title: Design, synthesis, and biological evaluation of a series of beta-lactam-based prodrugs.
abstract: 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.
authors.affiliation: TaiGen Biotechnology, 138 Hsin Ming Rd., Neihu Dist., Taipei, Taiwan, ROC. hosein@taigenbiotech.com.tw
authors.forename: Gholam Hossein
authors.initials: GH
authors.lastname: Hakimelahi
authors.forename: Kak-Shan
authors.initials: KS
authors.lastname: Shia
authors.forename: Cuihua
authors.initials: C
authors.lastname: Xue
authors.forename: Shahram
authors.initials: S
authors.lastname: Hakimelahi
authors.forename: Ali A
authors.initials: AA
authors.lastname: Moosavi-Movahedi
authors.forename: Ali A
authors.initials: AA
authors.lastname: Saboury
authors.forename: Ali
authors.initials: A
authors.lastname: Khalafi-Nezhad
authors.forename: Mohammad N
authors.initials: MN
authors.lastname: Soltani-Rad
authors.forename: Valeriy
authors.initials: V
authors.lastname: Osyetrov
authors.forename: Kung
authors.initials: K
authors.lastname: Wang
authors.forename: Jyh-Hsiung
authors.initials: JH
authors.lastname: Liao
authors.forename: Fen-Tair
authors.initials: FT
authors.lastname: Luo
mesh_terms: 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
chemical_list: D000900:Anti-Bacterial Agents; D002021:Buffers; D004791:Enzyme Inhibitors; D008055:Lipids; D011355:Prodrugs; D065093:beta-Lactamase Inhibitors; D019818:Clavulanic Acid; D000658:Amoxicillin