Boyd D B
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285.
J Med Chem. 1993 May 14;36(10):1443-9. doi: 10.1021/jm00062a017.
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.
双环吡唑烷酮是一类合成抗菌剂，其中β-内酰胺环被一个五元环取代。这些化合物具有抑制细菌细胞生长所必需的青霉素结合蛋白所需的电子和形状特性。一种基于三维计算机图形学的名为超表面迭代投影（HIP）方法的新方法，允许将可用的构效关系信息外推到新的合成靶点。通过随着构效关系的发展更新数据集，计算机图形学揭示了参数空间中有待探索以获得最佳活性的区域以及尚未探索的区域。一个大型取代基参数数据库用于提出合适的取代基。对于双环吡唑烷酮，3-取代基的亲脂性，特别是吸电子特性与最低抑菌浓度（MIC）密切相关。抗菌效力与3-取代基对化学反应性的活化作用密切相关。HIP方法成功地在合成之前提出了该系列中最有效的成员，并且还表明在化学允许的范围内何时对所有参数空间进行了合理充分的探索。
