Chemical Modification of Tazobactam: Synthesis of 2β-[(4-Substituted)-l, 2, 3-triazol-l-yl]methyl Penicillanic Acid Sulfone Derivatives

• Published in: Journal of antibiotics 1995/11/25, Vol.48(11), pp.1320-1329
• Main Authors: SETTI, EDUARDO L., FIAKPUI, CHARLES, PHILLIPS, OLUDOTUN A., CZAJKOWSKI, DAVID P., ATCHISON, KEVIN, MICETICH, RONALD G., MAITI, SAMARENDRA N., KUNUGITA, CHIEKO, HYODO, AKIO
• Format: Article
• Language: English
• Subjects: Ampicillin - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; beta-Lactamase Inhibitors; Biological and medical sciences; Chemical Phenomena; Chemistry, Physical; Drug Synergism; Electrochemistry; Enzyme Inhibitors - chemistry; Escherichia coli - drug effects; Gram-Negative Bacteria - drug effects; Klebsiella pneumoniae - drug effects; Medical sciences; Molecular Structure; Penicillanic Acid - analogs & derivatives; Penicillanic Acid - chemistry; Penicillanic Acid - pharmacology; Pharmacology. Drug treatments; Piperacillin - pharmacology; Plasmids; Pseudomonas aeruginosa - drug effects; Structure-Activity Relationship; Tazobactam; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 0021-8820; 1881-1469
• DOI: 10.7164/antibiotics.48.1320

A series of 2β-[(4-substituted)-l, 2, 3-triazol-l-yl]methyl penicillanic acid sulfones was synthesized as β-lactamase inhibitors. Many of these compounds showed good in vitro inhibitory activity against penicillinase, cefotaximase and plasmid-mediated class III TEM enzymes, but exhibited weaker cephalosporinase inhibition. One member in this series-2β-[(4-pyridiniummethyl)-l, 2, 3-triazol-lyl]methyl-6, 6-dihydropenicillanate 1, 1-dioxide (12a), when tested in combination with piperacillin, showed excellent synergistic activity against microorganisms producing plasmid-mediated enzymes, but had insufficient activity against microorganisms producing chromosomally mediated class I enzymes.