Synthesis and anti-Helicobacter pylori activity of pyloricidin derivatives II. The combination of amino acid residues in the dipeptidic moiety and its effect on the anti-Helicobacter pylori activity.
The novel natural antibiotics pyloricidin A, B and C, consisting of a common (2S,3R,4R,5S)-5-amino-2,3,4,6-tetrahydroxyhexanoyl-beta-D-phenylalanine moiety and a terminal peptidic moiety (pyloricidin A: L-valine-L-valine-L-leucine; pyloricidin B: L-valine-L-leucine; pyloricidin C: L-leucine), exhibit potent and highly selective anti-Helicobacter pylori activity. In order to develop more potent compounds and to investigate structure activity relationships for the peptidic moiety with regard to the combination of amino acids, a series of derivatives with various dipeptidic moieties were prepared and evaluated for their anti-H. pylori activity. The combination of the two amino acids in the moiety was found to have a significant effect on the activity; the compound with Nva-Abu showed excellent anti-H. pylori activity with an MIC value of 0.013 microg/ml against H. pylori TN2. In addition, this compound was found to show 60% clearance of H. pylori from infected Mongolian gerbils upon repetitive oral administration (10 mg/kg, b. i. d. for 7 days).
Medicinal Chemistry Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan. Hasuoka_Atsushi@takeda.co.jp
Atsushi
A
Hasuoka
Yuji
Y
Nishikimi
Yutaka
Y
Nakayama
Keiji
K
Kamiyama
Masafumi
M
Nakao
Ken-ichiro
K
Miyagawa
Osamu
O
Nishimura
Masahiko
M
Fujino
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D023181:Antimicrobial Cationic Peptides; D001419:Bacteria / Q000187:drug effects; D005849:Gerbillinae; D016481:Helicobacter Infections / Q000188:drug therapy / Q000382:microbiology; D016480:Helicobacter pylori / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D010455:Peptides; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D010455:Peptides; C462559:pyloricidin A; C456045:pyloricidin B; C456046:pyloricidin C