The Experts below are selected from a list of 321 Experts worldwide ranked by ideXlab platform
Ahcene Boumendjel - One of the best experts on this subject based on the ideXlab platform.
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Aurone derivatives as promising antibacterial agents against resistant Gram-positive pathogens
European Journal of Medicinal Chemistry, 2019Co-Authors: Hamza Olleik, Samir Yahiaoui, Brayan Roulier, Elise Courvoisier-dezord, Josette Perrier, Basile Peres, Akram Hijazi, Elias Baydoun, Josette Raymond, Ahcene BoumendjelAbstract: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.
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occurrences biosynthesis and properties of Aurones as high end evolutionary products
Phytochemistry, 2017Co-Authors: Benjamin Boucherle, Marine Peuchmaur, Ahcene Boumendjel, Romain HaudecoeurAbstract: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.
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disruption of fibers from the tau model acphf6 by naturally occurring Aurones and synthetic analogues
ACS Chemical Neuroscience, 2016Co-Authors: Laurent Lunven, Wei Yi, Ahcene Boumendjel, Samir Yahiaoui, Hugues Bonnet, Laurene Da Costa, Marine Peuchmaur, Sabine ChiericiAbstract: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...
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b ring modified Aurones as promising allosteric inhibitors of hepatitis c virus rna dependent rna polymerase
European Journal of Medicinal Chemistry, 2014Co-Authors: Amel Meguellati, Romain Haudecoeur, Abdelhakim Ahmedbelkacem, Wei Yi, Rozenn Brillet, Jeanmichel Pawlotsky, Ahcene Boumendjel, Marie Crouillere, Marine PeuchmaurAbstract: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.
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recent advances in the medicinal chemistry of Aurones
Current Medicinal Chemistry, 2012Co-Authors: Romain Haudecoeur, Ahcene BoumendjelAbstract:The first review regarding the potential of Aurones as promising drug candidates was reported in 2003. Since, considerable efforts have been made to explore the pharmacological and therapeutical activities of Aurones. In this regard, many biological areas were concerned, including major pathological, such as cancer and neurodegenerative disorders. The aim of the present report is to highlight the progress made during the last ten years on the medicinal chemistry of Aurones. A special focus will be made on the structure-activity relationship aspects among Aurones and especially in case where Aurones were found highly active than the corresponding flavones and chalcones.
Romain Haudecoeur - One of the best experts on this subject based on the ideXlab platform.
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occurrences biosynthesis and properties of Aurones as high end evolutionary products
Phytochemistry, 2017Co-Authors: Benjamin Boucherle, Marine Peuchmaur, Ahcene Boumendjel, Romain HaudecoeurAbstract: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.
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2 hydroxypyridine n oxide embedded Aurones as potent human tyrosinase inhibitors
ACS Medicinal Chemistry Letters, 2017Co-Authors: Romain Haudecoeur, Marcello Carotti, Aurelie Gouron, Elina Buitrago, Elisabetta Bergantino, Hele Ne Jamet, Catherine Belle, Renaud Hardré, Marc Maresca, Marius RéglierAbstract: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...
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2-hydroxypyridine-N-oxide-embedded Aurones as potent human tyrosinase inhibitors
ACS Medicinal Chemistry Letters, 2017Co-Authors: Romain Haudecoeur, Marcello Carotti, Aurelie Gouron, Elina Buitrago, Elisabetta Bergantino, Hele Ne Jamet, Catherine Belle, Renaud Hardré, Marc Maresca, Marius RéglierAbstract: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)]
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investigation of binding site homology between mushroom and bacterial tyrosinases by using Aurones as effectors
ChemBioChem, 2014Co-Authors: Romain Haudecoeur, Aurelie Gouron, Elisabetta Bergantino, Hele Ne Jamet, Renaud Hardré, Carole Dubois, Mark Lightbody, Anne Milet, Luigi Bubacco, Catherine BelleAbstract:Tyrosinase is a copper-containing enzyme found in plants and bacteria, as well as in humans, where it is involved in the biosynthesis of melanin-type pigments. Tyrosinase inhibitors have attracted remarkable research interest as whitening agents in cosmetology, antibrowning agents in food chemistry, and as therapeutics. In this context, commercially available tyrosinase from mushroom (TyM) is frequently used for the identification of inhibitors. This and bacterial tyrosinase (TyB) have been the subjects of intense biochemical and structural studies, including X-ray diffraction analysis, and this has led to the identification of structural homology and divergence among enzymes from different sources. To better understand the behavior of potential inhibitors of TyM and TyB, we selected the aurone family—previously identified as potential inhibitors of melanin biosynthesis in human melanocytes. In this study, a series of 24 Aurones with different hydroxylation patterns at the A- and B-rings were evaluated on TyM and TyB. The results show that, depending on the hydroxylation pattern of A- and B-rings, Aurones can behave as inhibitors, substrates, and activators of both enzymes. Computational analysis was performed to identify residues surrounding the Aurones in the active sites of both enzymes and to rationalize the interactions. Our results highlight similarities and divergence in the behavior of TyM and TyB toward the same set of molecules.
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b ring modified Aurones as promising allosteric inhibitors of hepatitis c virus rna dependent rna polymerase
European Journal of Medicinal Chemistry, 2014Co-Authors: Amel Meguellati, Romain Haudecoeur, Abdelhakim Ahmedbelkacem, Wei Yi, Rozenn Brillet, Jeanmichel Pawlotsky, Ahcene Boumendjel, Marie Crouillere, Marine PeuchmaurAbstract: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.
Jeanmichel Pawlotsky - One of the best experts on this subject based on the ideXlab platform.
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new pseudodimeric Aurones as palm pocket inhibitors of hepatitis c virus rna dependent rna polymerase
European Journal of Medicinal Chemistry, 2016Co-Authors: Amel Meguellati, Abdelhakim Ahmedbelkacem, Wei Yi, Antoine Fortune, Rozenn Brillet, Jeanmichel Pawlotsky, Alessandra Nurisso, Nawel Berqouch, Laura ChavoutierAbstract: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.
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b ring modified Aurones as promising allosteric inhibitors of hepatitis c virus rna dependent rna polymerase
European Journal of Medicinal Chemistry, 2014Co-Authors: Amel Meguellati, Romain Haudecoeur, Abdelhakim Ahmedbelkacem, Wei Yi, Rozenn Brillet, Jeanmichel Pawlotsky, Ahcene Boumendjel, Marie Crouillere, Marine PeuchmaurAbstract: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.
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discovery of naturally occurring Aurones that are potent allosteric inhibitors of hepatitis c virus rna dependent rna polymerase
Journal of Medicinal Chemistry, 2011Co-Authors: Romain Haudecoeur, Catherine Belle, Abdelhakim Ahmedbelkacem, Wei Yi, Antoine Fortune, Rozenn Brillet, Edwige Nicolle, Coralie Pallier, Jeanmichel Pawlotsky, Ahcene BoumendjelAbstract: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.
Weike Su - One of the best experts on this subject based on the ideXlab platform.
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copper catalyzed intramolecular tandem reaction of 2 halogenphenyl 3 phenyloxiran 2 yl methanones synthesis of z Aurones
ChemInform, 2014Co-Authors: Yiyi Weng, Qixu Chen, Weike SuAbstract:This is the first report on the synthesis of (Z)-Aurones through copper-catalyzed Ullmann coupling reaction employing substrates bearing an epoxide structural element.
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copper catalyzed intramolecular tandem reaction of 2 halogenphenyl 3 phenyloxiran 2 yl methanones synthesis of z Aurones
Journal of Organic Chemistry, 2014Co-Authors: Yiyi Weng, Qixu Chen, Weike SuAbstract:A convenient and efficient method for the copper-catalyzed synthesis of (Z)-Aurones via intramolecular tandem reaction of (2-halogenphenyl)(3-phenyloxiran-2-yl)methanones is reported. Moreover, a plausible mechanism for the formation of (Z)-Aurones is proposed. This is the first report on the synthesis of (Z)-Aurones through copper-catalyzed Ullmann coupling reaction employing epoxides as substrates.
Catherine Belle - One of the best experts on this subject based on the ideXlab platform.
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2 hydroxypyridine n oxide embedded Aurones as potent human tyrosinase inhibitors
ACS Medicinal Chemistry Letters, 2017Co-Authors: Romain Haudecoeur, Marcello Carotti, Aurelie Gouron, Elina Buitrago, Elisabetta Bergantino, Hele Ne Jamet, Catherine Belle, Renaud Hardré, Marc Maresca, Marius RéglierAbstract: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...
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2-hydroxypyridine-N-oxide-embedded Aurones as potent human tyrosinase inhibitors
ACS Medicinal Chemistry Letters, 2017Co-Authors: Romain Haudecoeur, Marcello Carotti, Aurelie Gouron, Elina Buitrago, Elisabetta Bergantino, Hele Ne Jamet, Catherine Belle, Renaud Hardré, Marc Maresca, Marius RéglierAbstract: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)]
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investigation of binding site homology between mushroom and bacterial tyrosinases by using Aurones as effectors
ChemBioChem, 2014Co-Authors: Romain Haudecoeur, Aurelie Gouron, Elisabetta Bergantino, Hele Ne Jamet, Renaud Hardré, Carole Dubois, Mark Lightbody, Anne Milet, Luigi Bubacco, Catherine BelleAbstract:Tyrosinase is a copper-containing enzyme found in plants and bacteria, as well as in humans, where it is involved in the biosynthesis of melanin-type pigments. Tyrosinase inhibitors have attracted remarkable research interest as whitening agents in cosmetology, antibrowning agents in food chemistry, and as therapeutics. In this context, commercially available tyrosinase from mushroom (TyM) is frequently used for the identification of inhibitors. This and bacterial tyrosinase (TyB) have been the subjects of intense biochemical and structural studies, including X-ray diffraction analysis, and this has led to the identification of structural homology and divergence among enzymes from different sources. To better understand the behavior of potential inhibitors of TyM and TyB, we selected the aurone family—previously identified as potential inhibitors of melanin biosynthesis in human melanocytes. In this study, a series of 24 Aurones with different hydroxylation patterns at the A- and B-rings were evaluated on TyM and TyB. The results show that, depending on the hydroxylation pattern of A- and B-rings, Aurones can behave as inhibitors, substrates, and activators of both enzymes. Computational analysis was performed to identify residues surrounding the Aurones in the active sites of both enzymes and to rationalize the interactions. Our results highlight similarities and divergence in the behavior of TyM and TyB toward the same set of molecules.
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Versatile Effects of Aurone Structure on Mushroom Tyrosinase Activity
ChemBioChem, 2012Co-Authors: Carole Dubois, Hele Ne Jamet, Catherine Belle, Romain Haudecoeur, Renaud Hardré, Ahcene Boumendjel, Maylis Orio, Constance Bochot, Marius RéglierAbstract:Elucidation of the binding modes of Ty inhibitors is an important step for in-depth studies on how to regulate tyrosinase activity. In this paper we highlight the extraordinarily versatile effects of the aurone structure on mushroom Ty activity. Depending on the position of the OH group on the B-ring, Aurones can behave either as substrates or as hyperbolic activators. The synthesis of a hybrid aurone through combination of an aurone moiety with HOPNO (2-hydroxypyridine N-oxide), a good metal chelate, led us to a new, efficient, mixed inhibitor for mushroom tyrosinase. Another important feature pointed out by our study is the presence of more than one site for aurone compounds on mushroom tyrosinase. Because study of the binding of the hybrid aurone was difficult to perform with the enzyme, we undertook binding studies with tyrosinase functional models in order to elucidate the binding mode (chelating vs. bridging) on a dicopper(II) center. Use of EPR combined with theoretical DFT calculations allowed us to propose a preferred chelating mode for the interaction of the hybrid aurone with a dicopper(II) center.
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discovery of naturally occurring Aurones that are potent allosteric inhibitors of hepatitis c virus rna dependent rna polymerase
Journal of Medicinal Chemistry, 2011Co-Authors: Romain Haudecoeur, Catherine Belle, Abdelhakim Ahmedbelkacem, Wei Yi, Antoine Fortune, Rozenn Brillet, Edwige Nicolle, Coralie Pallier, Jeanmichel Pawlotsky, Ahcene BoumendjelAbstract: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.