Design, synthesis, and biological evaluation of a series of beta-lactam-based prodrugs.
By use of pro-dual-drug concept the synthesis of 6-beta-[(R)-2-(clavaminio-9-N-yl)-2-(4-hydroxyphenylacetamido)]penicillanic acid (10), 6-beta-[(R)-2-(amino)-2-(4-(clavulano-9-O-yl)phenylacetamido)]penicillanic acid (13), (Z)-4-[2-(amoxycillin-4-O-yl)ethylidene]-2-(clavulano-9-O-yl)-3-methoxy-Delta(alpha,beta)-butenolide (19), and 3-[(amoxicillin-4-O-yl)methyl]-7-(phenoxyacetamido)-(1-oxo)-3-cephem-4-carboxylic acid (23) was accomplished. Unlike penicillin G, ampicillin, or amoxicillin, these four heretofore undescribed compounds 10, 13, 19, and 23 showed notable activity against beta-lactamase (betaL) producing microorganisms, Staphylococcus aureus A9606, S. aureus A15091, S. aureus A20309, S. aureus 95, Escherichia coli A9675, E. coli A21223, E. coli 27C7, Pseudomonas aeruginosa 18S-H, and Klebsiella pneumoniae A20634 TEM. In comparison with amoxicillin (9), alpha-amino-substituted compound 10 and butenolide derivative 19 showed a broadened spectrum of antibacterial activity; yet they were found to be less active than 13 and 23. Like clavulanic acid (7) or cephalosporin-1-oxide (21), the newly synthesized compounds 10, 13, 15, 16, 19, or 23 functioned as potent inhibitors of various bacterial betaLs.
Hakimelahi
Gholam Hossein
GH
TaiGen Biotechnology, 138 Hsin Ming Rd., Neihu Dist., Taipei, Taiwan, ROC. hosein@taigenbiotech.com.tw
Shia
Kak-Shan
KS
Xue
Cuihua
C
Hakimelahi
Shahram
S
Moosavi-Movahedi
Ali A
AA
Saboury
Ali A
AA
Khalafi-Nezhad
Ali
A
Soltani-Rad
Mohammad N
MN
Osyetrov
Valeriy
V
Wang
Kung
K
Liao
Jyh-Hsiung
JH
Luo
Fen-Tair
FT
D000658:Amoxicillin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D002021:Buffers; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D019818:Clavulanic Acid / Q000138:chemical synthesis / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006868:Hydrolysis; D008055:Lipids / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors
D000900:Anti-Bacterial Agents; D002021:Buffers; D004791:Enzyme Inhibitors; D008055:Lipids; D011355:Prodrugs; D065093:beta-Lactamase Inhibitors; D019818:Clavulanic Acid; D000658:Amoxicillin