Reactivity and antibacterial activity

D. Further Evidence for a Relationship between Predicted Reactivity and Antibacterial Activity... 

One of the major differences between penicillins and cephalosporins is the possibility for a concerted elimination of the C-3 substituent in the case of cephalosporins (6->7). There is now considerable evidence to support the idea that an increase in the ability of the C-3 substituent to act as a leaving group results in an increased reactivity of the 8-lactam carbonyl (75JMC408). Thus, both the hydrolysis rate of the 8-lactam and antibacterial activity... 

Studies on the mechanism of action of /3-lactam antibiotics have shed considerable light on how these agents kill bacteria. They also help explain qualitative differences between various agents and why there is a correlation between the reactivity of the /3-lactam and antibacterial activity. However, it is also clear that reactivity is only one factor in determining how effectively a given /3-lactam antibiotic will inactivate bacterial enzymes (82BJ(203)223). 

Thomassin, J.-M., Lenoir, S., Riga, J., Jerome, R., Detrembleur, C. 2007. Grafting of Poly[2-(Tert-Butylamino)Ethyl Methacrylate] onto Polypropylene by Reactive Blending and Antibacterial Activity of the Copolymer. 

The results presented in Table III show that any substitution in the 6a-position of penicillin G or penicillin V reduces both enzyme inhibition and antibacterial activity. In contrast, introduction of a 7a-methoxy group into cephalosporins results in antibiotics that are better inhibitors of transpeptidase than their unsubstituted counterparts, although they do not necessarily possess better antibacterial properties (Table III). To test the effect of 6a-substitution in penicillins and 7a-substitution in cephalosporins on the chemical stability of these respective 3-lactams, the relative rates of hydrolysis of the substituted compounds were determined in aqueous solution at pH 10 (Table IV). The results show that 7a-methoxy substitution in cephalosporins has no pronounced effect on the reactivity of the p-lactam, which is in contrast to the three- to fivefold decrease in reactivity found with 6a-methoxy substitution in penicillins G and V. Indelicato and Wilham (1974) have suggested that loss of... 

The antibacterial effectiveness of penicillins cephalospotins and other P-lactam antibiotics depends upon selective acylation and consequentiy, iaactivation, of transpeptidases involved ia bacterial ceU wall synthesis. This acylating ability is a result of the reactivity of the P-lactam ring (1). Bacteria that are resistant to P-lactam antibiotics often produce enzymes called P-lactamases that inactivate the antibiotics by cataly2ing the hydrolytic opening of the P-lactam ring to give products (2) devoid of antibacterial activity. 

By virtue of their fused /3-lactam-thiazolidine ring structure, the penicillins behave as acylating agents of a reactivity comparable to carboxylic acid anhydrides (see Section 5.11.2.1). This reactivity is responsible for many of the properties of the penicillins, e.g. difficult isolation due to hydrolytic instability (B-49MI51102), antibacterial activity due to irreversible transpeptidase inhibition (Section 5.11.5.1), and antigen formation via reaction with protein molecules. 

Substituted nitro derivatives of azoIo[5,l-c][l,2,4]triazines were examined for their antimicrobial activity. They displayed antibacterial, antifungal, and antiviral activities. Structure-reactivity relationships have been reported (90KFZ39). 

Boyd DB, Herron DK, Lunn WHW, Spitzer WA. Parabolic relationships between antibacterial activity of cephalosporins and beta-lactam reactivity predicted from molecular orbital calculations. / Am Chem Soc 1980 102 1812-14. 

Their antibacterial and mutagenic activity is closely related to the reduction of the 5-nitro group, which is common to all nitroimidazole drugs, and the subsequent formation of reactive metabolites that bind to bacterial DNA, inhibiting DNA and protein synthesis in the microorganisms. Metabolism of 5-nitroimidaz-oles in mammals usually leads to covalently bound residues with a persistent imidazole structure. 

---