Structural Requirements of Benzofuran Derivatives Dehydro- δ- and Dehydro- ε-Viniferin for Antimicrobial Activity Against the Foodborne Pathogen Listeria monocytogenes

Abstract

In a recent study, we investigated the antimicrobial activity of a collection of resveratrol-derived monomers and dimers against a series of foodborne pathogens. Out of the tested molecules, dehydro-δ-viniferin and dehydro-ε-viniferin emerged as the most promising derivatives. To define the structural elements essential to the antimicrobial activity against the foodborne pathogen L. monocytogenes Scott A as a model Gram-positive microorganism, the synthesis of a series of simplified benzofuran-containing derivatives was carried out. The systematic removal of the aromatic moieties of the parent molecules allowed a deeper insight into the most relevant structural features affecting the activity. While the overall structure of compound 1 could not be altered without a substantial loss of antimicrobial activity, the structural simplification of compound 2 (minimal inhibitory concentration (MIC) 16 µg/mL, minimal bactericidal concentration (MBC) >512 µg/mL) led to the analogue 7 with increased activity (MIC 8 µg/mL, MBC 64 µg/mL).

Keywords: Listeria monocytogenes; antimicrobials; benzofuran nucleus; viniferin derivatives.

Figure 1

Structures of resveratrol and representative resveratrol-derived monomers and dimers.

Figure 2

Structures of compounds 1 and 2 and of the simplified analogues 3–8 and 9–11.

Scheme 1

Reagents and conditions: (a) (i) PdCl₂(PPh₃)₂ (5% mol), CuI (3% mol), TEA:THF 1:1, N₂, 40 °C, 40 min; (ii) ACN, 100 °C, 90 min, 50%; (b) NIS, p-TsOH, ACN, N₂, overnight, 74%; (c) (3,5-dimethoxyphenyl)boronic acid, K₂CO₃, PdCl₂(dppf)·CH₂Cl₂, THF:H₂O 1:1, MW, 70 °C, 30 min, 83%; d) BBr₃, DCM, 0 °C to rt, overnight, 61%.

Scheme 2

Reagents and conditions: (a) (i) PdCl₂(PPh₃)₂ (5% mol), CuI (3% mol), TEA:THF 1:1, N₂, 40 °C, 40 min; (ii) ACN, 100 °C, 90 min, 62%; (b) (i) LiAlH₄, THF, N₂, 0 °C, 10 min; (ii) DMP, DCM, 0 °C 15 min, rt 90 min, 85%; (c) diethyl (3,5-dimethoxyphenyl)phosphonate, NaH, THF, MW, 120 °C, 30 min, 76%; (d) BBr₃, DCM, 0 °C to rt, overnight, 60%; (e) BCl₃, TBAI, DCM, N₂, 0 °C to rt, 6 h, 35%.

Scheme 3

Reagents and conditions: (a) 2-bromo-1,1-dimethoxyethane, Cs₂CO₃, MeCN, reflux, 3 days, 61%; (b) Amberlyst-15, toluene, reflux, 6 h, 51%; (c) Br₂, DCM, 0 °C to rt, 75 min, 82%; (d) KOH, MeOH, THF, 0 °C, 20 min, 82%; (e) (3,5-dimethoxyphenyl)boronic acid, Pd(PPh₃)₄, Na₂CO₃, DME:H₂O 5:1, 80 °C, overnight, 74%; (f) LiAlH₄, THF, 0 °C, 10 min, 97%; (g) DMP, DCM, 0 °C to rt, 90 min, 78%; (h) diethyl (3,5-dimethoxyphenyl)phosphonate, NaH, THF, MW, 120 °C, 30 min, 80%; (i) BBr₃, DCM, 0 °C to rt, overnight, 14%.

Scheme 4

Reagents and conditions: (a) CuBr₂, EtOAc:CHCl₃, reflux, overnight, 67%; (b) m-methoxyphenol, K₂CO₃, acetone, N₂, reflux, 2 h, 90%; (c) Bi(OTf)₃, DCM, N₂, reflux, overnight, 43%; (d) p-methoxybromobenzene, Pd(OAc)₂, PCy₃HBF₄, K₂CO₃, pivalic acid, DMA, N₂, 100 °C, 20 h, 80%; (e) BBr₃, DCM, 0 °C to rt, overnight, 52%; (f) 3-bromo-5-methoxyphenol, K₂CO₃, acetone, N₂, reflux, 2 h, 89%; (g) Bi(OTf)₃, DCM, N₂, reflux, overnight, 83%; (h) BBr₃, DCM, 0 °C to rt, overnight, 91%; (i) p-hydroxystyrene, Pd(OAc)₂, TEA, dppp, DMF, N₂, 120 °C, 20 h, 80%.

Scheme 5

Reagents and conditions: (a) K₂CO₃, CH₃I, DMF, rt, 45h, 35%; (b) 2-bromo-1,1-dimethoxyethane, Cs₂CO₃, CH₃CN, reflux, 72 h, 67%; (c) Amberlyst-15, C₆H₅Cl, 120 °C, 3 h, 63%; (d) NBS, DMF cat., ClCH₂CH₂Cl, 75 °C, 3 h, 80%; (e) (4-methoxyphenyl)boronic acid, Pd(PPh₃)₄, K₂CO₃, DMF, 70 °C, overnight, 91%; (f) LiAlH₄, DCM, 0 °C, 10 min, 89%; g) DMP, DCM, 0 °C to rt, 90 min, 97%; (h) diethyl (4-methoxybenzyl)phosphonate, NaH, dry THF, 120 °C - MW, 30 min, 54%; (i) BBr₃, 0 °C to rt, 6 h, 24%.