Structure-anti-MRSA activity relationship of macrocyclic bis(bibenzyl) derivatives.
We synthesized a series of macrocyclic bis(bibenzyl) derivatives, including riccardin-, isoplagiochin- and marchantin-class structures, and evaluated their antibacterial activity towards methicillin-resistant Staphylococcus aureus (anti-MRSA activity). The structure-activity relationships and the results of molecular dynamics simulations indicated that bis(bibenzyl)s with potent anti-MRSA activity commonly have a 4-hydroxyl group at the D-benzene ring and a 2-hydroxyl group at the C-benzene ring in the hydrophilic part of the molecule, and an unsubstituted phenoxyphenyl group in the hydrophobic part of the molecule containing the A-B-benzene rings. Pharmacological characterization of the bis(bibenzyl) derivatives and 2-phenoxyphenol fragment 25, previously proposed as the minimum structure of riccardin C 1 for anti-MRSA activity, indicated that they have different action mechanisms: the bis(bibenzyl)s are bactericidal, while 25 is bacteriostatic, showing only weak bactericidal activity.
Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
Hiromi
H
Sawada
Kenji
K
Onoda
Daichi
D
Morita
Erika
E
Ishitsubo
Kenji
K
Matsuno
Hiroaki
H
Tokiwa
Teruo
T
Kuroda
Hiroyuki
H
Miyachi
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001632:Bibenzyls / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D047028:Macrocyclic Compounds / Q000737:chemistry*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D056004:Molecular Dynamics Simulation; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D001632:Bibenzyls; D047028:Macrocyclic Compounds
Isoplagiochin; Marchantin; Methicillin resistance; Riccardin; Structure–activity relationship