Synthesis and antibacterial activity of hydrolytically stable (−)-epicatechin gallate analogues for the modulation of β-lactam resistance in Staphylococcus aureus

Abstract

Hydrolytically more stable analogues of (-)-epicatechin gallate (ECg) have been synthesised from ECg where an amine or amide function has been substituted for the ester linkage that joins the C-ring with the galloyl D-ring. Sub-inhibitory concentrations (25 mg/L) of the amide analogue 7, possessing the natural C-3 stereochemistry, were able to reduce the resistance to oxacillin of three strains of methicillin resistant Staphylococcus aureus (BB 568, EMRSA-15 and EMRSA-16) comparable to levels achieved with ECg.

Synthesis and structure–activity relationship of 3-O-acylated (–)-epigallocatechins as 5α-reductase inhibitors

“…The reaction provided EGCG octa-O-TBDMS (1) in 91% yield [22]. Reductive cleavage of the C3-O ester bond by use of LiAlH 4 in THF afforded EGC penta-O-TBDMS (2) in 80% yield.…”

“…Synthesis of (e)-epigallocatechin-3-gallate octa(tert-butyldimethylsilyl) ether (1) [22] To a solution of (e)-epigallocatechin-3-gallate (10.0 g, 21.8 mmol, 1.0 equiv) in DMF (50 mL) was added imidazole (14.9 g, 219 mmol, 10 equiv) followed by TBDMSCl (32.9 g, 218 mmol, 10 equiv) at 0 C. The solution was warmed to room temperature and stirred for 12 h. The reaction mixture was quenched with water (50 mL) and extracted with hexanes (100 mL Â 3). The combined organic layers were washed with water (50 mL Â 3), saturated aqueous NaCl (50 mL), dried over MgSO 4 (s), filtered, and concentrated under reduced pressure.…”

Potentiation of Catechin Gallate-Mediated Sensitization of Staphylococcus aureus to Oxacillin by Nongalloylated Catechins

“…EGCg has successfully undergone phase I (human safety) trials (4), and studies are under way to evaluate its efficacy in chronic lymphocytic leukemia. Although these activities are creating a precedent for therapeutic interventions with naturally occurring polyphenols, it is clear that the potential of catechins as antibiotic resistance-modifying agents would be significantly increased if their potency could be improved through synthesis by increasing stability (1) or by enhancing interactions with cellular targets (2). Evidence that nanomole concentrations of catechins are able to modulate the structure and function of model membranes through their capacity to partition into the phospholipid palisade is emerging (6).…”

“…However, as EC and EGC lack the gallate group, it is unlikely that they act as esterase inhibitors. In addition, esterase-stable derivatives of ECg have similar activities when used in combination with oxacillin against S. aureus, suggesting that esterase activity does not lead to the inactivation of the compounds in vitro (1). Other forms of inactivation, particularly modification to the catechin moiety, where EC and EGC could act as potential inhibitors, cannot be ruled out.…”

Synthesis and antimicrobial activities of 3-O-alkyl analogues of (+)-catechin: Improvement of stability and proposed action mechanism

“…In addition, catechin gallates such as (À)-ECG (3) and (À)-EGCG (1) are susceptible to hydrolysis by bacterial and possibly host esterases. To prevent the esterase-mediated removal of the galloyl moiety from catechin gallates, Anderson and coworkers have synthesized (À)-ECG (3) derivatives through the replacement of hydrolytically susceptible ester bond with a more stable amide bond [16]. Landis-Piwowar and coworkers developed acetyl-protected (À)-EGCG (1) analogues as putative pro-drugs which exhibited more potent proteasome inhibitory activity than (À)-EGCG (1) in cultured tumor cell [17].…”