title: Synthesis and substituent effects on antibacterial activity, alkaline hydrolysis rates, and infrared absorption frequencies of some cephem analogues related to latamoxef (moxalactam).
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.
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D009070:Moxalactam / Q000031:analogs & derivatives*; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D007202:Indicators and Reagents; D009070:Moxalactam