[Quantum chemical studies on substituted benzamidines as inhibitors of the serine proteinases trypsin and thrombin]. / Quantenchemische Untersuchungen an substituierten Benzamidinen als Inhibitoren der Serinproteinasen Trypsin und Thrombin.

Substituted benzamidines are competitive inhibitors of trypsin and thrombin. The aim of this work is to find an interpretation for the relation between chemical structure of the inhibitors and the activity on the both enzymes by quantum chemical methods. For the description of the electrostatic interaction between inhibitor and enzyme the molecular electrostatic potential (MEP) was used. The interpretation took place with the help of a simple model of reactive groups in the enzyme. The obtained results were discussed and compared with those resulting from CNDO/2--reactivity indices. The application of the MEP shows its advantage to investigations of enzyme-inhibitor interactions.

Structure-activity relationship in nonsteroidal antiinflammatory agents, including QSAR in fenamate derivatives.

First, it is shown that it is not yet possible to outline a generally valid receptor model for the non-steroidal anti-inflammatory agents. This is demonstrated by three examples of receptor models, namely by the model according to Shen, by the receptor concept of Appleton and Brown, and by the concept concerning chelate complex formation between NSA and heme iron of the cyclooxygenase complex according to Peterson et al. This means that the "custom-made" synthesis of NSA with, perhaps, quantitatively and qualitatively better properties is not yet possible. On the basis of this statement, QSAR investigations may be justified in order to optimize known NSA. In this paper, QSAR calculations on 21 fenamate derivatives are reported. For this, both the multivariate and the univariate Hansch Analysis were used. Altogether, 16 approaches to QSAR has been performed using 1 - 4 biological and 3 - 19 physico-chemical parameters, respectively, with 7 - 21 objects. In all cases a dominating influence of pi has been indicated. Other physico-chemical parameters seemed to be of less importance, e. g., sigma, Es, log xi MR, MV, parachor, and Verloop's steric constants. Possible new fenamate structures of higher biological activity are briefly discussed.