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).
Highlights
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]
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
Summary
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]. 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. Methods to access stilbenoid-derived 2,3-diaryl-5-substituted benzTohfuursa, nwse p[2la3n–n28ed], topaplrleapdaiurema ncoavteallyseset dof dreeahcytdiorno-sδ-hvainvieferpinroavneanlogtuoesbaendraipsoidstearensd, orssdac[Saaitur2beonlleookkc9htnrgnmah]yyeyvsoionndnaaegBeaeyrtsnealnioladecisapd-entchnδrohnbtdii-retrnyvaos.anCgmgiunImnoen.sicciiclnIcfdotopnoeheeedeuarbrsfap,iirpfasttnfeaataitylivwcerliicaiknttn,eunniseyglceglrayafunadeoltbrletoraadh,eigosrarmteitu,hofnrwafaepsoeenaeetsmlrryafeeiseetfnnrmnahmniyctttattieieuloematefrnrvmmnrnmmaitoatcetopmlaeroeodieodiordennrtbfittheatahycbita-oatthheypiue-lAneaiorroaueieedtncMd(dns,Fmto,oodiatiuvctrpgheerhocibthruketieuhlygneiers.lonoenodtbcIdaeilonl1ooscbmld)rnlaae,araeaddonewnrsvnidseiidoeefmhpdiytlrdtiooyiuloic.otapnethluosnndtemebwa,rdinlenwaraeobpoegrireybynollkaeoluptCeic-anonsslreaiaufdstmnccnebt,yicrnhenhs[chnne3etglaiaiid0tvtzgaltu]wainhte,ntotaodeieigtliomsdhkn,ucynoyhvenmntwwnotoeatrowehlrlyoivt.imteeereheaskrtvTisinietnezeehhddraersaee,sl 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). 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
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