that GPR101 constitutively activates not only Gs, but also Gq/11 and G12/13, which leads to GH secretion but not proliferation. These signatures of GPR101 signaling, notably PKC activation, are also present in human pituitary tumors with high GPR101 expression. These results underline a role for GPR101 in the regulation of somatotrope axis function. [less ▲]

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See detailSynthesis, crystal structure, Hirshfeld surface and interaction energies analysis of 5-methyl-1,3-bis(3-nitrobenzyl)pyrimidine-2,4(1H,3H)-dione
Etse, Koffi Senam ULiege; Comeron Lamela, Laura ULiege; Zaragoza, Guillermo et al

in European Journal of Chemistry (2020), 11/2

The title compound 5-methyl-1,3-bis(3-nitrobenzyl)pyrimidine-2,4(1H,3H)-dione was obtained by reaction of thymine with 3-nitrobenzylbromide in the presence of cesium carbonate. Characterization of the ... [more ▼]

The title compound 5-methyl-1,3-bis(3-nitrobenzyl)pyrimidine-2,4(1H,3H)-dione was obtained by reaction of thymine with 3-nitrobenzylbromide in the presence of cesium carbonate. Characterization of the product was achieved by NMR spectroscopy and its stability was probed in basic condition using UV-Visible analysis. Furthermore, the molecular structure was confirmed by X-ray diffraction analysis. The compound crystallizes in orthorhombic Pna21 space group with unit cell parameters a = 14.9594 (15) Å, b = 25.711 (3) Å, c = 4.5004 (4) Å, V = 1731.0 (3) Å3 and Z = 4. The crystal packing of the title compound is stabilized by intermolecular hydrogen bond, π···π and C−H···π stacking interactions. The intermolecular interactions were furthermore analyzed through the mapping of different Hirshfeld surfaces. The two-dimensional fingerprint revealed that the most important contributions to these surfaces come from O···H (37.1%), H···H (24%) and H···C/C···H (22.6%) interactions. The interaction energies stabilizing the crystal packing were calculated and were presented graphically as framework energy diagrams. Finally, the energy-framework analysis reveals that π···π and C−H···π interactions energies are mainly dispersive and are the most important forces in the crystal. [less ▲]

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See detailModulation of mitochondrial respiration rate and calcium-induced swelling by new cromakalim analogues.
Mouithys-Mickalad, Ange ULiege; Ceusters, Justine ULiege; Charif, Mounia et al

in Chemico-Biological Interactions (2020), 331

A cellular model of cardiomyocytes (H9c2 cell line) and mitochondria isolated from mouse liver were used to understand the drug action of BPDZ490 and BPDZ711, two benzopyran analogues of the reference ... [more ▼]

A cellular model of cardiomyocytes (H9c2 cell line) and mitochondria isolated from mouse liver were used to understand the drug action of BPDZ490 and BPDZ711, two benzopyran analogues of the reference potassium channel opener cromakalim, on mitochondrial respiratory parameters and swelling, by comparing their effects with those of the parent compound cromakalim. For these three compounds, the oxygen consumption rate (OCR) was determined by high-resolution respirometry (HRR) and their impact on adenosine triphosphate (ATP) production and calcium-induced mitochondrial swelling was investigated. Cromakalim did not modify neither the OCR of H9c2 cells and the ATP production nor the Ca-induced swelling. By contrast, the cromakalim analogue BPDZ490 (1) induced a strong increase of OCR, while the other benzopyran analogue BPDZ711 (2) caused a marked slowdown. For both compounds, 1 displayed a biphasic behavior while 2 still showed an inhibitory effect. Both compounds 1 and 2 were also found to decrease the ATP synthesis, with pronounced effect for 2, while cromakalim remained without effect. Overall, these results indicate that cromakalim, as parent molecule, does not induce per se any direct effect on mitochondrial respiratory function neither on whole cells nor on isolated mitochondria whereas both benzopyran analogues 1 and 2 display totally opposite behavior profiles, suggesting that compound 1, by increasing the maximal respiration capacity, might behave as a mild uncoupling agent and compound 2 is taken as an inhibitor of the mitochondrial electron-transfer chain. [less ▲]

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See detailGPR101 drives growth hormone hypersecretion and gigantism in mice via constitutive activation of Gs and Gq/11
Abboud, Dayana ULiege; Daly, Adrian ULiege; Dupuis, Nadine et al

Conference (2020)

Growth hormone (GH) is a key modulator of growth and GH over-secretion can lead to gigantism. One form is X-linked acrogigantism (X-LAG), in which infants develop GH secreting pituitary tumors over ... [more ▼]

Growth hormone (GH) is a key modulator of growth and GH over-secretion can lead to gigantism. One form is X-linked acrogigantism (X-LAG), in which infants develop GH secreting pituitary tumors over-expressing the orphan G-protein coupled receptor, GPR101. The role of GPR101 in GH secretion remains obscure. We studied GPR101 signaling pathways and their effects in HEK293 and rat pituitary GH3 cell lines, human tumors and in transgenic mice with elevated somatotrope Gpr101 expression driven by the rat Ghrhr promoter (GhrhrGpr101). We report that Gpr101 causes elevated GH/prolactin secretion in transgenic GhrhrGpr101 mice. We also show that GPR101 promotes GH secretion through the activation of not only Gs, but also Gq/11, in a PKA and PKC-dependent manner, respectively. Interestingly, in stark contrast with other Gs-coupled receptors, GPR101 activation did not lead to the proliferation of somatotrope cells. These signatures of GPR101 signaling, notably PKC activation, are also present in human X-LAG pituitary tumors with high GPR101 expression. These results underline a role for GPR101 in the regulation of somatotrope axis function. [less ▲]

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See detailInhibition of LTβR-signalling activates Wnt-induced regeneration in lung
Conlon, Thomas; John-Schuster, Gerrit; Heide, Danijela et al

in Nature (2020)

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See detailSynthesis of ticagrelor analogues belonging to 1,2,3-triazolo[4,5-d]pyrimidines and study of their antiplatelet and antibacterial activity.
Goffin, Eric ULiege; Jacques, Nicolas ULiege; Musumeci, Lucia ULiege et al

in European journal of medicinal chemistry (2020), 208

Based on the recent observation that the antiplatelet agent ticagrelor and one of its metabolite exert bactericidal activity against gram-positive bacteria, a series of 1,2,3-triazolo[4,5-d]pyrimidines ... [more ▼]

Based on the recent observation that the antiplatelet agent ticagrelor and one of its metabolite exert bactericidal activity against gram-positive bacteria, a series of 1,2,3-triazolo[4,5-d]pyrimidines structurally related to ticagrelor were synthesized and examined as putative antiplatelet and antibacterial agents. The aim was to assess the possibility of dissociating the two biological properties and to find novel 1,2,3-triazolo[4,5-d]pyrimidines expressing antiplatelet activity and devoid of in vitro antibacterial activity. The new compounds synthesized were known metabolites of ticagrelor as well as structurally simplified analogues. Some of them were found to express antiplatelet activity and to lose the antibacterial activity, supporting the view that the two activities were not necessarily linked. [less ▲]

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See detailFrom Metabolomics Study of Age Related Macular Degeneration (AMD) to the Development of New Pyruvate Dehydrogenase Kinase (PDK) Inhibitors
Arslan, Deniz ULiege; LAMBERT, Vincent ULiege; Noël, Agnès ULiege et al

Poster (2019, December 11)

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small zone of ... [more ▼]

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small zone of the retina specialized for the high-acuity vision. Exudative AMD, called “wet AMD”, is characterized by the formation of new blood vessels growing under the retina according to a process named choroidal neovascularization (CNV). Currently, the aetiology and pathogenesis of wet AMD remain unclear. Nevertheless, a recent metabolomics study performed on the serum of “wet” AMD patients and on a CNV murine model, that mimics the effect of “wet” AMD, has demonstrated that lactate is clearly involved in the severity and the evolution of the pathology and of CNV. According to this study, we suggest a new therapeutic approach of AMD based on the normalization of blood lactate level. The modulation of the lactate plasma concentration by treatment of the animals with synthetic compounds and more specifically Pyruvate Dehydrogenase Kinase (PDK) inhibitors significantly decrease the CNV. Starting from these results, development of new PDK inhibitors could open the way to innovative treatment for AMD disease. [less ▲]

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See detailDimerisation of gallic acid for malaria treatment.
Degotte, Gilles ULiege; Lempereur, Delphine ULiege; Adubofour, Yaa ULiege et al

Poster (2019, December 11)

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See detailGPR101 orphan receptor in XLAG syndrome
Abboud, Dayana ULiege; Daly, Adrian ULiege; Dupuis, Nadine et al

Conference (2019, December)

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See detailTotal synthesis approach: development of new antimalarial compounds.
Degotte, Gilles ULiege; Pirotte, Bernard ULiege; Frederich, Michel ULiege et al

Poster (2019, November 22)

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See detailCrystal structure and Hirshfeld surface analysis of N-(2-(N-methylsulfamoyl)phenyl)formamide: Degradation product of 2-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide
Etse, Koffi Senam ULiege; Zaragoza, Guillermo; Pirotte, Bernard ULiege

in European Journal of Chemistry (2019), 10(3), 189-194

The hydrolysis of 2-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide (2) during crystallization under humidity (85 %) conditions, lead to N-(2-(N-methylsulfamoyl)phenyl)formamide as second step hydrolysis ... [more ▼]

The hydrolysis of 2-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide (2) during crystallization under humidity (85 %) conditions, lead to N-(2-(N-methylsulfamoyl)phenyl)formamide as second step hydrolysis product, identified in the proposed degradation mechanism. Crystal of N-(2-(N-methylsulfamoyl)phenyl)formamide C8H10N2O3S (4), was obtained and characterized. The molecular structure determination was carried out with MoKα X-ray and data measured at 100 K. The compound 4 crystallizes in triclinic P􀔋1 space group with unit cell parameters a = 4.8465(4) Å, b = 8.1942(9) Å, c = 11.8686(13) Å, α = 77.080(4)°, β = 82.069(4)°, γ = 80.648(4)°, V = 450.76 (8) Å3 and Z = 2. The crystal structure is stabilized by intramolecular N-H···O and intermolecular C-H···O and N-H···O hydrogen bonds that extended as infinite 1D chain along [100]. Stabilization is also ensured by oxygen-π stacking interaction between the aromatic ring and oxygen of the sulfonamide group. The analysis of intermolecular interactions through the mapping of dnorm and shape-index revel that the most significant contributions to the Hirshfeld surface 40.6 and 33.9% are from H···H and O···H contacts, respectively. [less ▲]

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See detailPharmacomodulation of ellagic acid: a total synthesis approach.
Degotte, Gilles ULiege; Pirotte, Bernard ULiege; Frederich, Michel ULiege et al

Poster (2019, September 05)

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