seco-Cyclothialidines: new concise synthesis, inhibitory activity toward bacterial and human DNA topoisomerases, and antibacterial properties.
seco-Cyclothialidines are a promising class of bacterial DNA gyrase B subunit inhibitors. A new seco-cyclothialidine derivative containing a dioxazine moiety, BAY 50-7952, was synthesized through a new concise pathway. One key step of the synthesis is the straightforward formation of the 2-aminothiazole derivative of S-tritylcysteine. In biological tests, BAY 50-7952 and other known seco-cyclothialidines exhibited high and selective activity toward bacterial DNA gyrase and toward Gram-positive bacteria. The dioxazine moiety and other similar groups were found to be important for the ability of the seco-cyclothialidines to penetrate bacterial membranes. The opposite enantiomer ((S)-form) of BAY 50-7952 was also synthesized, and neither significant target activity nor in vitro antibacterial activity were found, suggesting a highly selective fit of the (R)-form. Despite promising in vitro activity, only poor activity was found in the murine infection model.
Rudolph
J
J
Bayer AG, Central Research, Chemistry for Life Sciences, D-51368 Leverkusen, Germany.
Theis
H
H
Hanke
R
R
Endermann
R
R
Johannsen
L
L
Geschke
F
F
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015169:Colony Count, Microbial; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D062425:Hydroxybenzoate Ethers; D062385:Hydroxybenzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D013237:Stereoisomerism; D013290:Streptococcal Infections / Q000188:drug therapy / Q000401:mortality; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D062425:Hydroxybenzoate Ethers; D062385:Hydroxybenzoates; D013844:Thiazoles; D059005:Topoisomerase II Inhibitors; C421628:methyl 2-bromo-6-(((2-(5,6-dihydro-1,4,2-dioxazin-3-yl)-2-((4-(4-nitrophenyl)-1,3-thiazol-2-yl)amino)ethyl)sulfanyl)-methyl)-5-hydroxy-3-methoxybenzoate