Novel Multi-Target Agents Based on the Privileged Structure of 4-Hydroxy-2-quinolinone
In this work, the privileged scaffold of 4-hydroxy-2quinolinone is investigated through the synthesis of carboxamides and hybrid derivatives, as well as through their bioactivity evaluation, focusing on the ability of the molecules to inhibit the soybean LOX, as an indication of their anti-inflammat...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-12-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/29/1/190 |
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| author | Ioanna Kostopoulou Andromachi Tzani Konstantina Chronaki Kyriakos C. Prousis Eleni Pontiki Dimitra Hadjiplavlou-Litina Anastasia Detsi |
| author_facet | Ioanna Kostopoulou Andromachi Tzani Konstantina Chronaki Kyriakos C. Prousis Eleni Pontiki Dimitra Hadjiplavlou-Litina Anastasia Detsi |
| author_sort | Ioanna Kostopoulou |
| collection | DOAJ |
| description | In this work, the privileged scaffold of 4-hydroxy-2quinolinone is investigated through the synthesis of carboxamides and hybrid derivatives, as well as through their bioactivity evaluation, focusing on the ability of the molecules to inhibit the soybean LOX, as an indication of their anti-inflammatory activity. Twenty-one quinolinone carboxamides, seven novel hybrid compounds consisting of the quinolinone moiety and selected cinnamic or benzoic acid derivatives, as well as three reverse amides are synthesized and classified as multi-target agents according to their LOX inhibitory and antioxidant activity. Among all the synthesized analogues, quinolinone–carboxamide compounds <b>3h</b> and <b>3s</b>, which are introduced for the first time in the literature, exhibited the best LOX inhibitory activity (IC<sub>50</sub> = 10 μM). Furthermore, carboxamide <b>3g</b> and quinolinone hybrid with acetylated ferulic acid <b>11e</b> emerged as multi-target agents, revealing combined antioxidant and LOX inhibitory activity (<b>3g</b>: IC<sub>50</sub> = 27.5 μM for LOX inhibition, 100% inhibition of lipid peroxidation, 67.7% ability to scavenge hydroxyl radicals and 72.4% in the ABTS radical cation decolorization assay; <b>11e</b>: IC<sub>50</sub> = 52 μM for LOX inhibition and 97% inhibition of lipid peroxidation). The in silico docking results revealed that the synthetic carboxamide analogues <b>3h</b> and <b>3s</b> and NDGA (the reference compound) bind at the same alternative binding site in a similar binding mode. |
| first_indexed | 2024-03-08T15:01:46Z |
| format | Article |
| id | doaj.art-cd6a7b2823ec4b4195c1feb79a6cc8fa |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-08T15:01:46Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-cd6a7b2823ec4b4195c1feb79a6cc8fa2024-01-10T15:04:27ZengMDPI AGMolecules1420-30492023-12-0129119010.3390/molecules29010190Novel Multi-Target Agents Based on the Privileged Structure of 4-Hydroxy-2-quinolinoneIoanna Kostopoulou0Andromachi Tzani1Konstantina Chronaki2Kyriakos C. Prousis3Eleni Pontiki4Dimitra Hadjiplavlou-Litina5Anastasia Detsi6Laboratory of Organic Chemistry, Department of Chemical Sciences, School of Chemical Engineering, National Technical University of Athens, Heroon Polytechniou 9, Zografou Campus, 15780 Athens, GreeceLaboratory of Organic Chemistry, Department of Chemical Sciences, School of Chemical Engineering, National Technical University of Athens, Heroon Polytechniou 9, Zografou Campus, 15780 Athens, GreeceLaboratory of Organic Chemistry, Department of Chemical Sciences, School of Chemical Engineering, National Technical University of Athens, Heroon Polytechniou 9, Zografou Campus, 15780 Athens, GreeceInstitute of Chemical Biology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635 Athens, GreeceLaboratory of Pharmaceutical Chemistry, Faculty of Health Sciences, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, GreeceLaboratory of Pharmaceutical Chemistry, Faculty of Health Sciences, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, GreeceLaboratory of Organic Chemistry, Department of Chemical Sciences, School of Chemical Engineering, National Technical University of Athens, Heroon Polytechniou 9, Zografou Campus, 15780 Athens, GreeceIn this work, the privileged scaffold of 4-hydroxy-2quinolinone is investigated through the synthesis of carboxamides and hybrid derivatives, as well as through their bioactivity evaluation, focusing on the ability of the molecules to inhibit the soybean LOX, as an indication of their anti-inflammatory activity. Twenty-one quinolinone carboxamides, seven novel hybrid compounds consisting of the quinolinone moiety and selected cinnamic or benzoic acid derivatives, as well as three reverse amides are synthesized and classified as multi-target agents according to their LOX inhibitory and antioxidant activity. Among all the synthesized analogues, quinolinone–carboxamide compounds <b>3h</b> and <b>3s</b>, which are introduced for the first time in the literature, exhibited the best LOX inhibitory activity (IC<sub>50</sub> = 10 μM). Furthermore, carboxamide <b>3g</b> and quinolinone hybrid with acetylated ferulic acid <b>11e</b> emerged as multi-target agents, revealing combined antioxidant and LOX inhibitory activity (<b>3g</b>: IC<sub>50</sub> = 27.5 μM for LOX inhibition, 100% inhibition of lipid peroxidation, 67.7% ability to scavenge hydroxyl radicals and 72.4% in the ABTS radical cation decolorization assay; <b>11e</b>: IC<sub>50</sub> = 52 μM for LOX inhibition and 97% inhibition of lipid peroxidation). The in silico docking results revealed that the synthetic carboxamide analogues <b>3h</b> and <b>3s</b> and NDGA (the reference compound) bind at the same alternative binding site in a similar binding mode.https://www.mdpi.com/1420-3049/29/1/1904-hydroxy-2-quinolinonecarboxamidesantioxidant activitylipoxygenase inhibitionstructure–activity relationshipsmolecular docking |
| spellingShingle | Ioanna Kostopoulou Andromachi Tzani Konstantina Chronaki Kyriakos C. Prousis Eleni Pontiki Dimitra Hadjiplavlou-Litina Anastasia Detsi Novel Multi-Target Agents Based on the Privileged Structure of 4-Hydroxy-2-quinolinone Molecules 4-hydroxy-2-quinolinone carboxamides antioxidant activity lipoxygenase inhibition structure–activity relationships molecular docking |
| title | Novel Multi-Target Agents Based on the Privileged Structure of 4-Hydroxy-2-quinolinone |
| title_full | Novel Multi-Target Agents Based on the Privileged Structure of 4-Hydroxy-2-quinolinone |
| title_fullStr | Novel Multi-Target Agents Based on the Privileged Structure of 4-Hydroxy-2-quinolinone |
| title_full_unstemmed | Novel Multi-Target Agents Based on the Privileged Structure of 4-Hydroxy-2-quinolinone |
| title_short | Novel Multi-Target Agents Based on the Privileged Structure of 4-Hydroxy-2-quinolinone |
| title_sort | novel multi target agents based on the privileged structure of 4 hydroxy 2 quinolinone |
| topic | 4-hydroxy-2-quinolinone carboxamides antioxidant activity lipoxygenase inhibition structure–activity relationships molecular docking |
| url | https://www.mdpi.com/1420-3049/29/1/190 |
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