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Synthesis and substituent effects on antibacterial activity, alkaline hydrolysis rates, and infrared absorption frequencies of some cephem analogues related to latamoxef (moxalactam)
- Source :
- Journal of medicinal chemistry. 26(11)
- Publication Year :
- 1983
-
Abstract
- Relationships between intrinsic antibacterial activity and beta-lactam reactivity of 7 beta-[(4-hydroxyphenyl)acetyl]amino- and 7 beta-[(4-hydroxyphenyl)malonyl]amino derivatives of 1-oxa- and 1-thiacephems, with or without the 7 alpha-methoxy group (1-8), were investigated in order to clarify the enhanced antibacterial activity of latamoxef disodium (1). Substituent effects of a carbon atom at the 1- and 7 alpha-positions were also investigated by using racemic 1-carbacephem 9 and 7 alpha-methyl-1-oxacephem 10. Syntheses of 2-8 and 10 are also described. Acid chlorides derived from the O-benzyloxycarbonyl derivative of (4-hydroxyphenyl)acetic acid and the p-methoxybenzyl derivative of (4-hydroxyphenyl)malonic acid smoothly effected the introduction of these side chains. Conjugate addition of lithium dimethylcuprate to the quinoid system in 16 proceeded stereospecifically, furnishing the 7 alpha-methyl group for the synthesis of 10. Values of log (1/C) averaged for the sensitive Gram-negative strains (Escherichia coli NIHJ JC-2 and Klebsiella pneumoniae SRL-1) were taken as an estimation of the intrinsic antibacterial activity. The chemical reactivity of the beta-lactam ring was estimated either by pseudo-first-order rate constants (k) of alkaline hydrolysis measured at pH 9.20 and 35.0 degrees C or by infrared stretching frequencies of the beta-lactam carbonyl measured in dimethyl sulfoxide. Substitution of an oxygen atom at the 1-position increases both the hydrolysis rates and the antibacterial activity by a factor of approximately 6.3, while substitution of a 7 alpha-methoxy group increases the antibacterial activity by a factor of approximately 3.2 without significant change in the hydrolysis rates. The effect of the 7 alpha-methoxy group on the transition state in alkaline hydrolysis is discussed. Substitutions at the 1-position with a methylene group and, especially, at the 7 alpha-position with a methyl group greatly diminished the antibacterial activity, whereas the hydrolysis rate remained high with the substitution of a methylene group. Substitution of an oxygen atom for the sulfur atom at the 1-position of 1-thiacephems increased the beta-lactam carbonyl frequencies by approximately 6 cm-1, whereas introduction of a 7 alpha-methoxy group in 1-thia- and 1-oxacephems reduced the frequencies by approximately 5 cm-1.
- Subjects :
- Magnetic Resonance Spectroscopy
Spectrophotometry, Infrared
Stereochemistry
Hydrolysis
Substituent
Microbial Sensitivity Tests
Malonic acid
Hydrogen-Ion Concentration
Medicinal chemistry
Anti-Bacterial Agents
chemistry.chemical_compound
Structure-Activity Relationship
chemistry
Drug Discovery
Gram-Negative Bacteria
Molecular Medicine
Indicators and Reagents
Methylene
Antibacterial activity
Alkaline hydrolysis
Methyl group
Antibacterial agent
Moxalactam
Subjects
Details
- ISSN :
- 00222623
- Volume :
- 26
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....f74af97b78b16adbe0c5b602cf90da58