Semisynthetic Vitamin E Derivatives as Potent Antibacterial Agents against Resistant Gram‐Positive Pathogens

Abstract

New 5‐substituted vitamin E derivatives were semisynthesized, and their antibacterial activity against human Gram‐positive and Gram‐negative pathogens was evaluated. Several vitamin E analogues were active against methicillin‐resistant Staphylococcus aureus (MRSA) and/or methicillin‐resistant Staphylococcus epidermidis (MRSE); structure‐activity relationships (SARs) are discussed. As a result, it is shown that the presence of a carboxylic acid function at the C‐5 position and/or at the end of the side chain is crucial for the antibacterial activity. The bactericidal or bacteriostatic action of three compounds against MRSA and MRSE was confirmed in a time‐kill kinetics study, and the cytotoxicity on human cells was evaluated. The preliminary mechanism study by confocal microscopy indicated that those vitamin E analogues led to bacterial cell death through membrane disruption.

Exploration of Long-Chain Vitamin E Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation

“… 46 Compound 3 was either protected as a methoxymethyl acetal 4 or oxidized through a Pinnick oxidation leading to the corresponding carboxylic acid 5 . 47 Similar conditions applied to aldehyde 54 ( 39 ) led to 15b and then 15a bearing a truncated 11-carbon long side-chain ( Scheme 4 ). Aldehydes 33 and 34 were further involved in a condensation step with β-carbonylesters toward coumarin-tocotrienol hybrids 41 – 43 ( Schemes 3 and 5 ).…”

“…Starting from 70 allowed the preparation of 48 . Compound 3 was either protected as a methoxymethyl acetal 4 or oxidized through a Pinnick oxidation leading to the corresponding carboxylic acid 5 . Similar conditions applied to aldehyde 54 led to 15b and then 15a bearing a truncated 11-carbon long side-chain (Scheme ).…”

“… a Reagents and conditions: (a) MeI, NaHCO 3 , DMF, MW 120 °C, 45 min, 93% for 52 , 85% for 25 ; (b) NaH, MeI, DMF, 0 °C, 1 h, 67% for 53 ; (c) Mg, MeOH, rt., 16 h, 66% for 21 , 72% for 22 ; (d) NaOH, MeOH, 70 °C, 4 h, 91% for 19b , 87% for 20 , 77% for 15b ; (e) TMDA, (CHO) n , 1,4-dioxane, MW 140 °C, 40 min and then NaBH 3 CN, EtOH, reflux, 14 h, 62% for 19a , 75% for 15a ; (f) see Ville et al; (g) NaClO 2 , H 2 NSO 3 H, 2-methyl-2-butene, 1,4-dioxane/H 2 O (1:1), 0 °C, 2 h, quant. ; (h) see Viault et al …”

“…To a solution of diacid 56 ( 47 ) (1 equiv) in dimethylformamide (0.13 M) were added sodium bicarbonate (4 equiv) and iodomethane (4 equiv). The reaction mixture was stirred at 120 °C under microwave irradiation for 2 h. Then, the reaction was quenched with water.…”

“…1 (R)-Methyl-6-hydroxy-2-((3E,7E,11E)-13-methoxy-4,8,12-trimethyl-13-oxotrideca-3,7,11-trien-1-yl)-2,8-dimethylchroman-5-carboxylate (25). To a solution of diacid 56 47 (1 equiv) in dimethylformamide (0.13 M) were added sodium bicarbonate (4 equiv) and iodomethane (4 equiv). The reaction mixture was stirred at 120 °C under microwave irradiation for 2 h. Then, the reaction was quenched with water.…”