Application of the hypersurface iterative projection method to bicyclic pyrazolidinone antibacterial agents.

Bicyclic pyrazolidinones are a class of synthetic antibacterial agents in which the beta-lactam ring is replaced by a five-membered ring. These compounds possess electronic and shape properties required for inhibiting penicillin-binding proteins essential for bacterial cell growth. A novel approach called the hypersurface iterative projection (HIP) method, which is based on three-dimensional computer graphics, allows available structure-activity information to be extrapolated to new synthetic targets. By updating the data set as the SAR evolves, the computer graphics reveal regions of parameter space to explore for optimum activity and regions yet unexplored. A large substituent parameter database is used to propose appropriate substituents. For the bicyclic pyrazolidinones, lipophilicity and particularly electron-withdrawing properties of the 3-substituent are shown to correlate strongly with minimum inhibitory concentrations (MIC). Antibacterial potency is intimately related to the activating effect of 3-substituents on chemical reactivity. The HIP method succeeded in proposing the most potent member of the series prior to synthesis and also showed when all of parameter space was reasonably well explored to the extent the chemistry allowed.