Hemisynthesis and Biological Evaluation of Cinnamylated, Benzylated, and Prenylated Dihydrochalcones from a Common Bio-Sourced Precursor
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antibiotics Article Hemisynthesis and Biological Evaluation of Cinnamylated, Benzylated, and Prenylated Dihydrochalcones from a Common Bio-Sourced Precursor Anne Ardaillou, Jérôme Alsarraf * , Jean Legault, François Simard and André Pichette * Centre de Recherche sur la Boréalie (CREB), Laboratoire d’Analyse et de Séparation des Essences Végétales (LASEVE), Université du Québec à Chicoutimi, 555 Boulevard de l’Université, Chicoutimi, QC G7H 2B1, Canada; [email protected] (A.A.); [email protected] (J.L.); [email protected] (F.S.) * Correspondence: [email protected] (J.A.); [email protected] (A.P.); Tel.: +1-418-545-5011 (ext. 2273) (J.A.); +1-418-545-5011 (ext. 5081) (A.P.) Abstract: Several families of naturally occurring C-alkylated dihydrochalcones display a broad range of biological activities, including antimicrobial and cytotoxic properties, depending on their alkylation sidechain. The catalytic Friedel–Crafts alkylation of the readily available aglycon moiety of neohesperidin dihydrochalcone was performed using cinnamyl, benzyl, and isoprenyl alcohols. This procedure provided a straightforward access to a series of derivatives that were structurally related to natural balsacones, uvaretin, and erioschalcones, respectively. The antibacterial and cytotoxic potential of these novel analogs was evaluated in vitro and highlighted some relations between the structure and the pharmacological properties of alkylated dihydrochalcones. Citation: Ardaillou, A.; Alsarraf, J.; Legault, J.; Simard, F.; Pichette, A. Keywords: antibacterial; Brønsted acid catalysis; dihydrochalcone; Friedel–Crafts alkylation; hemisyn- Hemisynthesis and Biological thesis; natural products; Staphylococcus aureus Evaluation of Cinnamylated, Benzylated, and Prenylated Dihydrochalcones from a Common Bio-Sourced Precursor. Antibiotics 1. Introduction 2021, 10, 620. https://doi.org/ Dihydrochalcones (DHCs) are a class of natural phenylpropanoids derived from 10.3390/antibiotics10060620 the biosynthetic pathway of shikimic acid [1]. They are the acyclic counterparts of fla- vanones and are found in several botanical families [2]. Their scaffold can feature various Academic Editor: Carlos M. Franco sidechains [3] resulting from C-glycosylation [4], C-cinnamylation [5–8], C-benzylation [9–11], or C-prenylation [12] (Figure1). The structural diversity of DHCs translates into a broad Received: 4 May 2021 range of biological activities such as antibacterial, antiviral, antidiabetic, antioxidant, anti- Accepted: 19 May 2021 Published: 22 May 2021 inflammatory, and cytotoxic properties [13]. Interestingly, DHCs may display different pharmacological properties compared to the corresponding chalcones. For instance, some S. aureus Publisher’s Note: MDPI stays neutral recently described 4’-methyl DHCs were more active against and less potent with regard to jurisdictional claims in against E. coli than the corresponding chalcones [14]. While functionalized DHCs are published maps and institutional affil- commonly isolated in low yields, simpler derivatives can be found in high concentrations iations. in plants. One of the most abundant natural DHCs is phloridzin, a DHC O-glucoside representing up to 14% of dry weight in apple tree leaves [15]. Some DHCs are also readily accessible by reduction of the corresponding chalcone or flavanone. This is for example the case of neohesperidin dihydrochalcone, a sweetener widely used in the food industry which is obtained by hydrogenation of the citrus metabolite neohesperidin [16]. We re- Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. cently demonstrated that abundant DHCs can serve as precursors in the hemisynthesis of This article is an open access article balsacones [17], a class of cinnamylated antibacterial and anti-psoriatic [18] DHCs from the distributed under the terms and bud of Populus balsamifera that are active against resistant strains of S. aureus (MRSA) and conditions of the Creative Commons did not induce resistance in treated MRSA [19]. In this context, the use of natural DHCs Attribution (CC BY) license (https:// advantageously saved the steps which would have been necessary for the construction creativecommons.org/licenses/by/ of a DHC scaffold from petrochemicals. Their conversion into balsacones was performed 4.0/). in a single-step, following a metal-free and protective group-free Brønsted acid-catalyzed Antibiotics 2021, 10, 620. https://doi.org/10.3390/antibiotics10060620 https://www.mdpi.com/journal/antibiotics Antibiotics 2021, 10, x FOR PEER REVIEW 2 of 14 Antibiotics 2021, 10, 620 2 of 14 was performed in a single-step, following a metal-free and protective group-free Brønsted Friedel–Craftsacid-catalyzed alkylation Friedel–Crafts protocol alkylation [20]. Bio-sourced protocol [20 cinnamyl]. Bio-sourced alcohols cinnamyl were privileged alcohols as thewere alkylation privileged reagents as the alkylation as their utilization reagents as saved their autilization harmful halogenationsaved a harmful step, halogena- and their conversiontion step, and generated their conversion water as thegenerated lone byproduct water as the making lone byproduct the process making overall the green process [21,22 ]. Theoverall use ofgreen natural [21,22 precursors]. The use of was natural also profitableprecursors from was also a drug profitable discovery from perspective, a drug dis- as thesecovery renewable perspective polyfunctional, as these renewable templates polyfunctional constitute a valuable templates source constitute of structural a valuable diver- sitysource [23]. of On structural the other diversity hand, the[23] scope. On the of other sidechains hand, the which scope could of sidechains readily be which incorporated could ontoreadily the frameworkbe incorporated of natural onto the DHCs framework remains of to natural be explored DHCs to remains access theto be wider explored sidechain to varietyaccess foundthe wider in DHCs. sidechain variety found in DHCs. FigureFigure 1. 1.Structure Structure ofof various dihydrochalcones, dihydrochalcones, including including the the aglycone aglycone moiety moiety of neohesperidin of neohesperidin dihydrochalconedihydrochalcone ( 1(1).). Among Among these these structures, structures,C -benzylatedC-benzylated DHCs DHCs have have been been found found in in the the Annonaceae Annonaceae fam- ily,family, in particular in particular in Uvaria in Uvariaspecies species [9,10 ,[249,10,2–26].4– Uvaretin26]. Uvaretin showed showed a considerable a considerable cytotoxicity cyto- toxicity against various human cancer cell lines with IC50 values in the low micromolar against various human cancer cell lines with IC50 values in the low micromolar range [27]. Otherrange 2-hydroxybenzyl-bearing [27]. Other 2-hydroxybenzyl flavonoids-bearing haveflavonoids also been have found also been in nature found such in nature as the C- benzylatedsuch as the flavanone C-benzylated dichamanetin flavanone fromdichamanetinPiper sarmentosum from Piper. Furthermore, sarmentosum. CFurthermore,-prenylation is aC relatively-prenylation common is a relatively modification common in naturalmodification flavonoids in natural that flavonoids is considered that tois enhanceconsidered their bioactivityto enhance by their increasing bioactivity lipophilicity by increasing [28,29]. lipophilicityC-prenylated [28,29 and C].-geranylated C-prenylated DHCs and C were- geranylated DHCs were notably found in the genus Piper. Recently, two prenylated notably found in the genus Piper. Recently, two prenylated DHCs, named erioschalcone A DHCs, named erioschalcone A and B, were isolated in Eriosema glomerata and showed at- and B, were isolated in Eriosema glomerata and showed attractive antimicrobial properties tractive antimicrobial properties against the pathogenic Gram-negative strains Escherichia against the pathogenic Gram-negative strains Escherichia coli and Klebsiella pneumoniae [12]. coli and Klebsiella pneumoniae [12]. It is worthy of note that erioschalcones were inactive It is worthy of note that erioschalcones were inactive against S. aureus, unlike balsacones, against S. aureus, unlike balsacones, which stressed the role of the alkylation fragment of which stressed the role of the alkylation fragment of DHCs on their antimicrobial prop- DHCs on their antimicrobial properties. Herein, we devise the catalytic single-step C-cin- erties. Herein, we devise the catalytic single-step C-cinnamylation, C-benzylation, and namylation, C-benzylation, and C-prenylation of the readily accessible neohesperidin di- C-prenylationhydrochalcone of theaglycon readily 1 as accessible a useful neohesperidinmethod to access dihydrochalcone derivatives that aglycon are structurally1 as a useful methodrelated toto accessnaturally derivatives occurring that balsacones, are structurally uvaretins, related and erioschalcones, to naturally occurring respectively. balsacones, The uvaretins,antibacterial and and erioschalcones, cytotoxic activity respectively. of the synthesized The antibacterial compound and is cytotoxicalso discussed. activity of the synthesized compound is also discussed. Antibiotics 2021, 10, 620 3 of 14 Antibiotics 2021, 10, x FOR PEER REVIEW 3 of 14 2.2. Results Results and and Discussion Discussion 2.1. Chemical Synthesis 2.1. Chemical Synthesis 2.1.1. Cinnamylation of DHC 1 2.1.1. Cinnamylation of DHC 1 Our first objective was to transpose the method developed for the hemisynthesis of balsaconesOur first to DHC objective1 (Table was1 ).to Briefly, transpose the the