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Article

Synthesis and Antimicrobial Activity of δ-Viniferin Analogues and Isosteres

by
Luce Micaela Mattio
1,
Cecilia Pinna
1,
Giorgia Catinella
1,
Loana Musso
1,
Kasandra Juliet Pedersen
2,
Karen Angeliki Krogfelt
2,
Sabrina Dallavalle
1,* and
Andrea Pinto
1
1
Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Via Celoria 2, 20133 Milan, Italy
2
Institute of Molecular and Medical Biology, Roskilde University, 4000 Roskilde, Denmark
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(24), 7594; https://doi.org/10.3390/molecules26247594
Submission received: 9 November 2021 / Revised: 8 December 2021 / Accepted: 12 December 2021 / Published: 15 December 2021
(This article belongs to the Special Issue Novel Natural and Derivative Products: Synthesis and Pharmacological Potential)
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Abstract

:
The natural stilbenoid dehydro-δ-viniferin, containing a benzofuran core, has been recently identified as a promising antimicrobial agent. To define the structural elements relevant to its activity, we modified the styryl moiety, appended at C5 of the benzofuran ring. In this paper, we report the construction of stilbenoid-derived 2,3-diaryl-5-substituted benzofurans, which allowed us to prepare a focused collection of dehydro-δ-viniferin analogues. The antimicrobial activity of the synthesized compounds was evaluated against S. aureus ATCC29213. The simplified analogue 5,5′-(2-(4-hydroxyphenyl)benzofuran-3,5-diyl)bis(benzene-1,3-diol), obtained in three steps from 4-bromo-2-iodophenol (63% overall yield), emerged as a promising candidate for further investigation (MIC = 4 µg/mL).

Graphical Abstract

1. Introduction

Resveratrol-derived natural products, belonging to the class of polyphenolic stilbenes, have increasingly attracted the attention of the scientific community because of their diverse biological activities and intriguing molecular architectures [1,2,3]. Nonetheless, the growing interest in the pharmacological potential of this class of molecules derives from the poor understanding of the in vivo mechanisms of action of their parent compound resveratrol, which severely limits its therapeutic use [4] and the necessity to increase its low bioavailability and in vivo stability. Over the last years, several efforts were made towards the synthesis of complex natural resveratrol oligomers, by biomimetic and de novo approaches [1,5,6,7,8,9]. However, only few research groups have focused on the synthesis of new resveratrol-derived chemical scaffolds with improved pharmacodynamics and pharmacokinetics with respect to the natural precursors [6,10,11,12,13,14]. In this scenario, we planned to set up a versatile and efficient synthetic strategy for the construction of dimeric resveratrol-derived benzofurans. Benzo[b]furan-containing molecules, present in numerous bioactive natural compounds, have been extensively studied because of their wide array of biological activities, including anticancer, antimicrobial, immunomodulatory, antioxidant, and anti-inflammatory properties [15,16,17,18]. It is noteworthy that, in the last years, the benzofuran motif has been revealed to be a pharmacophore of choice for the design of new antimicrobial agents [19,20]. We have recently reported the synthesis and the antimicrobial activity evaluation of a collection of resveratrol-derived monomers (i.e., resveratrol, pterostilbene, and piceatannol) and dimers (i.e., trans-δ-viniferin, trans-ε-viniferin, pallidol, dehydro-δ-viniferin, and viniferifuran) against a series of foodborne pathogens [21].

2. Results and Discussion

Dehydro-δ-viniferin (1, Figure 1), containing a benzofuran core, was identified as a promising compound against Gram-positive bacteria. In particular, it was shown to exert its antimicrobial activity on the foodborne pathogen Listeria monocytogenes Scott A, used as model of Gram-positive microorganisms (MIC and MBC values of 4.42 and 35.3 µM, respectively) [21]. The compound causes significant cytoplasmic membrane damage, by membrane depolarization, loss of membrane integrity, and severe morphological changes.
A previous SAR study performed by our group on simplified analogues of 1 (compounds 2, 3, 4) [22], which were obtained by the selective removal of the moieties linked in positions two, three, and five of the benzofuran core, showed that none of the structurally simplified compounds resulted to be more active than the precursor (Figure 1). In particular, a drastic drop of the antibacterial activity, due to the fatal lack of ring B, was observed for the derivative 3 (MIC value of 743 µM against 4.42 µM of dehydro-δ-viniferin), thus suggesting the fundamental role of the aryl ring in position three of the benzofuran core. An important loss of antimicrobial activity, albeit to a lesser extent, was observed for compounds 2 and 4, obtained by the removal of the styryl group at position five and of the aryl ring in position two, respectively (MIC values of 50.3 µM (2) and 44.5 µM (4), vs. 4.42 µM (1)) (Figure 1).
Thus, we planned to prepare a novel set of dehydro-δ-viniferin analogues and isosteres, obtained by modifying the styryl moiety A (Figure 1), while maintaining the unaltered rings B and C. In particular, a removal of the double bond or its replacement with moieties such as an amide, alkyne or a saturated chain, could clarify the role of the geometry and stereoelectronic effects for the antimicrobial activity. In addition, we planned to synthesize dehydro-δ-viniferin analogues that maintained the stilbene double bond, having, however, aromatic rings that were different from the resorcinol moiety.
In this perspective, we needed a versatile strategy to construct the 2,3-diaryl benzofuran ring bearing on C-5 a proper functional group (X) for the insertion of the appropriate fragment (Figure 2).
Among the various methods to access stilbenoid-derived 2,3-diaryl-5-substituted benzofurans [23,24,25,26,27,28], palladium catalysed reactions have proven to be rapid and convenient. In particular, an efficient one-pot method developed by Cacchi and coworkers [29] and successively implemented by Markina and coworkers [30], involves a Sonogashira coupling between an ortho-iodophenol and an aryl-substituted terminal alkyne to generate, at room temperature, the corresponding internal alkyne. The alkynylphenol obtained as an intermediate undergoes a simultaneous cyclization with the adjacent phenol group and an oxidative addition with the aryl-iodide-palladium complex with CuI, in acetonitrile at 100 °C, under microwave irradiation. Using this approach, we obtained C5-substituted 2,3-diarylbenzofurans in a three-component one-pot reaction in 48–72% yields.
Specifically, we generated the bromo functionalized intermediate 8 by reaction of 4-bromo-2-iodophenol 5, 4-ethynylanisole 6 and 3,5-dimethoxy-1-iodobenzene 7 (Scheme 1). Compound 8 underwent a Suzuki-coupling with (3,5-dimethoxyphenyl)boronic acid with Pd(PPh3)4 and aqueous 1 M Cs2CO3 in a mixture DMF/EtOH (1:1), under microwave irradiation, for 20 min at 120 °C [30] to afford compound 9 in 91% yield. Final demethylation with BBr3 provided 10, as a simplified analogue of our hit compound 1, lacking the stilbene double bond.
Then, we focused on the synthesis of the isosteres bearing an amide in place of the double bond. Amide isosteres of resveratrol have shown activity similar to the parent compound [31]. The amide linkage should allow to maintain the transoid architecture of the trans-stilbene, conferring however improved solubility and increased polarity [32,33] as well as differences in electronic perturbations [32,33]. Therefore, analogue 15 was synthesized (Scheme 2). The Sonogashira/Cacchi type cyclization of the commercially available methyl 4-hydroxy-3-iodobenzoate 11, 4-ethynylanisole 6 and 3,5-dimethoxy-1-iodobenze 7 gave the desired benzofuran 12 in 66% yield. Hydrolysis of the ester 12 was performed with LiOH∙H2O in a mixture of THF/water 1:1 for 24 h. The resulting carboxylic acid 13 was reacted with 3,5-dimethoxyaniline, in presence of EDC∙HCl and HOBt, to give amide 14, which was demethylated with BBr3 to afford compound 15 in 73% yield.
The ester 12 was envisaged as a versatile intermediate for the preparation of a set of dehydro-δ-viniferin derivatives, differently substituted on ring A (Scheme 3). Reduction with LiAlH4 gave, quantitatively, compound 16, which was converted into the corresponding bromide derivative with PBr3. Reaction with triethyl phosphite at 130 °C overnight, which afforded the phosphonate 17 in 80% yield over two steps. The HWE reaction with 4-methoxybenzaldehyde provided the desired stilbene 18, only as a trans isomer, in 86% yield. Unfortunately, attempts to deprotect the methyl groups with BBr3 at −78 °C in dry DCM, following the usual procedure, gave only degradation products.
Several troublesome efforts in the demethylation process confirmed that this step is an Achilles’ heel in the synthesis of stilbenoids-derived compounds [6,10,14,22].
Methyl groups are convenient protecting groups for phenolic moieties because of the availability of their starting reagents and their high stability to a wide variety of reaction conditions. However, as a not-negligible drawback, their high robustness requires harsh conditions in the deprotection step, often resulting in poor yields and product degradation in the presence of highly reactive double bonds [5,6,10,22].
As stilbenoids are known to form dimers and polymers with a variety of acids, including BBr3 [34,35], alternative protocols were investigated. We first attempted to obtain the desired compound 19 by the initial deprotection of bromoderivative 8, followed by a direct insertion of the p-hydroxystyryl moiety via the Heck reaction. However, the reaction gave a mixture of 19 and its isomer 20, coeluted in column chromatography (Scheme 3).
In another synthetic route, 2-iodo-4-methylphenol 22, prepared in excellent yields from para-cresol (21) with N-iodosuccinimide and para-toluenesulfonic acid in acetonitrile [36], was used as the starting material (Scheme 4). In the one-pot-Sonogashira-Cacchi reaction conditions, the obtained intermediate gave the desired benzofuran derivative 23 in 48% yield. Intermediate 23 was smoothly demethylated to afford compound 24 in 90% yield. The protection of hydroxy groups with tert-butyldimethylsilylchloride and imidazole was performed in 1,2-dichloroethane at 60 °C, to give compound 25 in a good yield (86%) [8]. Then, a radical bromination of the methyl group with NBS and AIBN as a radical initiator at reflux in CCl4 gave a brominated intermediate, which was converted into the corresponding phosphonate 26 with triethyl phosphite at 130 °C (84% yield). The intermediate 26 was reacted with the properly protected 3,4-bis((tert-butyldimethylsilyl)oxy)benzaldehyde in presence of LDA in THF in 16% yield. The use of NaH increased the yield to 52%. Eventually, the deprotection of silyl groups was performed with tetrabutylammonium fluoride (TBAF) at 0 °C in THF, to afford compound 28 with a catechol on the styryl moiety (60% yield).
The protection of phenol groups as t-butyldimethylsilylethers was applied also to the synthesis of the alkyne derivative 32 (Scheme 5). The high-yield demethylation of brominated intermediate 8 was thus followed by protection of the hydroxy groups as tert-butyldimethylsilyl ethers (28).
The alkyne 31 was obtained starting from 3,5-dihydroxybenzaldehyde 29, which was properly protected and then subjected to Corey-Fuchs conditions [37] to give the terminal dibromoalkene 30, which underwent lithium-halogen exchange and α-elimination with LDA to afford 31 in excellent yield.
The final Sonogashira coupling was performed with Pd(PPh3)4 and CuI in triethylamine at reflux for 8 h. The crude compound obtained was directly deprotected with KF to give the desired alkyne 32 in 38% yield, over two steps.
Finally, compound 33, having a saturated chain in place of the stilbene double bond, was obtained in a quantitative yield by the hydrogenation of dehydro-δ-viniferin 1 with Pd/C in ethanol at room temperature for 3 h (Scheme 6). Hydrogenation of δ-viniferin 34, applying the same protocol, led to a dihydrobenzofuran ring cleavage (compound 35) [38].
The model compound 1 and the novel derivatives 10, 15, 27, 32, 33, and 35 were tested against S. aureus ATCC29213, and the minimum inhibition concentration (MIC) and minimal bactericidal concentration (MBC) were determined. The concentration range was 0.25–512 µg/mL for the synthesized compounds and 0.5–64 µg/mL for the reference compound tobramycin. The results are reported in Table 1. The MIC was evaluated using two different growth media: Mueller Hilton Broth, cation adjusted (MHB-II 212322, Becton Dickinson and Company, 7 Loveton Circle Spark, MD, USA), and Tryptic Soy Broth (22092-500 G, MERCK, Vandtårnsvej 62A, 5 sal. Søborg, Denmark).
It has been shown that the growth media play an important role in the outcome of bacterial susceptibility to different charged peptides. Antimicrobial assays were performed in MHB cation-adjusted medium, a complex growth medium [39], and also in the less complex medium TSB [21]. In TSB we achieved approximately equal susceptibility results, uniform growth, and less variation in the repeated independent experiments. Unexpectedly, in both sets of experiments we noticed that at high concentrations the active compounds lost their ability to inhibit the growth of the microorganism. In particular, in the MHB-II medium, compound 1 lost its activity at concentrations higher than 8 µg/mL, compounds 10, 15, 27, and 32 at concentrations higher than 32 µg/mL, and compound 33 at concentrations higher than 16 µg/mL. A similar behaviour for all the compounds was observed in the TSB medium. These results could be explained, considering a self-aggregation process of the tested compounds in the solvent system.
In the MHB-II medium, the MICs of tested compounds ranged from 2 to 256 µg/mL. The majority of compounds showed detectable antimicrobial activity in the MIC range of 2–16 µg/mL. The removal of the double bond (compound 10; MIC 4 µg/mL), as well as the reduction of the double bond (compounds 33; MIC 2 µg/mL) and the replacement with the triple bond (compound 32; MIC 4 µg/mL), gave compounds which maintained a significant activity. Conversely, the replacement of the double bond with an amide group (compound 15) was deleterious (MIC 16 µg/mL). Also, the replacement of ring A with a catechol was not successful in terms of activity, as compound 27 had a MIC of 16 µg/mL. Compound 35, obtained by opening the benzofuran system, showed a very high MIC (256 µg/mL). This result confirmed that the heterocyclic ring plays an essential role for antimicrobial activity.

3. Materials and Methods

Synthesis. All chemicals used were of analytical grade. Procedures for the synthesis and characterization data for the various derivatives and intermediates are detailed in the Supplementary Materials.
Determination of minimum inhibition concentration (MIC) and minimum bactericidal concentration (MBC). The minimum inhibition concentration (MIC) of compounds was determined for S. aureus ATCC29213. The concentration range of the compounds were 0.25–512 µg/mL. Tobramycin (T2503, TCI Europe N.V) was used as a control with a concentration range of 0.5–64 µg/mL. One colony of S. aureus was inoculated in 5 mL growth media and incubated overnight in a water bath at 37 °C, 180 rmp. Three biological replicas were used. The overnight cultures were diluted 1:50 and grown to exponential phase at OD600~0.4, either in MHB-II and in TSB. The bacterial culture was diluted 1:500 and transferred to a microdilution plate together with the compounds. The plate was then sealed and incubated overnight at 37 °C. After incubation, the plates were examined for microbial growth. A CFU assay was performed to estimate the final concentration of the 1:500 diluted culture. The expected concentration range was 2 × 105–8 × 105 CFU/mL. The results were obtained 24 h after incubation. To determine the MBC, 10 µL of each compound concentration from the MIC, was transferred to LB (L3022 Sigma Aldrich) agar plates. The plates were incubated overnight at 37 °C. After incubation, the concentration at which no visible microbial growth was found was considered as the MBC.

4. Conclusions

The resveratrol dimer dehydro-δ-viniferin, containing a benzofuran core, has been identified as a promising antimicrobial compound. As part of the research for new antimicrobials, our recent interest has been directed to the synthesis of new dehydro-δ-viniferin analogues, to gain insights into the structural determinants for their activity. We investigated various protocols to access stilbenoid-derived 2,3-diaryl-5-substituted benzofurans, evidencing critical steps such as the demethylation of phenolic groups. Following these strategies, we prepared a focused collection of analogues, which were tested to evaluate their antimicrobial activity. Because of the modular nature of the synthetic approaches, ready access to diversity-oriented libraries of stilbenoid derived-benzofurans could be available.
Our study has evidenced that the styryl moiety, appended at C5 of the benzofuran ring, can be modified without affecting the antimicrobial activity of the compounds. Notably, the removal of the double bond (compound 10) andits conversion into a rigid linear triple bond (compound 32), or into a more flexible saturated chain (compound 33), gave compounds which were still endowed with significant antimicrobial activity. In this context, the simplified analogue 10 could represent a promising model compound for further development and investigation.

Supplementary Materials

The following are available online. Synthesis and characterization of compounds 1, 10, 15, 27, 32, 33, 35 [40,41].

Author Contributions

Conceptualization, A.P. and S.D.; methodology, L.M.M., C.P., G.C., L.M. and K.J.P.; investigation, L.M.M., C.P., G.C., L.M. and K.J.P.; resources, A.P., S.D. and K.A.K.; data curation, L.M.M., C.P., G.C., L.M. and K.J.P.; writing—original draft preparation, S.D., A.P. and K.A.K.; writing—review and editing, all authors. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

This work was financially supported by “Transition Grant 2015–2017-Linea 1A” of the University of Milan. The work of Giorgia Catinella has been partially funded by Fondazione F.lli Confalonieri (Ph.D. Scholarship).

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 1, 10, 15, 27, 32, 33, 35 are available from the authors.

References

  1. Keylor, M.H.; Matsuura, B.S.; Stephenson, C.R.J. Chemistry and Biology of Resveratrol-Derived Natural Products. Chem. Rev. 2015, 115, 8976–9027. [Google Scholar] [CrossRef] [PubMed]
  2. Mattio, L.M.; Catinella, G.; Dallavalle, S.; Pinto, A. Stilbenoids: A natural arsenal against Bacterial pathogens. Antibiotics 2020, 9, 336. [Google Scholar] [CrossRef]
  3. Pecyna, P.; Wargula, J.; Murias, M.; Kucinska, M. More than resveratrol: New insights into stilbene-based compounds. Biomolecules 2020, 10, 1111. [Google Scholar] [CrossRef] [PubMed]
  4. Weiskirchen, S.; Weiskirchen, R. Resveratrol: How Much Wine Do You Have to Drink to Stay Healthy? Adv. Nutr. An Int. Rev. J. 2016, 7, 706–718. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Lindgren, A.E.G.; Öberg, C.T.; Hillgren, J.M.; Elofsson, M. Total synthesis of the resveratrol oligomers (±)-Ampelopsin B and (±)-σ-Viniferin. Eur. J. Org. Chem. 2016, 2016, 426–429. [Google Scholar] [CrossRef]
  6. Vo, D.D.; Elofsson, M. Total Synthesis of Viniferifuran, Resveratrol-Piceatannol Hybrid, Anigopreissin A and Analogues—Investigation of Demethylation Strategies. Adv. Synth. Catal. 2016, 358, 4085–4092. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Snyder, S.A.; Breazzano, S.P.; Ross, A.G.; Lin, Y.; Zografos, A.L. Total synthesis of diverse carbogenic complexity within the resveratrol class from a common building block. J. Am. Chem. Soc. 2009, 131, 1753–1765. [Google Scholar] [CrossRef]
  8. Romero, K.J.; Keylor, M.H.; Griesser, M.; Zhu, X.; Strobel, E.J.; Pratt, D.A.; Stephenson, C.R.J. Synthesis of Vitisins A and D Enabled by a Persistent Radical Equilibrium. J. Am. Chem. Soc. 2020, 142, 6499–6504. [Google Scholar] [CrossRef]
  9. Keylor, M.H.; Matsuura, B.S.; Griesser, M.; Chauvin, J.P.R.; Harding, R.A.; Kirillova, M.S.; Zhu, X.; Fischer, O.J.; Pratt, D.A.; Stephenson, C.R.J. Synthesis of resveratrol tetramers via a stereoconvergent radical equilibrium. Science 2016, 354, 1260–1265. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Krzyzanowski, A.; Saleeb, M.; Elofsson, M. Synthesis of Indole-, Benzo[b]thiophene-, and Benzo[b]selenophene-Based Analogues of the Resveratrol Dimers Viniferifuran and (±)-Dehydroampelopsin B. Org. Lett. 2018, 20, 6650–6654. [Google Scholar] [CrossRef]
  11. Saleeb, M.; Mojica, S.; Eriksson, A.U.; Andersson, C.D.; Gylfe, Å.; Elofsson, M. Natural product inspired library synthesis—Identification of 2,3-diarylbenzofuran and 2,3-dihydrobenzofuran based inhibitors of Chlamydia trachomatis. Eur. J. Med. Chem. 2018, 143, 1077–1089. [Google Scholar] [CrossRef]
  12. Chen, D.Y.K.; Kang, Q.; Wu, T.R. Modular synthesis of polyphenolic benzofurans, and application in the total synthesis of malibatol A and shoreaphenol. Molecules 2010, 15, 5909–5927. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Liu, J.T.; Do, T.J.; Simmons, C.J.; Lynch, J.C.; Gu, W.; Ma, Z.X.; Xu, W.; Tang, W. Total synthesis of diptoindonesin G and its analogues as selective modulators of estrogen receptors. Org. Biomol. Chem. 2016, 14, 8927–8930. [Google Scholar] [CrossRef] [PubMed]
  14. Vo, D.D.; Elofsson, M. Synthesis of 4-Formyl-2-arylbenzofuran Derivatives by PdCl(C3H5)dppb-Catalyzed Tandem Sonogashira Coupling-Cyclization under Microwave Irradiation—Application to the Synthesis of Viniferifuran Analogues. ChemistrySelect 2017, 2, 6245–6248. [Google Scholar] [CrossRef] [Green Version]
  15. Khanam, H. Shamsuzzaman Bioactive Benzofuran derivatives: A review. Eur. J. Med. Chem. 2015, 97, 483–504. [Google Scholar] [CrossRef] [PubMed]
  16. Naik, R.; Harmalkar, D.S.; Xu, X.; Jang, K.; Lee, K. Bioactive benzofuran derivatives: Moracins A-Z in medicinal chemistry. Eur. J. Med. Chem. 2015, 90, 379–393. [Google Scholar] [CrossRef] [PubMed]
  17. Chand, K.; Hiremathad, A.; Singh, M.; Santos, M.A.; Keri, R.S. A review on antioxidant potential of bioactive heterocycle benzofuran: Natural and synthetic derivatives. Pharmacol. Rep. 2017, 69, 281–295. [Google Scholar] [CrossRef] [PubMed]
  18. Miao, Y.H.; Hu, Y.H.; Yang, J.; Liu, T.; Sun, J.; Wang, X.J. Natural source, bioactivity and synthesis of benzofuran derivatives. RSC Adv. 2019, 9, 27510–27540. [Google Scholar] [CrossRef] [Green Version]
  19. Hiremathad, A.; Patil, M.R.; Chethana, K.R.; Chand, K.; Santos, M.A.; Keri, R.S. Benzofuran: An emerging scaffold for antimicrobial agents. RSC Adv. 2015, 5, 96809–96828. [Google Scholar] [CrossRef]
  20. Elsherif, M.A.; Hassan, A.S.; Moustafa, G.O.; Awad, H.M.; Morsy, N.M. Antimicrobial evaluation and molecular properties prediction of pyrazolines incorporating benzofuran and pyrazole moieties. J. Appl. Pharm. Sci. 2020, 10, 37–43. [Google Scholar] [CrossRef] [Green Version]
  21. Mattio, L.M.; Dallavalle, S.; Musso, L.; Filardi, R.; Franzetti, L.; Pellegrino, L.; D’Incecco, P.; Mora, D.; Pinto, A.; Arioli, S. Antimicrobial activity of resveratrol-derived monomers and dimers against foodborne pathogens. Sci. Rep. 2019, 9, 1–13. [Google Scholar] [CrossRef]
  22. Catinella, G.; Mattio, L.M.; Musso, L.; Arioli, S.; Mora, D.; Beretta, G.L.; Za, N.; Pinto, A.; Dallavalle, S. Structural Requirements of Benzofuran Derivatives Dehydro-δ-and Dehydro-ε-Viniferin for Antimicrobial Activity Against the Foodborne Pathogen Listeria monocytogenes. Int. J. Mol. Sci. 2020, 21, 2168. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Lamaa, D.; Hauguel, C.; Lin, H.-P.; Messe, E.; Gandon, V.; Alami, M.; Hamze, A. Sequential One-Pot Synthesis of 3-Arylbenzofurans from N-Tosylhydrazones and Bromophenol Derivatives. J. Org. Chem. 2020, 85, 13664–13673. [Google Scholar] [CrossRef] [PubMed]
  24. Basu, P.; Satam, N.; Namboothiri, I.N.N. Synthesis of indenofurans, benzofurans and spiro-lactones: Via Hauser-Kraus annulation involving 1,6-addition of phthalide to quinone methides. Org. Biomol. Chem. 2020, 18, 5677–5687. [Google Scholar] [CrossRef] [PubMed]
  25. Das, P.; Maity, S.; Ghosh, P.; Dutta, A.; Das, S. Condensation of ninhydrin with phenols: Regioselective formation of diverse organic scaffolds and crystal structure studies. J. Mol. Struct. 2020, 1202, 127260. [Google Scholar] [CrossRef]
  26. Singh, G.; Goswami, P.; Sharma, S.; Anand, R.V. A One-Pot Approach to 2,3-Diarylbenzo[b]furans through N-Heterocyclic Carbene-Catalyzed 1,6-Conjugate Addition Followed by Acid Mediated Dehydrative Annulation. J. Org. Chem. 2018, 83, 56. [Google Scholar] [CrossRef] [PubMed]
  27. Fan, X.; He, H.; Li, J.; Luo, G.; Zheng, Y.; Zhou, J.K.; He, J.; Pu, W.; Zhao, Y. Discovery of 4,6-bis(benzyloxy)-3-phenylbenzofuran as a novel Pin1 inhibitor to suppress hepatocellular carcinoma via upregulating microRNA biogenesis. Bioorg. Med. Chem. 2019, 27, 2235–2244. [Google Scholar] [CrossRef] [PubMed]
  28. Liou, Y.C.; Karanam, P.; Jang, Y.J.; Lin, W. Synthesis of Functionalized Benzofurans from para-Quinone Methides via Phospha-1,6-Addition/ O-Acylation/Wittig Pathway. Org. Lett. 2019, 21, 8008–8012. [Google Scholar] [CrossRef] [PubMed]
  29. Arcadi, A.; Cacchi, S.; Del Rosario, M.; Fabrizi, G.; Marinelli, F. Palladium-catalyzed reaction of o-ethynylphenols, o-((trimethylsilyl)ethynyl)phenyl acetates, and o-alkynylphenols with unsaturated triflates or halides: A route to 2-substituted-, 2,3-disubstituted-, and 2-substituted-3-acylbenzo[b]furans. J. Org. Chem. 1996, 61, 9280–9288. [Google Scholar] [CrossRef]
  30. Markina, N.A.; Chen, Y.; Larock, R.C. Efficient microwave-assisted one-pot three-component synthesis of 2,3-disubstituted benzofurans under Sonogashira conditions. Tetrahedron 2013, 69, 2701–2713. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  31. St. John, S.E.; Jensen, K.C.; Kang, S.; Chen, Y.; Calamini, B.; Mesecar, A.D.; Lipton, M.A. Design, synthesis, biological and structural evaluation of functionalized resveratrol analogues as inhibitors of quinone reductase 2. Bioorganic Med. Chem. 2013, 21, 6022–6037. [Google Scholar] [CrossRef] [Green Version]
  32. Stockdale, D.P.; Titunick, M.B.; Biegler, J.M.; Reed, J.L.; Hartung, A.M.; Wiemer, D.F.; McLaughlin, P.J.; Neighbors, J.D. Selective opioid growth factor receptor antagonists based on a stilbene isostere. Bioorganic Med. Chem. 2017, 25, 4464–4474. [Google Scholar] [CrossRef] [PubMed]
  33. Stockdale, D.P.; Beutler, J.A.; Wiemer, D.F. Synthesis of amide isosteres of schweinfurthin-based stilbenes. Bioorganic Med. Chem. 2017, 25, 5483–5489. [Google Scholar] [CrossRef] [PubMed]
  34. Li, X.C.; Ferreira, D. Stereoselective cyclization of stilbene derived carbocations. Tetrahedron 2003, 59, 1501–1507. [Google Scholar] [CrossRef]
  35. Velu, S.; Thomas, N.; Weber, J.F. Strategies and methods for the syntheses of natural oligomeric stilbenoids and analogues. Curr. Org. Chem. 2012, 16, 605–662. [Google Scholar] [CrossRef] [Green Version]
  36. Schmidt, B.; Riemer, M.; Karras, M. 2,2′-Biphenols Via Protecting Group-Free Thermal or Microwave-Accelerated Suzuki-Miyaura Coupling in Water. J. Org. Chem. 2013, 78, 8680–8688. [Google Scholar] [CrossRef] [PubMed]
  37. Gibtner, T.; Hampel, F.; Gisselbrecht, J.P.; Hirsch, A. End-cap stabilized oligoynes: Model compounds for the linear sp carbon allotrope carbyne. Chem. A Eur. J. 2002, 8, 408–432. [Google Scholar] [CrossRef]
  38. Yue, F.; Lu, F.; Regner, M.; Sun, R.; Ralph, J. Lignin-Derived Thioacidolysis Dimers: Reevaluation, New Products, Authentication, and Quantification. ChemSusChem 2017, 10, 830–835. [Google Scholar] [CrossRef] [Green Version]
  39. Wiegand, I.; Hilpert, K.; Hancock, R.E.W. Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nat. Protoc. 2008, 3, 163–175. [Google Scholar] [CrossRef]
  40. Teng, B.H.; Zhu, Q.B.; Fan, Y.Y.; Yao, C.S. Total synthesis of the active resveratrol dimer dehydro- δ-viniferin. J. Asian. Nat. Prod. Res. 2020, 22, 947–955. [Google Scholar] [CrossRef]
  41. Hoshino, J.; Park, E.J.; Kondratyuk, T.P.; Marler, L.; Pezzuto, J.M.; van Breemen, R.B.; Mo, S.; Li, Y.; Cushman, M. Selective Synthesis and Biological Evaluation of Sulfate-Conjugated Resveratrol Metabolites. J. Med. Chem. 2010, 53, 5033–5043. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Molecules 26 07594 g001 550
Figure 1. Structures and MIC values of model compounds 2, 3 and 4.
Figure 1. Structures and MIC values of model compounds 2, 3 and 4.
Molecules 26 07594 g001
Molecules 26 07594 g002 550
Figure 2. Retrosynthetic analysis for the obtainment of desired compounds.
Figure 2. Retrosynthetic analysis for the obtainment of desired compounds.
Molecules 26 07594 g002
Molecules 26 07594 sch001 550
Scheme 1. Reagents and conditions: (a) (i) PdCl2(PPh3)2∙DCM, CuI, THF/TEA 1:3, rt, MW, 30 min, (ii) ACN, 100 °C, MW, 25 min, 72%; (b) (3,5-dimethoxyphenyl)boronic acid, Pd(PPh3)4, DMF/EtOH 1:1, aq 1 M CssCO3, 120 °C, 20 min, MW, 91%; (c) BBr3 1 M DCM, DCM, −78 °C to rt, overnight, 96%.
Scheme 1. Reagents and conditions: (a) (i) PdCl2(PPh3)2∙DCM, CuI, THF/TEA 1:3, rt, MW, 30 min, (ii) ACN, 100 °C, MW, 25 min, 72%; (b) (3,5-dimethoxyphenyl)boronic acid, Pd(PPh3)4, DMF/EtOH 1:1, aq 1 M CssCO3, 120 °C, 20 min, MW, 91%; (c) BBr3 1 M DCM, DCM, −78 °C to rt, overnight, 96%.
Molecules 26 07594 sch001
Molecules 26 07594 sch002 550
Scheme 2. Reagents and conditions: (a) (i) PdCl2(PPh3)2∙DCM, CuI, THF/TEA 1:3, rt, MW, 30 min, (ii) ACN, 100 °C, MW, 25 min, 66%; (b) LiOH∙H2O, THF/H2O 1:1, rt, 24 h, quantitative yield; (c) (i) EDC∙HCl, HOBt, DMF; 0 °C to rt, 90 min, (ii) 3,5-dimethoxyaniline, DIPEA, DMF, 0 °C to rt, overnight, 70%; (d) BBr3 1 M DCM, DCM, −78 °C to rt, overnight, 73%.
Scheme 2. Reagents and conditions: (a) (i) PdCl2(PPh3)2∙DCM, CuI, THF/TEA 1:3, rt, MW, 30 min, (ii) ACN, 100 °C, MW, 25 min, 66%; (b) LiOH∙H2O, THF/H2O 1:1, rt, 24 h, quantitative yield; (c) (i) EDC∙HCl, HOBt, DMF; 0 °C to rt, 90 min, (ii) 3,5-dimethoxyaniline, DIPEA, DMF, 0 °C to rt, overnight, 70%; (d) BBr3 1 M DCM, DCM, −78 °C to rt, overnight, 73%.
Molecules 26 07594 sch002
Molecules 26 07594 sch003 550
Scheme 3. Reagents and conditions: (a) LiAlH4, THF, 0 °C, 20 min, quantitative yield; (b) PBr3, cat pyridine, Et2O, rt to reflux, 2 h, (c) P(OEt)3, 130 °C, overnight, 80% over two steps; (d) 4-methoxybenzaldehyde, NaH, 120 °C, 30 min, MW, 86%; (e) BBr3 1 M DCM, DCM, −78 °C to rt, overnight, 87%; (f) 4-hydroxystirene, TEA, dppp (1,3-bis(diphenylphosphino)propane), Pd(OAc)2, dry DMF, 120 °C, 48 h.
Scheme 3. Reagents and conditions: (a) LiAlH4, THF, 0 °C, 20 min, quantitative yield; (b) PBr3, cat pyridine, Et2O, rt to reflux, 2 h, (c) P(OEt)3, 130 °C, overnight, 80% over two steps; (d) 4-methoxybenzaldehyde, NaH, 120 °C, 30 min, MW, 86%; (e) BBr3 1 M DCM, DCM, −78 °C to rt, overnight, 87%; (f) 4-hydroxystirene, TEA, dppp (1,3-bis(diphenylphosphino)propane), Pd(OAc)2, dry DMF, 120 °C, 48 h.
Molecules 26 07594 sch003
Molecules 26 07594 sch004 550
Scheme 4. Reagents and conditions: (a) (i) p-TsOH∙H2O, ACN, rt, 10 min; (ii) NIS, rt, overnight, 97%; (b) (i) 4-ethynianisole, PdCl2(PPh3)2∙DCM, CuI, THF/TEA 1:3, rt, MW, 30 min, (ii) 3,5-dimethoxy-1-iodobenzene, ACN, 100 °C, MW, 25 min, 48%; (c) BBr3 1 M DCM, DCM, −78 °C to rt, overnight, 90%; (d) TBDMSCl, imidazole, DCE, 60 °C, 8 h, 86%; (e) NBS, AIBN, CCl4, reflux, 8 h, 37%; (f) P(OEt)3, 130 °C, overnight, 84%; (g) 4-bis((tert-butyldimethylsilyl)oxy)benzaldehyde, NaH, THF, 0 °C to rt, 24 h, 52%; (h) TBAF, THF, 0 °C to rt, 2 h, 60%.
Scheme 4. Reagents and conditions: (a) (i) p-TsOH∙H2O, ACN, rt, 10 min; (ii) NIS, rt, overnight, 97%; (b) (i) 4-ethynianisole, PdCl2(PPh3)2∙DCM, CuI, THF/TEA 1:3, rt, MW, 30 min, (ii) 3,5-dimethoxy-1-iodobenzene, ACN, 100 °C, MW, 25 min, 48%; (c) BBr3 1 M DCM, DCM, −78 °C to rt, overnight, 90%; (d) TBDMSCl, imidazole, DCE, 60 °C, 8 h, 86%; (e) NBS, AIBN, CCl4, reflux, 8 h, 37%; (f) P(OEt)3, 130 °C, overnight, 84%; (g) 4-bis((tert-butyldimethylsilyl)oxy)benzaldehyde, NaH, THF, 0 °C to rt, 24 h, 52%; (h) TBAF, THF, 0 °C to rt, 2 h, 60%.
Molecules 26 07594 sch004
Molecules 26 07594 sch005 550
Scheme 5. Reagents and conditions: (a) BBr3 1 M DCM, dry DCM, −78 °C to rt, overnight, 87%; (b) TBDMSCl, imidazole, DMF, 0 °C to rt, overnight, 81%; (c) TBDMSCl, imidazole, DMF, 0 °C to rt, overnight, 74%; (d) CBr4, PPh3, DCM, 0 °C to rt, 1 h, 83%, (e) LDA, THF, −78 °C, 1 h, 91%; (f) Pd(PPh3)4, CuI, TEA, 90 °C, 8 h; (g) KF, MeOH/THF, rt, overnight, 38% over 2 steps.
Scheme 5. Reagents and conditions: (a) BBr3 1 M DCM, dry DCM, −78 °C to rt, overnight, 87%; (b) TBDMSCl, imidazole, DMF, 0 °C to rt, overnight, 81%; (c) TBDMSCl, imidazole, DMF, 0 °C to rt, overnight, 74%; (d) CBr4, PPh3, DCM, 0 °C to rt, 1 h, 83%, (e) LDA, THF, −78 °C, 1 h, 91%; (f) Pd(PPh3)4, CuI, TEA, 90 °C, 8 h; (g) KF, MeOH/THF, rt, overnight, 38% over 2 steps.
Molecules 26 07594 sch005
Molecules 26 07594 sch006 550
Scheme 6. Reagents and conditions: (a) H2/Pd/C 10% wt, EtOH, rt, 4 h, quantitative yield.
Scheme 6. Reagents and conditions: (a) H2/Pd/C 10% wt, EtOH, rt, 4 h, quantitative yield.
Molecules 26 07594 sch006
Table
Table 1. Susceptibility testing of S. aureus towards model compound 1 and newly synthesized analogues.
Table 1. Susceptibility testing of S. aureus towards model compound 1 and newly synthesized analogues.
S. aureus ATCC29213
MHB-IITSB
CompoundsStructureMIC
(µg/mL)		MBC
(µg/mL)		MIC
(µg/mL)		MBC
(µg/mL)
1 Molecules 26 07594 i0012 *≥512≥512≥512
10 Molecules 26 07594 i0024 *≥51232 *≥512
15 Molecules 26 07594 i00316 *≥51232 *≥512
27 Molecules 26 07594 i00416 *≥51216 *16 *
32 Molecules 26 07594 i0052 *82 *2 *
33 Molecules 26 07594 i0064 *44 *4 *
35 Molecules 26 07594 i007256≥512≥512≥512
Tobramycin <0.5<0.5<0.5<0.5
* The bacteria were able to grow at high concentrations of the tested compounds (see main text).
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Mattio, L.M.; Pinna, C.; Catinella, G.; Musso, L.; Pedersen, K.J.; Krogfelt, K.A.; Dallavalle, S.; Pinto, A. Synthesis and Antimicrobial Activity of δ-Viniferin Analogues and Isosteres. Molecules 2021, 26, 7594. https://doi.org/10.3390/molecules26247594

AMA Style

Mattio LM, Pinna C, Catinella G, Musso L, Pedersen KJ, Krogfelt KA, Dallavalle S, Pinto A. Synthesis and Antimicrobial Activity of δ-Viniferin Analogues and Isosteres. Molecules. 2021; 26(24):7594. https://doi.org/10.3390/molecules26247594

Chicago/Turabian Style

Mattio, Luce Micaela, Cecilia Pinna, Giorgia Catinella, Loana Musso, Kasandra Juliet Pedersen, Karen Angeliki Krogfelt, Sabrina Dallavalle, and Andrea Pinto. 2021. "Synthesis and Antimicrobial Activity of δ-Viniferin Analogues and Isosteres" Molecules 26, no. 24: 7594. https://doi.org/10.3390/molecules26247594

APA Style

Mattio, L. M., Pinna, C., Catinella, G., Musso, L., Pedersen, K. J., Krogfelt, K. A., Dallavalle, S., & Pinto, A. (2021). Synthesis and Antimicrobial Activity of δ-Viniferin Analogues and Isosteres. Molecules, 26(24), 7594. https://doi.org/10.3390/molecules26247594

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