Structure activity relationships among the monobactams.

Abstract

The monobactam nucleus (3-AMA) exhibits weak antibacterial activity and thus, as with the penicillins and cephalosporins, molecular substitution around the central nucleus is essential to realize the antibacterial potential of these molecules. Side chain structure/activity relationships in monobactams parallel those of the penicillins and cephalosporins. Such a relationship is not unexpected in view of the common enzymatic targets shared by these structurally divergent types. Side chain substitution of the monobactam nucleus leads to compounds exhibiting primarily Gram-positive, primarily Gram-negative or broad-spectrum activity. However, incorporation of small polar groups (amino, hydroxyl, carboxylic or sulphonic) at the alpha position of these side chains leads to poorly active compounds. This observation is the most striking divergence between monobactam and penicillin/cephalosporin structure-activity relationships. The most striking gain in anti-bacterial activity is observed with the introduction of an aminothiazoleoxime side chain as the 3-acyl substituent. In the case of carbonyl-activated and phosphate activated compounds, there is total reliance on this side chain grouping for achieving activity. Activity against Gram-positive bacteria, if present, is closely related to the nature of the acyl side chain. The aminothiazoleoxime side chains characteristically reduce activity against this organism class. Substitution at the 4-position of the monocyclic ring although capable of producing dramatic changes in biological activity, is highly unpredictable. In the SO3-activated molecules 4-substitution is essential for beta-lactamase stability and in many instances results in increased intrinsic activity of the molecule. Incorporation of 4-substituents on the beta-lactamase susceptible O-activated molecules has little or no effect on beta-lactamase stability or antibacterial activity. In the case of carbonyl- and phosphate-activated species, while offering no advantages, 4-substitution in many instances is highly deleterious to the activity of the molecule. The 'activating' group on the beta-lactam nitrogen, responsible for the activation of the beta-lactam ring can be varied quite widely while retaining high intrinsic activity. The O-activated compounds although showing the potential for broad-spectrum activity are beta-lactamase unstable, while the beta-lactamase stable compounds tend to show preferential activity against Gram-negative rods. There can be little doubt that additional activating groups will be incorporated on the monocyclic beta-lactam ring and it will be interesting to see what additional properties can be achieved by this approach.