Anti-Helicobacter pylori activity of derivatives of the phthalide-containing antibacterial agents spirolaxine methyl ether, CJ-12,954, CJ-13,013, CJ-13,102, CJ-13,104, CJ-13,108 and CJ-13,015.
The naturally occurring phthalide-containing antibiotics spirolaxine methyl ether, CJ-12,954, CJ-13,013, CJ-13,015, CJ-13,102, CJ-13,103, CJ-13,104 and CJ-13,108, have been reported to exhibit anti-H. pylori activity. However, the exact stereochemistry of spirolaxine methyl ether, CJ-12,954 or CJ-13,013, contributing to this observed activity has not been confirmed. The anti-H. pylori activity of several analogues of spirolaxine methyl ether, CJ-12,954 and CJ-13,013 of defined stereochemistry together with the anti-H. pylori activity of several indole analogues of the simpler phthalide-containing antibiotics CJ-13,102, CJ-13,104, CJ-13,108 and CJ-13,015 is reported herein. A 1:1 mixture of spiroacetals 5b and 6b in which the phthalide substituent exhibited (3R)-stereochemistry was sixty times more active than the corresponding 1:1 mixture of spiroacetals with (3S)-stereochemistry. Notably, the unnatural (2''S)-diastereomer of spirolaxine methyl ether exhibited more potent anti-H. pylori activity than the natural product spirolaxine methyl ether. The 4,6-dimethoxyindoles 9, 10, 11 and 13 were all found to be less active than their parent compounds 1, 2, 3 and 4, respectively. Chain-shortened 4,6-dimethoxyindole analogue 12 of CJ-13,108 3 and 4,6-dimethoxyindole-spiroacetal 13 exhibited weak anti-H. pylori activity thus providing future opportunity for drug discovery programs.
Radcliff
Fiona J
FJ
Department of Molecular Medicine and Pathology, University of Auckland, 85 Park Road, Grafton, Auckland 1142, New Zealand.
Fraser
John D
JD
Wilson
Zoe E
ZE
Heapy
Amanda M
AM
Robinson
James E
JE
Bryant
Christina J
CJ
Flowers
Christopher L
CL
Brimble
Margaret A
MA
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016480:Helicobacter pylori / Q000187:drug effects* / Q000254:growth & development; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D001572:Benzofurans; C109706:CJ 12954; C109705:CJ 13014; D006571:Heterocyclic Compounds; D013141:Spiro Compounds; C517924:spirolaxine methyl ether; C082022:phthalide