Synthesis and substituent effects on antibacterial activity, alkaline hydrolysis rates, and infrared absorption frequencies of some cephem analogues related to latamoxef (moxalactam).

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.

Effect of latamoxef (moxalactam) and its related compounds on platelet aggregation in vitro--structure activity relationships.

Latamoxef, 1-S replaced and/or decarboxylated derivatives of latamoxef, compounds possessing a partial structure of latamoxef, and a beta-lactam ring-opened derivative of latamoxef were examined for their effects on human platelet aggregation in vitro. Latamoxef produced a dose-dependent inhibition of ADP-induced platelet aggregation at high concentrations over about 2000 micrograms/ml (or 4 mM), and the potency was similar to that produced by cefotaxime, carbenicillin or ceftizoxime. Replacement of the oxygen atom in the oxacephem ring with a sulfur atom caused no significant change in the potency. The decarboxylated derivatives of latamoxef and the 1-S replaced analogue of latamoxef showed stronger inhibition for both ADP- and collagen-induced aggregation than the parent compounds. The effects of the compounds possessing a partial structure of latamoxef were weaker than that of latamoxef, but the effect of the beta-lactam ring-opened compound was about 3-fold stronger than that of latamoxef. These data suggest that neither the oxygen atom in the oxacephem ring nor the carboxyl group in the amide side chain is responsible for the inhibitory effect of latamoxef on platelet aggregation.

Epimerization kinetics of moxalactam, its derivatives, and carbenicillin in aqueous solution.

The mechanism of the epimerization of moxalactam was studied by measuring the rate of epimerization after deuteration of the C-7 side-chain chiral carbon, introduction of different substituents on the side chain, and variation of the ring system. Deuteration slowed the epimerization rate considerably. The rate was also influenced by the choice of the ring system and the substituent on the C-7 side-chain chiral carbon. When the penicillin ring system with the 2-carboxy-2-phenyl-acetamide was studied, the epimerization rate decreased indicating that the same ring system needed to be used throughout the epimerization studies. Thus, experiments were conducted with different substituents replacing the phenolic group at the C-7 side-chain chiral carbon of moxalactam. The epimerization rate decreased in the substituent order thienyl, phenyl, 4-hydroxyphenyl, the ionized form of 4-hydroxyphenyl, and ethyl. These results showed that dehydrogenation of the chiral carbon seems to be the rate-determining step and that the stronger the electron-donating effect of the substituent, the slower the epimerization rate becomes.