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Chalcones and Flavanones Bearing Hydroxyl And/Or Methoxyl Groups: Synthesis and Biological Assessments

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Chalcones and Flavanones Bearing Hydroxyl And/Or Methoxyl Groups: Synthesis and Biological Assessments applied sciences Article Chalcones and Flavanones Bearing Hydroxyl and/or Methoxyl Groups: Synthesis and Biological Assessments Gonçalo P. Rosa 1 , Ana M. L. Seca 1,2 , Maria do Carmo Barreto 1 , Artur M. S. Silva 2 and Diana C. G. A. Pinto 2,* 1 cE3c—Centre for Ecology, Evolution and Environmental Changes/Azorean Biodiversity Group & University of Azores, Rua Mãe de Deus, 9501-801 Ponta Delgada, Portugal 2 QOPNA & LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal * Correspondence: [email protected]; Tel.: +351-234-401-407 Received: 20 June 2019; Accepted: 14 July 2019; Published: 17 July 2019 Abstract: Chalcones and flavanones are isomeric structures and also classes of natural products, belonging to the flavonoid family. Moreover, their wide range of biological activities makes them key scaffolds for the synthesis of new and more efficient drugs. In this work, the synthesis of hydroxy and/or methoxychalcones was studied using less common bases, such as sodium hydride (NaH) and lithium bis(trimethylsilyl)amide (LiHMDS), in the aldol condensation. The results show that the use of NaH was more effective for the synthesis of 20-hydroxychalcone derivatives, while LiHMDS led to the synthesis of polyhydroxylated chalcones in a one-pot process. During this study, it was also possible to establish the conditions that favor their isomerization into flavanones, allowing at the same time the synthesis of hydroxy and/or methoxyflavanones. The chalcones and flavanones obtained were evaluated to disclose their antioxidant, anticholinesterasic, antibacterial and antitumor activities. 20,40,4-Trihydroxychalcone was the most active compound in terms of antioxidant, anti-butyrylcholinesterase (IC 26.55 0.55 µg/mL, similar to control drug donepezil, 50 ± IC 28.94 1.76 µg/mL) and antimicrobial activity. 4 ,7-Dihydroxyflavanone presented dual 50 ± 0 inhibition, that is, the ability to inhibit both cholinesterases. 40-Hydroxy-5,7-dimethoxyflavanone and 20-hydroxy-4-methoxychalcone were the compounds with the best antitumor activity. The substitution pattern and the biological assay results allowed the establishment of some structure/activity relationships. Keywords: chalcones; aldol condensation; biological activity; flavanones; cytotoxic; antioxidant; anticholinesterase 1. Introduction The (E)-1,3-diphenylpropen-1-ones, best known as chalcones, belong to the flavonoids family and are an important class of natural products across the plant kingdom [1]. Structurally, these compounds contain two aromatic rings, bonded by a three-carbon α,β unsaturated carbonyl bridge (Figure1), which are synthesized in plants as the C15 key intermediate in the biosynthesis of the other flavonoids [2]. Flavanones are also naturally occurring compounds and are chalcones’ isomeric forms. In fact, the equilibrium between chalcones and flavanones is common in nature and is regulated by chalcone-isomerase [3]. Appl. Sci. 2019, 9, 2846; doi:10.3390/app9142846 www.mdpi.com/journal/applsci Appl. Sci. 2019, 9, 2846 2 of 17 Appl. Sci. 2019, 9, x 2 of 17 Figure 1. Basic chalcone structure. Besides their natural occurrence, both chalcones and flavanonesflavanones can be obtainedobtained synthetically and are often used as thethe preferredpreferred startingstarting materialmaterial for thethe synthesissynthesis of otherother polycyclicpolycyclic aromatic compounds [[4].4]. Furthermore, Furthermore, they they present present great ph pharmacologicalarmacological potential with a wide variety of biological activities,activities, includingincluding antioxidant antioxidant [5 ],[5], anticancer anticancer [6 –[6–8],8], and and antimicrobial antimicrobial activities activities [9–12 [9–12],], and alsoand also the ability the ability to treat to treat cardiovascular cardiovascular diseases diseases and theirand their risk factorsrisk factors [13–16 [13–16],], among among others others [17]. [17]. On the otherother hand,hand, cancer,cancer, neurodegenerativeneurodegenerative diseases,diseases, oxidative stress-related diseases and multi-resistant bacterialbacterial infectionsinfections are, are, after after cardiovascular cardiovascular diseases, diseases, the the top top four four health health problems problems that causethat cause the most the most victims victims every every year, leading year, leading to higher to medicinehigher medicine consumption consumption and putting and greatputting pressure great onpressure the national on the health national systems health of systems many countries of many [countries18–24]. These [18–24]. problems These occur problems either occur due toeither a lack due of etoff ectivea lack medicinesof effective to medicines treat diseases, to treat such diseases as neurodegenerative, such as neurodegenerative ones, or due to ones, the increasing or due to drug the resistanceincreasing presenteddrug resistance by numerous presented pathogenic by numero bacteriaus pathogenic and by some bacteria cancers. and Therefore, by some exploring cancers. well-knownTherefore, exploring scaffolds well-known as lead compounds scaffolds will as lead help compounds in the battle will against help diseases in the battle that against affect humanity. diseases that affectPutting humanity. together the facts stated above, the synthesis of chalcone-based functionalized derivatives remainsPutting a popular together research the objective.facts stated The mostabove, common the synthesis and efficient of approachchalcone-b toased obtain functionalized the chalcone nucleusderivatives is the remains aldol condensation a popular research of substituted objective. acetophenones The most common with proper and efficient substituted approach benzaldehydes to obtain inthe the chalcone presence nucleus of a base, is the namely aldol condensation sodium or potassium of substituted hydroxide acetophenones [25–28]. Despitewith proper the e ffisubstitutedciency of thisbenzaldehydes method, when in the planning presence a synthesisof a base, somenamely drawbacks sodium or should potassium be considered. hydroxide For[25–28]. instance, Despite the protectionthe efficiency of the of this reagents’ method, hydroxyl when groupsplanning should a synthesis be done some previously, drawbacks the acetophenoneshould be considered. hydrogen Forα acidityinstance, should the beprotection analyzed, of and the by-products reagents’ canhydr beoxyl obtained groups if theshould bases arebe alsodone good previously, nucleophilic the speciesacetophenone [29,30]. hydrogen α acidity should be analyzed, and by-products can be obtained if the bases are alsoIn this good regard, nucleophilic the objective species of this [29,30]. work is to synthesize hydroxy- and/or methoxychalcones by aldol condensation,In this regard, using the the objective less common of this bases work sodium is to hydridesynthesize and hydroxy- lithium bis(trimethylsilyl)amide. and/or methoxychalcones Also, by thisaldol work condensation, studies their antioxidant,using the anticholinesterasic, less common antibacterialbases sodium and antitumorhydride activities, and lithium aiming tobis(trimethylsilyl)amide. establish some potential Also, medicinal this work applications. studies th Simultaneously,eir antioxidant, anticholinesterasic, a structure/activity antibacterial relationship wasand established,antitumor activities, and the isomericaiming to equilibrium establish some chalcone-flavanone potential medicinal was alsoapplications. studied. Simultaneously, a structure/activity relationship was established, and the isomeric equilibrium chalcone-flavanone 2. Materials and Methods was also studied. 2.1. General Methods 2. Materials and Methods The 1H, 13C, HSQC and HMBC NMR spectra were measured on Bruker AMC 300 or 500 instruments,2.1. General Methods operating at 300.13 MHz and 75.47 or 500.13 and 125.75 MHz. Chemical shifts were reported relative to tetramethysilane (TMS) in δ units (ppm) and coupling constants (J) in Hz. The 1H, 13C, HSQC and HMBC NMR spectra were measured on Bruker AMC 300 or 500 Chromatographic purifications were carried out by prep. TLC on silica gel (Merck silica gel 60 F ), instruments, operating at 300.13 MHz and 75.47 or 500.13 and 125.75 MHz. Chemical shifts were254 the spots being visualized under a UV lamp (at 254 and/or 366 nm). Melting points were determined reported relative to tetramethysilane (TMS) in δ units (ppm) and coupling constants (J) in Hz. with a Stuart scientific SPM3 apparatus and are uncorrected. The mass spectra were acquired using Chromatographic purifications were carried out by prep. TLC on silica gel (Merck silica gel 60 F254), ESI(+) with a Micromass Q-Tof 2TM mass spectrometer. the spots being visualized under a UV lamp (at 254 and/or 366 nm). Melting points were determined 2.2.with Synthesis a Stuart ofscientific Chalcones SPM3 and Flavanonesapparatus and are uncorrected. The mass spectra were acquired using ESI(+) with a Micromass Q-Tof 2TM mass spectrometer. Synthesis of the compounds described below follows the general scheme outlined in 3.1 (Scheme1). 2.2. Synthesis of Chalcones and Flavanones 20-Hydroxy-4,40,60-trimethoxychalcone 1. Compound 1 was synthesized by mixing 20-hydroxy-40,60- dimethoxyacetophenoneSynthesis of the compounds (661.3 mg,descri 3.37bed mmol)below follows dissolved the general in a minimum scheme outlined (~15 mL) in 3.1 amount (Scheme of tetrahydrofuran1). (THF) with sodium hydride (NaH) (2.5 equivalents), under nitrogen atmosphere at room temperature. After 30 min of stirring, 4-methoxybenzaldehyde (1.2 equivalents) was added to the2′-Hydroxy-4,4
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