FTIR spectral study of intramolecular hydrogen bonding in E-type of 15-keto-prostaglandins in dilute CCl4 solution: structure-activity relationships.

FTIR spectra of 15-keto-prostaglandin (PG)E2 (1), 15-keto-PGE1 (2), 13,14-dihydro-15-keto-PGE2 (3), 13,14-dihydro-15-keto-PGE1 (4), and their related compounds were measured in dilute tetrachloromethane solution in order to examine the structure-activity relationships for the 5,6-cis-double bond of the alpha-side chain and the 13,14-trans-double bond and the 15-hydroxyl group of the omega-side chain in PGE2, PGD2, and PGF2 alpha. The spectra were subjected to curve analysis to separate overlapping absorption bands. For compounds 1-4, an intramolecular hydrogen bond involving a 15-membered ring similar to that observed for PGE2, PGD2, and PGF2 alpha was found between the carboxyl and 15-carbonyl groups. The percentages (rho) of the intramolecular hydrogen-bonded molecules with the 15-membered rings in 1-4 and PGE2 were compared with the known binding activities of PGs for various PG receptors, and we found that these activities decrease as the rho values decrease. These results strongly supported our hypothesis that, in PGs, the conformation with the 15-membered ring formed by the intramolecular hydrogen bonds between the carboxyl group of the alpha-side chain and the 15-hydroxyl group of the omega-side chain is a precursory conformation of the active one.

FTIR spectral study of intramolecular hydrogen bonding in thromboxane A2 receptor agonist (U-46619), prostaglandin (PG)E2, PGD2, PGF2 alpha, prostacyclin receptor agonist (carbacyclin), and their related compounds in dilute CCl4 solution: structure-activity relationships.

FTIR spectra measurements and full optimization curve analysis of their spectra were done to obtain parameters of the OH and C = O stretching vibration bands for intramolecular hydrogen bondings in thromboxane (TX)A2 receptor partial agonist (CTA2), prostaglandin (PG)E2, PGD2, PGF2 alpha, prostacyclin (PGI2) receptor agonist (carbacyclin), and their related compounds in dilute CCl4 solutions. For CTA2, PGE2, PGD2, and PGF2 alpha, cyclic intramolecular hydrogen bonds involving a 15-membered ring similar to that observed for the TXA2 receptor agonist (U-46619) were found between a carboxyl group of the alpha-side chain and a 15-hydroxyl group of the omega-side chain. The arrangement of these side chains was P-shaped, and the percentage of the intramolecular hydrogen-bonded molecules with the 15-membered ring in CCl4 solution showed a high value of ca. 80% for these compounds. In addition, it was found that the cyclic intramolecular hydrogen bonds involving the 13-, 12-, and 12-membered rings in PGE2, PGD2, and PGF2 alpha, respectively, are formed between the carboxyl group of the alpha-side chain and the 11-, 9-, and 9-hydroxyl groups of a cyclopentane ring, respectively, although the percentages of the intramolecular hydrogen-bonded molecules with these membered rings are very small. It was also found that the hydrogen bond is more easily formed in the order of the 11-, 9-, and 15-hydroxyl groups. For carbacyclin, the cyclic intramolecular hydrogen bond involving the 13-membered ring was found between the carboxyl group of the alpha-side chain and the 11-hydroxyl group. The percentage of the intramolecular hydrogen-bonded molecules showed the value of 58% for carbacyclin. On the basis of information on the side-chain conformations in CCl4, we examined the structure-activity relationships for U-46619 in place of TXA2, PGE2, PGD2, PGF2 alpha, and carbacyclin in place of PGI2.

FTIR spectral study of intramolecular hydrogen bonding in thromboxane A2 receptor antagonist S-145 and related compounds. 3. Conformation and activity of S-145 analogues.

S-145, (+/-)-(5Z)-7-[3-endo-[(phenylsulfonyl)amino]bicyclo[2.2.1] heptenoic acid, its chain analogues HO2C(CH2)nNHSO2Ph (n = 3-8, 10, and 11) 1-8, and (5Z)-9-(phenylsulfonyl) aminonon-5-enoic acid (9) were synthesized in order to elucidate the dependence of the conformation in solution and of the pharmacological activity on the side-chain length. Their FTIR spectra were measured in dilute CCl4 solution. For these compounds, intramolecular hydrogen bonds similar to those observed for S-145 were found between the carboxyl and sulfonamido groups. A linear relationship was also found between the percentage (rho) of the intramolecular hydrogen-bonded molecules and the n value. Compounds 1-9 were examined in vitro for inhibitory concentrations (IC50) against U-46619- and collagen-induced aggregations for rabbit and rat washed platelets (WP), respectively, and U-46619-induced contraction for rat aorta. Three kinds of TXA2 receptor antagonistic potencies [log(1/IC50)] showed parabolic correlations with the n value, though the rho value was in direct proportion to the n value. The log (1/IC50) values for 6 (n = 8), which forms a 12-membered ring similar to the one observed for S-145, were found to be maximal values in 1-8 and were comparable to those for BM-13177. In compounds 9 (rho = 83%) and S-145 (rho = 89%), the IC50 values of 41 and 2.9 nM for rat WP were 10 and 141 times lower than that of 6 (rho = 52%), respectively. In these compounds, which form the 12-membered ring, the inhibitory potencies increase as the rho value increases.

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.

1-Oxacephalosporins: enhancement of beta-lactam reactivity and antibacterial activity.

The effect of replacement of sulfur in the cephem nucleus by oxygen upon the beta-lactamase stability, infrared carbonyl frequency of the beta-lactam ring, and antibacterial activity was investigated. The replacement reduced the stability of beta-lactam compounds to beta-lactamases, increased the IR frequencies, and enhanced the intrinsic antibacterial activity against bacterial strains without beta-lactamase. The instability of 1-oxacephalosporins to beta-lactamases, in other words, high reactivity to the enzymes, seemed to be due to the enhanced chemical reactivity of their beta-lactam rings which was indicated by their higher IR beta-lactam carbonyl frequencies. Based on a view that acylation of the enzyme by beta-lactam compounds occurred in both cases of beta-lactamase hydrolysis and target enzyme inhibition, the suggestion was made that one of the factors which conferred the higher intrinsic antibacterial activity on 1-oxacephalosporins was their high reactivity to the target enzyme(s), as was the case with beta-lactamases.