Publications by authors named "Pascal Marchand"

46 Publications

Streptomyces hygroscopicus UFPEDA 3370: A valuable source of the potent cytotoxic agent nigericin and its evaluation against human colorectal cancer cells.

Chem Biol Interact 2021 Jan 4;333:109316. Epub 2020 Dec 4.

Departamento de Antibióticos, Rua Prof. Moraes Rego, 1235, Universidade Federal de Pernambuco, Recife, Pernambuco, 50670-901, Brazil. Electronic address:

Streptomyces hygroscopicus UFPEDA 3370 was fermented in submerged cultivation and the biomass extract was partitioned, obtaining a fraction purified named EB1. After purification of EB1 fraction, nigericin free acid was obtained and identified. Nigericin presented cytotoxic activity against several cancer cell lines, being most active against HL-60 (human leukemia) and HCT-116 (human colon carcinoma) cell lines, presenting IC and (IS) values: 0.0014 μM, (30.0) and 0.0138 μM (3.0), respectively. On HCT-116, nigericin caused apoptosis and autophagy. In this study, nigericin was also screened both in vitro and in silico against a panel of cancer-related kinases. Nigericin was able to inhibit both JAK3 and GSK-3β kinases in vitro and its binding affinities were mapped through the intermolecular interactions with each target in silico.
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http://dx.doi.org/10.1016/j.cbi.2020.109316DOI Listing
January 2021

In vitro identification of imidazo[1,2-a]pyrazine-based antileishmanial agents and evaluation of L. major casein kinase 1 inhibition.

Eur J Med Chem 2021 Jan 23;210:112956. Epub 2020 Oct 23.

Université de Nantes, Cibles et Médicaments des Infections et du Cancer, IICiMed, EA 1155, F-44000, Nantes, France. Electronic address:

Leishmaniasis constitutes a severe public health problem, with an estimated prevalence of 12 million cases. This potentially fatal disease has a worldwide distribution and in 2012, the fatal Visceral Leishmaniasis (VL) was declared as new emerging disease in Europe, mainly due to global warming, with expected important public health impact. The available treatments are toxic, costly or lead to parasite resistance, thus there is an urgent need for new drugs with new mechanism of action. Previously, we reported the discovery of CTN1122, a potent imidazo[1,2-a]pyrazine-based antileishmanial hit compound targeting L-CK1.2 at low micromolar ranges. Here, we described structurally related, safe and selective compounds endowed with antiparasitic properties, better than miltefosine, the reference therapy by oral route. L-CK1.2 homology model gave the first structural explanations of the role of 4-pyridyl (CTN1122) and 2-aminopyrimidin-4-yl (compound 21) moieties, at the position 3 of the central core, in the low micromolar to nanomolar L-CK1.2 inhibition, whereas N-methylpyrazole derivative 11 remained inactive against the parasite kinase.
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http://dx.doi.org/10.1016/j.ejmech.2020.112956DOI Listing
January 2021

Microwave-Assisted Synthesis of Potential Bioactive Benzo-, Pyrido- or Pyrazino-thieno[3,2-]pyrimidin-4-amine Analogs of MPC-6827.

Pharmaceuticals (Basel) 2020 Aug 19;13(9). Epub 2020 Aug 19.

Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA UMR 6014, 76000 Rouen, France.

Efficient microwave-assisted chemical processes were applied to the synthesis of an array of novel -(4-methoxyphenylamino)-2-methyl benzo-, pyrido- or pyrazino-thieno[3,2-]pyrimidin-4-amine derivatives. These heteroaromatic systems were envisioned as potent bioisosteric analogues of , an anticancer agent previously developed until phase II clinical studies. A brief evaluation and comparison of their antiproliferative activity on HT-29 and Caco-2, two human colorectal cancer cell lines, were also reported. At the tested concentrations (5 and 10 µM), thieno[3,2-]pyrimidin-4-amines and exhibited an inhibitory effect similar to on human colorectal cancer cell proliferation.
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http://dx.doi.org/10.3390/ph13090202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558077PMC
August 2020

Exploring Kinase Inhibition Properties of 9-pyrimido[5,4-]- and [4,5-]indol-4-amine Derivatives.

Pharmaceuticals (Basel) 2020 May 9;13(5). Epub 2020 May 9.

Université de Nantes, Cibles et Médicaments des Infections et du Cancer, IICiMed, EA 1155, F-44000 Nantes, France.

We previously highlighted the interest in 6,5,6-fused tricyclic analogues of 4-aminoquinazolines as kinase inhibitors in the micromolar to the nanomolar range of IC values. For the generation of chemical libraries, the formamide-mediated cyclization of the cyanoamidine precursors was carried out under microwave irradiation in an eco-friendly approach. In order to explore more in-depth the pharmacological interest in such tricyclic skeletons, the central five member ring, i.e., thiophène or furan, was replaced by a pyrrole to afford 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine derivatives inspired from harmine. The inhibitory potency of the final products was determined against four protein kinases (CDK5/p25, CK1/ε, GSK3 and DYRK1A). As a result, we have identified promising compounds targeting CK1/ε and DYRK1A and displaying micromolar and submicromolar IC values.
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http://dx.doi.org/10.3390/ph13050089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281298PMC
May 2020

Genetic epidemiology of the Alpine ibex reservoir of persistent and virulent brucellosis outbreak.

Sci Rep 2020 03 10;10(1):4400. Epub 2020 Mar 10.

Université de Lyon, VetAgro Sup - Campus vétérinaire de Lyon, Marcy l'Étoile, France.

While it is now broadly accepted that inter-individual variation in the outcomes of host-pathogen interactions is at least partially genetically controlled, host immunogenetic characteristics are rarely investigated in wildlife epidemiological studies. Furthermore, most immunogenetic studies in the wild focused solely on the major histocompatibility complex (MHC) diversity despite it accounts for only a fraction of the genetic variation in pathogen resistance. Here, we investigated immunogenetic diversity of the Alpine ibex (Capra ibex) population of the Bargy massif, reservoir of a virulent outbreak of brucellosis. We analysed the polymorphism and associations with disease resistance of the MHC Class II Drb gene and several non-MHC genes (Toll-like receptor genes, Slc11A1) involved in the innate immune response to Brucella in domestic ungulates. We found a very low neutral genetic diversity and a unique MHC Drb haplotype in this population founded few decades ago from a small number of individuals. By contrast, other immunity-related genes have maintained polymorphism and some showed significant associations with the brucellosis infection status hence suggesting a predominant role of pathogen-mediated selection in their recent evolutionary trajectory. Our results highlight the need to monitor immunogenetic variation in wildlife epidemiological studies and to look beyond the MHC.
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http://dx.doi.org/10.1038/s41598-020-61299-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064506PMC
March 2020

Should I stay or should I go? Determinants of immediate and delayed movement responses of female red deer (Cervus elaphus) to drive hunts.

PLoS One 2020 9;15(3):e0228865. Epub 2020 Mar 9.

Direction de la Recherche et de l'Appui Scientifique-Unité Ongulés Sauvages, Office Français de la Biodiversité, Birieux, France.

Hunting can be used as a tool for wildlife management, through limitation of population densities and dissuading game from using sensitive areas. The success of these approaches requires in depth knowledge of prey movement. Indeed, movement decisions of game during hunting may affect the killing success of hunters as well as the subsequent location of surviving animals. We thus investigated red deer movement responses to drive hunts and their causal factors. We studied 34 hunting events in the National Estate of Chambord (France) and thereby provided a fine-scale characterization of the immediate and delayed movement responses of red deer to drive hunts. Red deer responded to drive hunts either by immediately fleeing the hunted area, or by initially remaining before ultimately fleeing after the hunters had departed. A few hours after the hunt, all individuals were located in distant areas (> 2 kilometres) from the hunted area. Immediate flight responses were less common when drive hunts occurred in areas with dense understorey. However, neither beater/dog densities nor site familiarity influenced the immediate flight decision. Following a drive hunt, red deer remained outside the hunted areas for periods twice as long compared to periods when no hunting occurred (34 hours vs. 17 hours). Such knowledge of game movement rates in response to drive hunts may help the development of informed management policy for hunted red deer populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228865PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062277PMC
June 2020

Evaluation of anti-inflammatory activity and molecular docking study of new aza-bicyclic isoxazoline acylhydrazone derivatives.

Medchemcomm 2019 Nov 12;10(11):1916-1925. Epub 2019 Sep 12.

Departamento de Antibióticos , Universidade Federal de Pernambuco (UFPE) , Rua Prof. Arthur Sá, s/n , CEP 50560-901 , Recife-PE , Brazil . Email: ; Email:

The aim of this study was to investigate the anti-inflammatory effects of two new isoxazoline-acylhydrazone derivatives: '-(4-methoxybenzylidene)-6-(4-nitro-benzoyl)-3,5,6,6-tetrahydro-4-pyrrolo[3,2-]isoxazole-3-carbohydrazide (R-123) and '-(4-chlorobenzylidene)-6-(4-chlorobenzoyl)-3,5,6,6-tetrahydro-4-pyrrolo[3,2-]isoxazole-3-carbohydrazide (R-99). An air pouch induced by carrageenan was used for screening the best dose of R-99 and R-123. Using this mouse model, leukocyte migration and cytokine levels (TNF-α and IL-1β) were determined. Paw edema induced by several phlogistic agents and vascular permeability induced by acetic acid were employed to investigate the mechanism of action of the isoxazoline-acylhydrazone derivatives. A docking study was performed with the human histamine H1 receptor to investigate potential antihistaminic activity. Treatment with the compounds reduced leukocyte migration in the air pouch at all doses tested. TNF-α and IL-1β levels were similarly reduced by the two compounds. Vasoactive amines were inhibited in models of paw edema induced by several agents and vascular permeability induced by acetic acid. The docking study suggests that R-99 and R-123 may be inhibitors of the histamine H1 receptor. In conclusion, the results indicate that R-99 and R-123 exhibit promising anti-inflammatory activity related to their ability to inhibit TNF-α, IL-1β, and vasoactive amine production, as well as reduce leukocyte migration and inhibit mast cell degranulation.
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http://dx.doi.org/10.1039/c9md00276fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977463PMC
November 2019

A Decade of Antifungal Leads from Natural Products: 2010-2019.

Pharmaceuticals (Basel) 2019 Dec 12;12(4). Epub 2019 Dec 12.

School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK.

In this review, we discuss novel natural products discovered within the last decade that are reported to have antifungal activity against pathogenic species. Nearly a hundred natural products were identified that originate from bacteria, algae, fungi, sponges, and plants. Fungi were the most prolific source of antifungal compounds discovered during the period of review. The structural diversity of these antifungal leads encompasses all the major classes of natural products including polyketides, shikimate metabolites, terpenoids, alkaloids, and peptides.
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http://dx.doi.org/10.3390/ph12040182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958371PMC
December 2019

27th Annual GP2A Medicinal Chemistry Conference.

Pharmaceuticals (Basel) 2019 Dec 6;12(4). Epub 2019 Dec 6.

School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, UK.

The 27th annual GP2A (Groupement des Pharmacochimistes de l'Arc Atlantique/Group of Medicinal Chemists in the Atlantic Arc) conference took place from 21 to 23 August 2019, at the East Midlands Conference Centre (University Park, Nottingham, United Kingdom) and was hosted by the Division of Biomolecular Science and Medicinal Chemistry (BSMC), within the School of Pharmacy at the University of Nottingham. The event brought together an international delegation of researchers with interests in medicinal chemistry and interfacing disciplines. In addition, a pre-conference workshop provided an opportunity for younger researchers to develop their theoretical knowledge in quantitative pharmacology. Abstracts of presentations by the 14 invited speakers and 6 young researchers, in addition to 41 posters, are included in this report.
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http://dx.doi.org/10.3390/ph12040179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958382PMC
December 2019

Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents.

Pharmaceuticals (Basel) 2019 Nov 17;12(4). Epub 2019 Nov 17.

Departamento de Antibióticos, Centro de Biociências, Universidade Federal de Pernambuco, Recife, PE, 50740-520, Brazil.

Fourteen arylsemicarbazone derivatives were synthesized and evaluated in order to find agents with potential anticancer activity. Cytotoxic screening was performed against K562, HL-60, MOLT-4, HEp-2, NCI-H292, HT-29 and MCF-7 tumor cell lines. Compounds and were active against the tested cancer cell lines, being more cytotoxic for the HL-60 cell line with IC values of 13.08 μM and 11.38 μM, respectively. Regarding the protein kinase inhibition assay, inhibited seven different kinases and strongly inhibited the CK1δ/ε kinase. The studied kinases are involved in several cellular functions such as proliferation, migration, cell death and cell cycle progression. Additional analysis by flow cytometry revealed that and caused depolarization of the mitochondrial membrane, suggesting apoptosis mediated by the intrinsic pathway. Compound induced arrest in G1 phase of the cell cycle on HL-60 cells, and in the annexin V assay approximately 50% of cells were in apoptosis at the highest concentration tested (26 μM). Compound inhibited cell cycle by accumulation of abnormal postmitotic cells at G1 phase and induced DNA fragmentation at the highest concentration (22 μM).
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http://dx.doi.org/10.3390/ph12040169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958387PMC
November 2019

Design, synthesis and pharmacological evaluation of CVIB, a codrug of carvacrol and ibuprofen as a novel anti-inflammatory agent.

Int Immunopharmacol 2019 Nov 31;76:105856. Epub 2019 Aug 31.

Laboratory of Synthesis and Drug Delivery, State University of Paraiba, João Pessoa, PB 58071-160, Brazil; Post-Graduation Program in Natural and Synthetic Bioactive Products, Federal University of Paraiba, João Pessoa, PB 58051-900, Brazil. Electronic address:

The search for new drugs with anti-inflammatory properties remains a challenge for modern medicine. Among the various strategies for drug discovery, deriving new chemical entities from known bioactive natural and/or synthetic compounds remains a promising approach. Here, we designed and synthesized CVIB, a codrug developed by association of carvacrol (a phenolic monoterpene) with ibuprofen (a non-steroidal anti-inflammatory drug). In silico pharmacokinetic and physicochemical properties evaluation indicated low aqueous solubility (LogP ≥5.0). Nevertheless, the hybrid presented excellent oral bioavailability, gastrointestinal tract absorption, and low toxicity. CVIB did not present cytotoxicity in peripheral blood mononuclear cells (PBMCs), and promoted a significant reduction in IL-2, IL-10, IL-17, and IFN-γ cytokine levels in vitro. The LD was estimated to be approximately 5000 mg/kg. CVIB was stable and detectable in human plasma after 24 h. In vivo anti-inflammatory evaluations revealed that CVIB at 10 and 50 mg/kg i.p. caused a significant decrease in total leukocyte count (p < 0.01) and provoked a significant reduction in IL-1β (p < 0.01). CVIB at 10 mg/kg i.p. efficiently decreased inflammatory parameters better than the physical mixture (carvacrol + ibuprofen 10 mg/kg i.p.). The results suggest that the codrug approach is a good option for drug design and development, creating the possibility of combining NSAIDs with natural products in order to obtain new hybrid drugs may be useful for treatment of inflammatory diseases.
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http://dx.doi.org/10.1016/j.intimp.2019.105856DOI Listing
November 2019

Thiazolidinedione and thiazole derivatives potentiate norfloxacin activity against NorA efflux pump over expression in Staphylococcus aureus 1199B strains.

Bioorg Med Chem 2019 09 4;27(17):3797-3804. Epub 2019 Jul 4.

Departamento de Antibióticos, Universidade Federal de Pernambuco (UFPE), Av. Prof. Artur de Sá, s/n, Cidade Universitária, Recife, PE 54740-520, Brazil. Electronic address:

Thiazol and thiazolidinedione derivatives are known in the literature for presenting several biological activities, such as anti-diabetic, anti-inflammatory, antiparasitic, antifungal and antimicrobial activity. With this in mind, this study reports on the synthesis and antibacterial activity of thiazole (NJ) and thiazolidinedione (NW) derivatives, as well as their effects in association with norfloxacin, against NorA efflux pumps in the Staphylococcus aureus 1199B (SA-1199B) strain. Among the 14 compounds evaluated, 9 were found to potentiate norfloxacin activity, with 4 compounds from the NJ series promoting a threefold norfloxacin MIC reduction. Molecular docking assays were used to confirm the binding mode of most active compounds. In the in silico study, the efficiency of the interaction of NJ series compounds with the NorA pump were evaluated. Derivatives from both series did not show considerable intrinsic antibacterial activity (MIC > 1024 μg/mL) against any of the tested strains. However, the NJ16 and NJ17 compounds, when associated with norfloxacin, reduced the MIC of this drug threefold and inhibited NorA pumps in the 1199B strain. Moreover, some NW (05, 10, 18, 19 and 21) and NJ compounds (16, 17, 18 and 20) presented low to moderate cytotoxicity against normal cells. Molecular docking studies supported the potent in vitro inhibitory activity of NJ16 and NJ17, which showed NJ16 and NJ17 possessed more favorable binding energies of -9.03 Kcal/mol and -9.34 Kcal/mol, respectively. In addition, NJ16 showed different types of interactions involved in complex stabilization. In conclusion, NJ16 and NJ17, in combination with norfloxacin, were able to completely restore the antibacterial activity of norfloxacin against S. aureus SA-1199B, the norA-overexpressing strain, with low cytotoxicity in normal cells.
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http://dx.doi.org/10.1016/j.bmc.2019.07.006DOI Listing
September 2019

5-Nitro-Thiophene-Thiosemicarbazone Derivatives Present Antitumor Activity Mediated by Apoptosis and DNA Intercalation.

Curr Top Med Chem 2019 ;19(13):1075-1091

Laboratory of Synthesis and Drug Delivery, Department of Biological Sciences, State University of Paraiba, Joao Pessoa-PB, Brazil.

Background: Considering the need for the development of new antitumor drugs, associated with the great antitumor potential of thiophene and thiosemicarbazonic derivatives, in this work we promote molecular hybridization approach to synthesize new compounds with increased anticancer activity.

Objective: Investigate the antitumor activity and their likely mechanisms of action of a series of N-substituted 2-(5-nitro-thiophene)-thiosemicarbazone derivatives.

Methods: Methods were performed in vitro (cytotoxicity, cell cycle progression, morphological analysis, mitochondrial membrane potential evaluation and topoisomerase assay), spectroscopic (DNA interaction studies), and in silico studies (docking and molecular modelling).

Results: Most of the compounds presented significant inhibitory activity; the NCIH-292 cell line was the most resistant, and the HL-60 cell line was the most sensitive. The most promising compound was LNN-05 with IC50 values ranging from 0.5 to 1.9 µg.mL-1. The in vitro studies revealed that LNN-05 was able to depolarize (dose-dependently) the mitochondrial membrane, induceG1 phase cell cycle arrest noticeably, promote morphological cell changes associated with apoptosis in chronic human myelocytic leukaemia (K-562) cells, and presented no topoisomerase II inhibition. Spectroscopic UV-vis and molecular fluorescence studies showed that LNN compounds interact with ctDNA forming supramolecular complexes. Intercalation between nitrogenous bases was revealed through KI quenching and competitive ethidium bromide assays. Docking and Molecular Dynamics suggested that 5-nitro-thiophene-thiosemicarbazone compounds interact against the larger DNA groove, and corroborating the spectroscopic results, may assume an intercalating interaction mode.

Conclusion: Our findings highlight 5-nitro-thiophene-thiosemicarbazone derivatives, especially LNN-05, as a promising new class of compounds for further studies to provide new anticancer therapies.
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http://dx.doi.org/10.2174/1568026619666190621120304DOI Listing
October 2019

26th Annual GP2A Medicinal Chemistry Conference & 32nd Journées Franco-Belges de Pharmacochimie.

Pharmaceuticals (Basel) 2019 May 16;12(2). Epub 2019 May 16.

Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA UMR 6014, F-76000 Rouen, France.

As a joint meeting, the 26th Medicinal Chemistry Conference of GP2A and 32nd Journées Franco-Belges de Pharmacochimie took place between 13th and 15th June at Asnelles sur Mer (Normandie, France), providing a unique opportunity for a wide group of European medicinal chemists to engage. Topics included chemical tools for medicinal chemistry, protein-protein interactions, epigenetics, natural product-inspired molecules, computer-aided drug design, and new strategies for the design and development of drugs. Abstracts of invited lectures, proffered young researcher communications, flash communications and posters presented during the meeting are collected in this report.
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http://dx.doi.org/10.3390/ph12020073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630807PMC
May 2019

Synthesis and anticancer activity of novel bisindolylhydroxymaleimide derivatives with potent GSK-3 kinase inhibition.

Bioorg Med Chem 2018 08 9;26(14):4209-4224. Epub 2018 Jul 9.

School of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Western Road, Cork, Ireland. Electronic address:

Synthesis and biological evaluation of a series of novel indole derivatives as anticancer agents is described. A bisindolylmaleimide template has been derived as a versatile pharmacophore with which to pursue chemical diversification. Starting from maleimide, the introduction of an oxygen to the headgroup (hydroxymaleimide) was initially investigated and the bioactivity assessed by screening of kinase inhibitory activity, identifying substituent derived selectivity. Extension of the hydroxymaleimide template to incorporate substitution of the indole nitrogens was next completed and assessed again by kinase inhibition identifying unique selectivity patterns with respect to GSK-3 and CDK kinases. Subsequently, the anticancer activity of bisindolylmaleimides were assessed using the NCI-60 cell screen, disclosing the discovery of growth inhibitory profiles towards a number of cell lines, such as SNB-75 CNS cancer, A498 and UO-31 renal, MDA MB435 melanoma and a panel of leukemia cell lines. The potential for selective kinase inhibition by modulation of this template is evident and will inform future selective clinical candidates.
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http://dx.doi.org/10.1016/j.bmc.2018.07.012DOI Listing
August 2018

Circadian periodicity in space use by ungulates of temperate regions: How much, when and why?

J Anim Ecol 2018 09 2;87(5):1299-1308. Epub 2018 Jul 2.

Laboratoire d'Ecologie Alpine, UMR CNRS 5553, Université de Savoie, Le Bourget-du-Lac, France.

When they visit and revisit specific areas, animals may reveal what they need from their home range and how they acquire information. The temporal dimension of such movement recursions, that is, periodicity, is however rarely studied, yet potentially bears a species, population or individual-specific signature. A recent method allows estimating the contribution of periodic patterns to the variance in a movement path. We applied it to 709 individuals from five ungulate species, looking for species signatures in the form of seasonal variation in the intensity of circadian patterns. Circadian patterns were commonplace in the movement tracks, but the amount of variance they explained was highly variable among individuals. It increased in intensity during spring and summer, when key resources were spatially segregated, and decreased during winter, when food availability was more uniformly low. Other periodicity-inducing mechanisms supported by our comparison of species- and sex-specific patterns involve young antipredator behaviour, territoriality and behavioural thermoregulation. Model-based continuous-time movement metrics represent a new avenue for researchers interested in finding individual-, population- or species-specific signatures in heterogeneous movement databases featuring various study designs and sampling resolutions. However, we observed large amounts of individual variation, so comparative analyses should ideally use both GPS and animal-borne loggers to augment the discriminatory power and be based on large samples. We briefly outline potential uses of the intensity of circadian patterns as a metric for the study of animal personality and community ecology.
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http://dx.doi.org/10.1111/1365-2656.12857DOI Listing
September 2018

Benzofuro[3,2-d]pyrimidines inspired from cercosporamide CaPkc1 inhibitor: Synthesis and evaluation of fluconazole susceptibility restoration.

Bioorg Med Chem Lett 2018 07 23;28(13):2250-2255. Epub 2018 May 23.

Université de Nantes, Nantes Atlantique Universités, Département de Chimie Thérapeutique, EA1155 - IICiMed, Institut de Recherche en Santé 2, F-44200 Nantes, France. Electronic address:

In a context of growing resistance to classical antifungal therapy, the design of new drugs targeting alternative pathways is highly expected. Benzofuro[3,2-d]pyrimidine derivatives, derived from (-)-cercosporamide, were synthesized and evaluated as potential Candida albicans PKC inhibitors in the aim of restoring susceptibility to azole treatment. Co-administration assay of benzofuropyrimidinedione 23 and fluconazole highlighted a synergistic effect on inhibition of cell growth of a Candida albicans resistant strain.
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http://dx.doi.org/10.1016/j.bmcl.2018.05.044DOI Listing
July 2018

Introduction history overrides social factors in explaining genetic structure of females in Mediterranean mouflon.

Ecol Evol 2017 11 16;7(22):9580-9591. Epub 2017 Nov 16.

Laboratoire de Biométrie et Biologie Evolutive CNRS Université Claude Bernard Lyon 1 Université de Lyon Villeurbanne France.

Fine-scale spatial genetic structure of populations results from social and spatial behaviors of individuals such as sex-biased dispersal and philopatry. However, the demographic history of a given population can override such socio-spatial factors in shaping genetic variability when bottlenecks or founder events occurred in the population. Here, we investigated whether socio-spatial organization determines the fine-scale genetic structure for both sexes in a Mediterranean mouflon (×  sp.) population in southern France 60 years after its introduction. Based on multilocus genotypes at 16 loci of microsatellite DNA ( = 230 individuals), we identified three genetic groups for females and two for males, and concurrently defined the same number of socio-spatial units using both GPS-collared individuals ( = 121) and visual resightings of marked individuals ( = 378). The socio-spatial and genetic structures did not match, indicating that the former was not the main driver of the latter for both sexes. Beyond this structural mismatch, we found significant, yet low, genetic differentiation among female socio-spatial groups, and no genetic differentiation in males, with this suggesting female philopatry and male-biased gene flow, respectively. Despite spatial disconnection, females from the north of the study area were genetically closer to females from the south, as indicated by the spatial analysis of the genetic variability, and this pattern was in accordance with the common genetic origin of their founders. To conclude, more than 14 generations later, genetic signatures of first introduction are not only still detectable among females, but they also represent the main factor shaping their present-time genetic structure.
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http://dx.doi.org/10.1002/ece3.3433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696436PMC
November 2017

Sociospatial structure explains marked variation in brucellosis seroprevalence in an Alpine ibex population.

Sci Rep 2017 11 15;7(1):15592. Epub 2017 Nov 15.

Office National de la Chasse et de la Faune Sauvage, Unité Sanitaire de la Faune, 5 allée de Béthléem, F-38610, Gières, France.

In a context of (re)emerging infectious diseases with wildlife reservoirs, understanding how animal ecology shapes epidemiology is a key issue, particularly in wild ungulates that share pathogens with domestic herbivores and have similar food requirements. For the first time in Europe, brucellosis (Brucella melitensis), a virulent zoonosis, persisted in an Alpine ibex (Capra ibex) population and was transmitted to cattle and humans. To better understand disease dynamics, we investigated the relationships between the spatial ecology of ibex and the epidemiology of brucellosis. Combining home range overlap between 37 GPS-collared individuals and visual observations of 148 visually-marked individuals monitored during the 2013-2016 period, we showed that females were spatially segregated in at least 4 units all year round, whereas males were more prone to move between female units, in particular during the rutting period. In addition to ibex age, the spatial structure in females largely contributed to variation in seroprevalence in the whole population. These results suggest that non-sexual routes are the most likely pathways of intraspecific transmission, crucial information for management. Accounting for wildlife spatial ecology was hence decisive in improving our ability to better understand this health challenge involving a wildlife reservoir.
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http://dx.doi.org/10.1038/s41598-017-15803-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5688143PMC
November 2017

Integrating Multidisciplinary Results to Produce New Knowledge About the Physician-Patient Relationship: A Methodology Applied to the INTERMEDE Project.

J Mix Methods Res 2017 Apr 13;11(2):174-201. Epub 2015 Aug 13.

INSERM UMR 1027, Toulouse, France.

The INTERMEDE Project brought together a number of research teams to study the interaction between a patient and their general practitioner, and how this can produce social inequalities in health. The ultimate objective of the project was to formalize a core of common findings by integrating qualitative and quantitative results. The methodology chosen for the integration was inspired by the Delphi participatory method. It involves several rounds of questions and feedback in writing between all members of project teams, in order to compare contradictory opinions and identify key concepts arising from the project. This interdisciplinary research has provided a more nuanced understanding of the mechanisms underlying physician-patient interaction by revealing the convergences of the various disciplinary approaches.
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http://dx.doi.org/10.1177/1558689815588643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407513PMC
April 2017

Fission-fusion dynamics over large distances in raven non-breeders.

Sci Rep 2017 03 23;7(1):380. Epub 2017 Mar 23.

Department of Cognitive Biology, University of Vienna, Althanstrasse 14, A-1090, Vienna, Austria.

The influence of fission-fusion dynamics, i.e., temporal variation in group size and composition, on social complexity has been studied in large-brained mammals that rely on social bonds. Little is known about birds, even though some species like ravens have recently received attention for their socio-cognitive skills and use of social bonds. While raven breeders defend territories year-round, non-breeders roam through large areas and form groups at food sources or night roosts. We here examined the fission-fusion patterns of non-breeding ravens over years, investigating whether birds meet repeatedly either at the same or at different locations. We combined four large datasets: presence-absence observations from two study sites (Austria, Italy) and GPS-tracking of ravens across two study areas (Austria, France). As expected, we found a highly dynamic system in which individuals with long phases of temporary settlement had a high probability of meeting others. Although GPS-tagged ravens spread out over thousands of square kilometres, we found repeated associations between almost half of the possible combinations at different locations. Such a system makes repeated interactions between individuals at different sites possible and likely. High fission-fusion dynamics may thus not hinder but shape the social complexity of ravens and, possibly, other long-term bonded birds.
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http://dx.doi.org/10.1038/s41598-017-00404-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428508PMC
March 2017

Combining familiarity and landscape features helps break down the barriers between movements and home ranges in a non-territorial large herbivore.

J Anim Ecol 2017 Mar 23;86(2):371-383. Epub 2017 Jan 23.

Laboratoire d'Ecologie Alpine, CNRS UMR 5553, Centre Interdisciplinaire des Sciences de la Montagne, Université Savoie Mont-Blanc, Bâtiment Belledonne Ouest, F-73376, Le Bourget-du-Lac, France.

Recent advances in animal ecology have enabled identification of certain mechanisms that lead to the emergence of territories and home ranges from movements considered as unbounded. Among them, memory and familiarity have been identified as key parameters in cognitive maps driving animal navigation, but have been only recently used in empirical analyses of animal movements. At the same time, the influence of landscape features on movements of numerous species and on space division in territorial animals has been highlighted. Despite their potential as exocentric information in cognitive maps and as boundaries for home ranges, few studies have investigated their role in the design of home ranges of non-territorial species. Using step selection analyses, we assessed the relative contribution of habitat characteristics, familiarity preferences and linear landscape features in movement step selection of 60 GPS-collared Mediterranean mouflon Ovis gmelini musimon × Ovis sp. monitored in southern France. Then, we evaluated the influence of these movement-impeding landscape features on the design of home ranges by testing for a non-random distribution of these behavioural barriers within sections of space differentially used by mouflon. We reveal that familiarity and landscape features are key determinants of movements, relegating to a lower level certain habitat constraints (e.g. food/cover trade-off) that we had previously identified as important for this species. Mouflon generally avoid crossing both anthropogenic (i.e. roads, tracks and hiking trails) and natural landscape features (i.e. ridges, talwegs and forest edges) while moving in the opposite direction, preferentially toward familiar areas. These specific behaviours largely depend on the relative position of each movement step regarding distance to the landscape features or level of familiarity in the surroundings. We also revealed cascading consequences on the design of home ranges in which most landscape features were excluded from cores and relegated to the peripheral areas. These results provide crucial information on landscape connectivity in a context of marked habitat fragmentation. They also call for more research on the role of landscape features in the emergence of home ranges in non-territorial species using recent methodological developments bridging the gap between movements and space use patterns.
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http://dx.doi.org/10.1111/1365-2656.12616DOI Listing
March 2017

Characterization of the biochemical, physiological, and medicinal properties of Streptomyces hygroscopicus ACTMS-9H isolated from the Amazon (Brazil).

Appl Microbiol Biotechnol 2017 Jan 18;101(2):711-723. Epub 2016 Oct 18.

Departamento de Antibióticos, Rua Prof. Moraes Rego, 1235, Universidade Federal de Pernambuco, Recife, Pernambuco, 50670-901, Brazil.

Actinomycetes are known to produce numerous secondary bioactive metabolites of pharmaceutical interest. The purpose of this study was to isolate, characterize, and investigate the antibacterial, antifungal, and anticancer activities of metabolites produced by Actinobacteria isolated from the rhizosphere of Paullinia cupana. The Actinobacteria was identified as Streptomyces hygroscopicus ACTMS-9H. Based on a bioguided study, the methanolic biomass extract obtained from submerged cultivation had the most potent antibacterial, antifungal, and cytotoxic activities. This extract was partitioned with n-hexane, ethyl acetate, and 2-butanol. Elaiophylin was isolated from the methanolic biomass extract, and its molecular formula was determined (CHO) based on H and C NMR, IR and MS analyses. The 2-butanol phase was fractionated into four fractions (EB1, EB2A, EB2B, and EB3M). Chemical prospecting indicated the presence of alkaloids, saponins, and reducing sugars in the methanolic extract and 2-butanol phase. The elaiophylin displayed anticancer activity in HEp-2 and HL-60 cells with an IC of 1 μg/mL. The EB1 fraction was selectively toxic to HL-60 cells with IC of 9 ng/mL. Bioautography showed that the EB1 fraction contained an alkaloid with antibacterial and antifungal activities (MIC values ≤1.9 and <3.9 μg/mL, respectively). In conclusion, the EB1 fraction and elaiophylin of S. hygroscopicus have potent antimicrobial, antifungal, and anticancer activities.
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http://dx.doi.org/10.1007/s00253-016-7886-9DOI Listing
January 2017

Discovery of Novel (Imidazo[1,2-a]pyrazin-6-yl)ureas as Antiproliferative Agents Targeting P53 in Non-small Cell Lung Cancer Cell Lines.

Anticancer Res 2016 Apr;36(4):1621-30

Medicinal Chemistry Department, Nantes University, Targets and Drugs for Infectious Diseases and Cancer, IICiMed EA 1155, Faculty of Pharmacy, Nantes, France

A series of (imidazo[1,2-a]pyrazin-6-yl)ureas were synthesized through 6-aminoimidazo[1,2-a]pyrazine as a key intermediate. 1-(Imidazo[1,2-a]pyrazin-6-yl)-3-(4-methoxy - phenyl)urea displayed a cytostatic activity against a non-small cell lung cancer cell line and was chosen for further mechanistic studies. Growth kinetics highlighted a selective dose-dependent response of P53-mutant NSCLC-N6-L16 cell line and overexpression of TP53 gene induced by this compound. These pharmacological data suggest a promising reactivation of p53 mutant in NSCLC-N6-L16 cell line.
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April 2016

Synthesis, antileishmanial activity and cytotoxicity of 2,3-diaryl- and 2,3,8-trisubstituted imidazo[1,2-a]pyrazines.

Eur J Med Chem 2015 Oct 9;103:381-95. Epub 2015 Sep 9.

Université de Nantes, Nantes Atlantique Universités, Laboratoire de Parasitologie et Mycologie Médicale, Cibles et Médicaments des Infections et du Cancer, IICiMed UPRES EA 1155, UFR de Sciences Pharmaceutiques et Biologiques, 1 rue Gaston Veil, 44035 Nantes, France.

A series of original 2-phenyl-3-(pyridin-4-yl)imidazo[1,2-a]pyrazines and the 3-iodo precursors, bearing a polar moiety at the C-8 position, was synthesized and evaluated for their antileishmanial activities. Two derivatives exhibited very good activity against the promastigote and the amastigote forms of Leishmania major in the micromolar to submicromolar ranges, coupled with a low cytotoxicity against macrophages and 3T3 mouse fibroblast cells. Through LmCK1 inhibition assay, investigations of the putative molecular target of these promising antileishmanial compounds will be discussed.
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http://dx.doi.org/10.1016/j.ejmech.2015.09.002DOI Listing
October 2015

Synthesis and molecular modelling studies of 8-arylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amines as multitarget Ser/Thr kinases inhibitors.

Eur J Med Chem 2015 Mar 23;92:124-34. Epub 2014 Dec 23.

Normandie Univ, COBRA, UMR 6014 & FR 3038; Univ Rouen; INSA Rouen; CNRS, Bâtiment IRCOF, 1 rue Tesnière, 76821 Mont St Aignan Cedex, France. Electronic address:

This paper reports the design and synthesis of a novel series of 8-arylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amines via microwave-assisted multi-step synthesis. A common precursor of the whole series, 3-amino-5-bromothieno[2,3-b]pyridine-2-carbonitrile, was rapidly synthesized in one step from commercially-available 5-bromo-2-chloronicotinonitrile. Formylation with DMF-DMA led to (E)-N'-(5-bromo-2-cyanothieno[2,3-b]pyridin-3-yl)-N,N-dimethylformimidamide (4) which was conveniently functionalized at position 8 by palladium-catalyzed Suzuki-Miyaura cross-coupling to introduce a heteroaromatic ring. High-temperature formamide-mediated cyclization of the cyanoamidine intermediate gave seventeen 8-arylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amines. The inhibitory potency of the final products was evaluated against five protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, DYRK1A and CLK1) and revealed that 8-(2,4-dichlorophenyl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine 1g specifically inhibits CK1δ/ε and CLK1 (220 and 88 nM, respectively) while its 7-(2,4-dichlorophenyl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine isomer 10 showed no activity on the panel of tested kinases. Molecular modelling of 10 and 1g in the ATP binding sites of CK1δ/ε and CLK1 showed that functionalization at position 7 of pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amines is likely to induce a steric clash on the CK1δ/ε P-loop and thus a complete loss of inhibitory activity.
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http://dx.doi.org/10.1016/j.ejmech.2014.12.038DOI Listing
March 2015

Discovery of (7-aryl-1,5-naphthyridin-2-yl)ureas as dual inhibitors of ERK2 and Aurora B kinases with antiproliferative activity against cancer cells.

Bioorg Med Chem Lett 2014 Aug 3;24(16):3748-52. Epub 2014 Jul 3.

Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer IICiMed EA 1155, UFR des Sciences Pharmaceutiques et Biologiques, 1 rue Gaston Veil, 44035 Nantes, France. Electronic address:

A novel series of (7-aryl-1,5-naphthyridin-2-yl)ureas was discovered as dual ERK2 and Aurora B kinases inhibitors. Several analogues were active at micromolar and submicromolar range against ERK2 and Aurora B, associated with very promising antiproliferative activity toward various cancer cell lines. Synthesis, structure activity relationship and docking study are reported. In vitro ADME properties and safety data are also discussed.
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http://dx.doi.org/10.1016/j.bmcl.2014.06.078DOI Listing
August 2014

Discovery of 7-aryl-substituted (1,5-naphthyridin-4-yl)ureas as aurora kinase inhibitors.

ChemMedChem 2014 Jan 24;9(1):217-32. Epub 2013 Nov 24.

Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer IICiMed EA 1155, UFR des Sciences Pharmaceutiques et Biologiques, 1 rue Gaston Veil, 44035 Nantes (France).

As part of our research projects to identify new chemical entities of biological interest, we developed a synthetic approach and the biological evaluation of (7-aryl-1,5-naphthyridin-4-yl)ureas as a novel class of Aurora kinase inhibitors for the treatment of malignant diseases based on pathological cell proliferation. 1,5-Naphthyridine derivatives showed excellent inhibitory activities toward Aurora kinases A and B, and the most active compound, 1-cyclopropyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]urea (49), displayed IC₅₀ values of 13 and 107 nM against Aurora kinases A and B, respectively. In addition, the selectivity toward a panel of seven cancer-related protein kinases was highlighted. In vitro ADME properties were also determined in order to rationalize the difficulties in correlating antiproliferative activity with Aurora kinase inhibition. Finally, the good safety profile of these compounds imparts promising potential for their further development as anticancer agents.
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http://dx.doi.org/10.1002/cmdc.201300384DOI Listing
January 2014

Synthesis of novel 7-substituted pyrido[2',3':4,5]furo[3,2-d]pyrimidin-4-amines and their N-aryl analogues and evaluation of their inhibitory activity against Ser/Thr kinases.

Bioorg Med Chem Lett 2013 Dec 17;23(24):6784-8. Epub 2013 Oct 17.

Normandie Univ, COBRA, UMR 6014 & FR 3038; Univ Rouen; INSA Rouen; CNRS, Bâtiment IRCOF, 1 rue Tesnière, 76821 Mont St Aignan Cedex, France.

The efficient synthesis of 7-substituted pyrido[2',3':4,5]furo[3,2-d]pyrimidin-4-amines and their N-aryl analogues is described. 3,5-Dibromopyridine was converted into 3-amino-6-bromofuro[3,2-b]pyridine-2-carbonitrile intermediate which was formylated with DMFDMA. Functionalization at position 7 of the tricyclic scaffold was accomplished, before or after cyclisation step, by palladium-catalyzed Suzuki-Miyaura cross-coupling while the pyrimidin-4-amines and N-aryl counterparts were synthesized by microwave-assisted formamide degradation and Dimroth rearrangement, respectively. The final products were evaluated for their potent inhibition of a series of five Ser/Thr kinases (CDK5/p25, CK1δ/ε, CLK1, DYRK1A, GSK3α/β). Compound 35 showed the best inhibitory activity with an IC50 value of 49 nM and proved to be specific to CLK1 among the panel of tested kinases.
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http://dx.doi.org/10.1016/j.bmcl.2013.10.019DOI Listing
December 2013