Exploring the 2′-Hydroxy-Chalcone Framework for the Development of Dual Antioxidant and Soybean Lipoxygenase Inhibitory Agents
Ioanna Kostopoulou,
Andromachi Tzani,
Nestor-Ioannis Polyzos,
Maria-Anna Karadendrou,
Eftichia Kritsi,
Eleni Pontiki,
Thalia Liargkova,
Dimitra Hadjipavlou-Litina,
Panagiotis Zoumpoulakis,
Anastasia Detsi
Affiliations
Ioanna Kostopoulou
Laboratory of Organic Chemistry, Department of Chemical Sciences, School of Chemical Engineering, National Technical University of Athens, Heroon Polytechniou 9, Zografou Campus, 15780 Athens, Greece
Andromachi Tzani
Laboratory of Organic Chemistry, Department of Chemical Sciences, School of Chemical Engineering, National Technical University of Athens, Heroon Polytechniou 9, Zografou Campus, 15780 Athens, Greece
Nestor-Ioannis Polyzos
Laboratory of Organic Chemistry, Department of Chemical Sciences, School of Chemical Engineering, National Technical University of Athens, Heroon Polytechniou 9, Zografou Campus, 15780 Athens, Greece
Maria-Anna Karadendrou
Laboratory of Organic Chemistry, Department of Chemical Sciences, School of Chemical Engineering, National Technical University of Athens, Heroon Polytechniou 9, Zografou Campus, 15780 Athens, Greece
Eftichia Kritsi
Institute of Chemical Biology, National Hellenic Research Foundation, 48, Vas. Constantinou Avenue, 11635 Athens, Greece
Eleni Pontiki
Laboratory of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
Thalia Liargkova
Laboratory of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
Dimitra Hadjipavlou-Litina
Laboratory of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
Panagiotis Zoumpoulakis
Institute of Chemical Biology, National Hellenic Research Foundation, 48, Vas. Constantinou Avenue, 11635 Athens, Greece
Anastasia Detsi
Laboratory of Organic Chemistry, Department of Chemical Sciences, School of Chemical Engineering, National Technical University of Athens, Heroon Polytechniou 9, Zografou Campus, 15780 Athens, Greece
2′-hydroxy-chalcones are naturally occurring compounds with a wide array of bioactivity. In an effort to delineate the structural features that favor antioxidant and lipoxygenase (LOX) inhibitory activity, the design, synthesis, and bioactivity profile of a series of 2′-hydroxy-chalcones bearing diverse substituents on rings A and B, are presented. Among all the synthesized derivatives, chalcone 4b, bearing two hydroxyl substituents on ring B, was found to possess the best combined activity (82.4% DPPH radical scavenging ability, 82.3% inhibition of lipid peroxidation, and satisfactory LOX inhibition value (IC50 = 70 μM). Chalcone 3c, possessing a methoxymethylene substituent on ring A, and three methoxy groups on ring B, exhibited the most promising LOX inhibitory activity (IC50 = 45 μM). A combination of in silico techniques were utilized in an effort to explore the crucial binding characteristics of the most active compound 3c and its analogue 3b, to LOX. A common H-bond interaction pattern, orienting the hydroxyl and carbonyl groups of the aromatic ring A towards Asp768 and Asn128, respectively, was observed. Regarding the analogue 3c, the bulky (-OMOM) group does not seem to participate in a direct binding, but it induces an orientation capable to form H-bonds between the methoxy groups of the aromatic ring B with Trp130 and Gly247.
