Electronic structures of cephalosporins and penicillins. 11. Parabolic relationships between antibacterial activity of cephalosporins and .beta.-lactam reactivity predicted from molecular orbital calculations

Boyd, Donald B.; Herron, David K.; Lunn, W. H. W.; Spitzer, Wayne A.

doi:10.1021/ja00526a009

Cited by 52 publications

(17 citation statements)

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“…In other words, there must be more than one factor, including the basicity of the leaving group, that determines the reaction rate for the elimination reaction of the 1 -phenylethylammonium ions. Leaving group ability (nucleofugality) has been investigated in detail for several elimination processes (27)(28)(29)(30)(31)(32)(33)(34)(35). It has been pointed out (32) that it is difficult to quantitatively evaluate the nucleofugality of a particular leaving group for reaction proceeding by the concerted E2 mechanism where the rupture of 1 both the P-carbon-hydrogen and a-carbon -leaving group i bonds occurs at the transition state.…”

Section: Introductionmentioning

confidence: 99%

The effect of the nature of the amine leaving group on the nature of the E2 transition state for the reaction of 1-phenylethylammonium ions with sodium ethoxide in ethanol

Smith¹,

Amin²

1989

Can. J. Chem.

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To investigate the effect of the leaving group on the elimination reaction of 1-phenylethylammonium ions with sodium ethoxide in ethanol at 60°C, the reaction of seven different quaternary ammonium salts and their P-deuterated analogues with trimethylamine, N-methylpipendine, N-methyldiethylamine, triethylamine, N,N-dimethylbenzylamine, tripropylamine, and N,N-diethylbenzylamine as leaving groups has been studied. In all cases the elimination, which was shown to proceed via the concerted E2 process, was accompanied by competing substitution reactions. Although a significant dependence of the rate of the elimination process on the nature of the leaving group was noted, there was not any linear correlation with the basicity of the amine leaving group. The primary hydrogen-deuterium kinetic isotope effect for the elimination process, (kH/kD)E, was found to increase initially with an increase of reaction rate, kF, for substrates containing the leaving roups trimethylamine, N-methylpipendine, N-methyldiethylamine, triethylamine, and N,N-dimethylbenzylamine; i.e., (kH/$)E = 5. 03,5.26,5.40, 5.83, and 5.85, respectively. A further increase in rate, using substrates with tripropylamine and N,N-diethylbenzylamine as leaving groups resulted in a decrease of the magnitude of the hydrogen-deuterium isotope effect; i.e., (kH / kDIE = 5.42 and 4.67, respectively. It is concluded that steric effects mainly determine leaving group ability. As well, it is concluded that the leaving group ability of the amine determines the structure of the E2 transition state. For the reaction of the poorer leaving groups, trimethylamine, N-methylpipendine, and N-methyldiethylamine, the proton is more than one-half transferred at the transition state while for reaction involving the two best leaving groups, tripropylamine and N,N-diethylbenzylamine, the Cp-H bond is less than one-half broken at the transition state. The conclusions are considered in the light of the More O'Ferrall -Jencks potential energy surface diagram.Key words: elimination mechanism, transition state, isotope effects, leaving group, quaternary salts.PETER JAMES SMITH et MD. AMIN. Can. J. Chem. 67, 1457 (1989).Dans le but d'Ctudier l'effet du groupement nuclCofuge sur la rtaction d'klimination des ions 1-phCnylCthylammonium sous l'influence de 1'Cthylate de sodium dans l'tthanol a 60°C, on aCtudiC la rkaction de sept sels d'ammonium quaternaire diffirents, ainsi que leurs analogues deutCrCs en position P, portant la trimkthylamine, la N-mCthylpipCridine, la N-mCthyldiCthylamine, la tritthylamine, la N,N-dimCthylbenzylamine, la tripropylamine et N,N-ditthylbenzylamine comme groupements nuclCofuges. Dans tous les cas, 1'Climination qui prockde par un processus concerte E2 est accompagnCe par les reactions de substitution qui sont en compttition. MCme si on a not6 une corrClation importante entre la vitesse du processus d'klimination et la nature du groupement nuclCofuge, il n'existe aucune corrClation linkaire avec la basicit6 de l'amine qui quitte. On a trouvC que, au dkbut d...

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Section: Introductionmentioning

confidence: 99%

The effect of the nature of the amine leaving group on the nature of the E2 transition state for the reaction of 1-phenylethylammonium ions with sodium ethoxide in ethanol

Smith¹,

Amin²

1989

Can. J. Chem.

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“…AGENTS CHEMOTHER. (5) and electronic properties (4,6,8).' Better activity is achieved 'with compounds of the series that more readily bind covalently via the P-lactam without jeopardizing chemical stability of the compound.…”

Section: Resultsmentioning

confidence: 99%

Lack of relevance of kinetic parameters for exocellular DD-peptidases to cephalosporin MICs

Boyd¹,

Ott²

1986

Antimicrob Agents Chemother

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MICs of a set of cephalosporins against a variety of gram-positive and gram-negative pathogens showed no strong correlations with the rate at which these inhibitors acylate or are deacylated by P-lactam-sensitive DD-peptidases excreted by Streptomyces sp. strain R61 and Actinomadura sp. strain R39.Detailed biochemical investigations of the 3-lactamsensitive enzymes with D-alanyl-D-alanine transpeptidase and carboxypeptidase activities date back over 10 years and have been comprehensively reviewed (16-23). The R61 and R39 DD-peptidases, which are excreted by Streptomyces and Actinomadura spp., respectively, have been advanced as models for membrane-bound, P-lactam-sensitive proteins.The model DD-peptidases catalyze transpeptidation and hydrolysis reactions of peptides like Ac2-L-Lys-D-Ala-D-Ala which are analogs of the natural pentapeptide substrates of the enzymes that regulate peptidoglycan biosynthesis. In addition, the model enzymes are inhibited to varying degrees by a variety of P-lactams, including penicillins, cephalosporins, penems, carbapenems, and monobactams (17,22).There is accumulating evidence that the DD-peptidases bind covalently to ,-lactam antibiotics, and possibly also the substrate analogs, through a serine in the active site (17,22). This is a feature which they share in common with membrane-bound penicillin-binding proteins (PBPs) and with many ,B-lactamases (49). The DD-peptidases have been assumed to interact with ,B-lactams via the kinetic modelwhere K is the dissociation constant of the reversible complex, k2 is the first-order rate constant for covalent Even the very early research (18) with the DD-peptidases showed that cephalosporin C, a clinically unimportant compound, was one of the most potent, long-acting inhibitors, whereas ampicillin, a widely used therapeutic agent, was relatively ineffective in those studies. Recently, it was concluded that the exocellular enzymes are not the killing targets in the R61 and R39 strains (17). The sensitivity profiles of the purified enzymes to an assortment of ,B-lactam antibiotics were not related to those of the organisms that generated the enzymes.Prior to the latest publications (17, 22), attempts to make in-depth, quantitative comparisons of biochemical and microbiological data have been thwarted by lack of sufficient kinetic data on a structurally related set of ,3-lactam antibiotics. Structure-activity relationships are most likely to be discernible and meaningful when closely related chemical structures are compared. The longest series of compounds for which there are now in vitro kinetic data are A3-cephalosporins. There are 17 in this group. However, of these, only six are clinically useful ones, the rest being experimental compounds about which much less is known microbiologically.It is the purpose of this paper to make use of available biochemical and microbiological data to determine if relationships between them exist. That none are found calls attention to the need to study enzymes more relevant to the mode of action of ,B-lact...

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“…In essence, it is an approximation of the contribution of the 3-substituent to stabilization of the complex formed with the impinging hydroxyl ion (presumably representative of complex formation with the active sites of appropriate enzymes). Plots of these two values (average gram-negative MIC in J.Lg/ml versus transition state energy in Kcal/mol) fall fairly accurately on a hyperbolic curve (BoYD and LUNN 1979;BoYD et al 1980). The values obtained in this way, calculated from the published curves, are listed for the appropriate 3-substituents on the left side of Table 19.…”

Section: D) Effects Of 3'-substituents On In Vitro Activitymentioning

confidence: 88%

β-Lactam Antibiotics: Structure-Activity Relationships

Hoover¹

1983

Antibiotics

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Electronic structures of cephalosporins and penicillins. 11. Parabolic relationships between antibacterial activity of cephalosporins and .beta.-lactam reactivity predicted from molecular orbital calculations

Cited by 52 publications

References 0 publications

The effect of the nature of the amine leaving group on the nature of the E2 transition state for the reaction of 1-phenylethylammonium ions with sodium ethoxide in ethanol

The effect of the nature of the amine leaving group on the nature of the E2 transition state for the reaction of 1-phenylethylammonium ions with sodium ethoxide in ethanol

Lack of relevance of kinetic parameters for exocellular DD-peptidases to cephalosporin MICs

β-Lactam Antibiotics: Structure-Activity Relationships

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