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Aurones

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Ahcene Boumendjel – 1st expert on this subject based on the ideXlab platform

  • Aurone derivatives as promising antibacterial agents against resistant Gram-positive pathogens
    European Journal of Medicinal Chemistry, 2019
    Co-Authors: Hamza Olleik, Samir Yahiaoui, Brayan Roulier, Elise Courvoisier-dezord, Josette Perrier, Basile Peres, Akram Hijazi, Elias Baydoun, Josette Raymond, Ahcene Boumendjel

    Abstract:

    Abstract A set of variously substituted Aurones was synthesized and evaluated against Methicillin-Resistant S. aureus (MRSA) and P. aeruginosa. Several analogues were found active against MRSA, but no effect was recorded against P. aeruginosa. Compounds 27, 30 and 33 showed low cytotoxicity, and were tested against a full range of bacterial (Gram-positive and Gram-negative) and fungal species, including resistant strains. These Aurones displayed a selective inhibition of Gram-positive bacteria with excellent Therapeutic Index values, while showing no significant action on several Gram-negative strains, H. pylori and V. alginolyticus being the only susceptible strains among the Gram-negative bacteria tested. A permeabilization assay showed that the antibacterial activity of at least some of the Aurones could be linked to alterations of the bacterial membrane. Overall, this study endorses the use of the aurone scaffold for the development of new potent and selective antibacterial agents.

  • occurrences biosynthesis and properties of Aurones as high end evolutionary products
    Phytochemistry, 2017
    Co-Authors: Benjamin Boucherle, Marine Peuchmaur, Ahcene Boumendjel, Romain Haudecoeur

    Abstract:

    Recent years have witnessed a considerable renewed interest for the uncommon flavonoid class of Aurones. The characterization of two major biosynthetic machineries involved in their biosynthesis in flowers has encouraged the revival of phytochemical studies and identification of original structures, a process started almost seventy-five years ago. This review draws up an exhaustive map of natural occurrences of Aurones their biosynthetic pathways and roles, with the aim to link their original structural properties among flavonoids to their place in evolution and the selective advantages they bring to some of the most advanced taxa in the plant kingdom.

  • disruption of fibers from the tau model acphf6 by naturally occurring Aurones and synthetic analogues
    ACS Chemical Neuroscience, 2016
    Co-Authors: Laurent Lunven, Ahcene Boumendjel, Wei Yi, Samir Yahiaoui, Hugues Bonnet, Laurene Da Costa, Marine Peuchmaur, Sabine Chierici

    Abstract:

    The formation of tau aggregates is strongly linked to the neurodegenerative process in tauopathies such as Alzheimer’s disease (AD). Yet only a few molecules have shown to efficiently prevent the in vitro formation of those aggregates, and the identification of such molecules is still an ongoing interest in a therapeutic context. Herein, we report the in vitro evaluation of a series of Aurones against the fibrillation of the tau-derived hexapeptide AcPHF6 model. Using thioflavin T-based fluorescence assays, circular dichroism and atomic force microscopy, we showed that Aurones are capable of efficiently interacting with the tau-derived hexapeptide. Importantly, this work reveals a significant activity observed for polyhydroxylated Aurones. In particular, aurone 23 displayed an almost complete inhibition of fibers formation as shown by AFM at a peptide/inhibitor 1:1 ratio. It is similar to that observed for myricetin, a polyphenolic compound, well-known to prevent the in vitro elongation of tau fibers. Mor…

Romain Haudecoeur – 2nd expert on this subject based on the ideXlab platform

  • occurrences biosynthesis and properties of Aurones as high end evolutionary products
    Phytochemistry, 2017
    Co-Authors: Benjamin Boucherle, Marine Peuchmaur, Ahcene Boumendjel, Romain Haudecoeur

    Abstract:

    Recent years have witnessed a considerable renewed interest for the uncommon flavonoid class of Aurones. The characterization of two major biosynthetic machineries involved in their biosynthesis in flowers has encouraged the revival of phytochemical studies and identification of original structures, a process started almost seventy-five years ago. This review draws up an exhaustive map of natural occurrences of Aurones their biosynthetic pathways and roles, with the aim to link their original structural properties among flavonoids to their place in evolution and the selective advantages they bring to some of the most advanced taxa in the plant kingdom.

  • 2 hydroxypyridine n oxide embedded Aurones as potent human tyrosinase inhibitors
    ACS Medicinal Chemistry Letters, 2017
    Co-Authors: Romain Haudecoeur, Marcello Carotti, Aurelie Gouron, Marc Maresca, Elina Buitrago, Renaud Hardré, Elisabetta Bergantino, Hele Ne Jamet, Catherine Belle, Marius Réglier

    Abstract:

    With the aim to develop effective and selective human tyrosinase inhibitors, we investigated aurone derivatives whose B-ring was replaced by a non-oxidizable 2-hydroxypyridine-N-oxide (HOPNO) moiety. These Aurones were synthesized and evaluated as inhibitors of purified human tyrosinase. Excellent inhibition activity was revealed and rationalized by theoretical calculations. The aurone backbone was especially found to play a crucial role, as the HOPNO moiety alone provided very modest activity on human tyrosinase. Furthermore, the in vitro activity was confirmed by measuring the melanogenesis suppression ability of the compounds in melanoma cell lysates and whole cells. Our study reveals that HOPNO-embedded 6-hydroxyaurone is to date the most effective inhibitor of isolated human tyrosinase. Owing to its low toxicity and its high inhibition activity, it could represent a milestone on the path toward new valuable agents in dermocosmetics, as well as in medical fields where it was recently suggested that ty…

  • 2-hydroxypyridine-N-oxide-embedded Aurones as potent human tyrosinase inhibitors
    ACS Medicinal Chemistry Letters, 2017
    Co-Authors: Romain Haudecoeur, Marcello Carotti, Aurelie Gouron, Marc Maresca, Elina Buitrago, Renaud Hardré, Elisabetta Bergantino, Hele Ne Jamet, Catherine Belle, Marius Réglier

    Abstract:

    With the aim to develop effective and selective human tyrosinase inhibitors, we investigated aurone derivs. whose B-ring was replaced by a non-oxidizable 2-hydroxypyridine-N-oxide (HOPNO) moiety. These Aurones were synthesized and evaluated as inhibitors of purified human tyrosinase. Excellent inhibition activity was revealed and rationalized by theor. calcns. The aurone backbone was esp. found to play a crucial role, as the HOPNO moiety alone provided very modest activity on human tyrosinase. Furthermore, the in vitro activity was confirmed by measuring the melanogenesis suppression ability of the compds. in melanoma cell lysates and whole cells. Our study reveals that HOPNO-embedded 6-hydroxyaurone is to date the most effective inhibitor of isolated human tyrosinase. Owing to its low toxicity and its high inhibition activity, it could represent a milestone on the path toward new valuable agents in dermocosmetics, as well as in medical fields where it was recently suggested that tyrosinase could play key roles. [on SciFinder(R)]

Jeanmichel Pawlotsky – 3rd expert on this subject based on the ideXlab platform

  • new pseudodimeric Aurones as palm pocket inhibitors of hepatitis c virus rna dependent rna polymerase
    European Journal of Medicinal Chemistry, 2016
    Co-Authors: Amel Meguellati, Abdelhakim Ahmedbelkacem, Wei Yi, Antoine Fortune, Rozenn Brillet, Jeanmichel Pawlotsky, Alessandra Nurisso, Nawel Berqouch, Laura Chavoutier

    Abstract:

    The NS5B RNA-dependent RNA polymerase (RdRp) is a key enzyme for Hepatitis C Virus (HCV) replication. In addition to the catalytic site, this enzyme is characterized by the presence of at least four allosteric pockets making it an interesting target for development of inhibitors as potential anti-HCV drugs. Based on a previous study showing the potential of the naturally occurring Aurones as inhibitors of NS5B, we pursued our efforts to focus on pseudodimeric Aurones that have never been investigated so far. Hence, 14 original compounds characterized by the presence of a spacer between the benzofuranone moieties were synthesized and investigated as HCV RdRp inhibitors by means of an in vitro assay. The most active inhibitor, pseudodimeric aurone 4, induced high inhibition activity (IC50 = 1.3 μM). Mutagenic and molecular modeling studies reveal that the binding site for the most active derivatives probably is the palm pocket I instead of the thumb pocket I as for the monomeric derivatives.

  • b ring modified Aurones as promising allosteric inhibitors of hepatitis c virus rna dependent rna polymerase
    European Journal of Medicinal Chemistry, 2014
    Co-Authors: Amel Meguellati, Romain Haudecoeur, Ahcene Boumendjel, Abdelhakim Ahmedbelkacem, Wei Yi, Rozenn Brillet, Jeanmichel Pawlotsky, Marie Crouillere, Marine Peuchmaur

    Abstract:

    Abstract Following our recent report showing the potential of naturally occurring Aurones (2-benzylidenebenzofuran-3(2 H )-ones) as anti-hepatitis C virus (HCV) agents, efforts were continued in order to refine the structural requirements for the inhibitory effect on HCV RNA-dependent RNA polymerase (RdRp). In this study, we targeted the B-ring moiety of Aurones with the aim to improve structural features associated with higher inhibition of the targeted polymerase. In vitro evaluation of the RdRp inhibitory activity of the 37 newly synthesized compounds pointed out that the replacement of the B-ring with an N -substituted indole moiety induced the highest inhibitory effect. Of these, compounds 31 , 40 and 41 were found to be the most active (IC 50  = 2.3–2.4 μM). Docking experiments performed with the most active compounds revealed that the allosteric thumb pocket I of RdRp is the binding pocket for aurone analogues.

  • discovery of naturally occurring Aurones that are potent allosteric inhibitors of hepatitis c virus rna dependent rna polymerase
    Journal of Medicinal Chemistry, 2011
    Co-Authors: Romain Haudecoeur, Catherine Belle, Abdelhakim Ahmedbelkacem, Wei Yi, Antoine Fortune, Rozenn Brillet, Edwige Nicolle, Coralie Pallier, Jeanmichel Pawlotsky, Ahcene Boumendjel

    Abstract:

    We have identified naturally occurring 2-benzylidenebenzofuran-3-ones (Aurones) as new templates for non-nucleoside hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) inhibitors. The aurone target site, identified by site-directed mutagenesis, is located in thumb pocket I of HCV RdRp. The RdRp inhibitory activity of 42 Aurones was rationally explored in an enzyme assay. Molecular docking studies were used to determine how Aurones bind to HCV RdRp and to predict their range of inhibitory activity. Seven aurone derivatives were found to have potent inhibitory effects on HCV RdRp, with IC(50) below 5 μM and excellent selectivity index (inhibition activity versus cellular cytotoxicity). The most active aurone analogue was (Z)-2-((1-butyl-1H-indol-3-yl)methylene)-4,6-dihydroxybenzofuran-3(2H)-one (compound 51), with an IC(50) of 2.2 μM. Their potent RdRp inhibitory activity and their low toxicity make these molecules attractive candidates as direct-acting anti-HCV agents.