X-ray structures of the anticoagulants coumatetralyl and chlorophacinone. Theoretical calculations and SAR investigations on thirteen anticoagulant rodenticides

Coumatetralyl and chlorophacinone, two substances related to 4-hydroxycouma rin (HC) and to 1,3-indandione (ID), respectively, show activity as anticoa gulant rodenticides. In the present study we have investigated the solid-st ate structures of coumatetralyl and chlorophacinone by means of X-ray singl e-crystal and powder diffraction, along with thermal analysis. The crystal structures of the two compounds have been used as input geometries for a se ries of computational chemistry efforts, involving other anticoagulant deri vatives as well. Thus, ab initio, semiempirical molecular orbital, molecula r mechanics and molecular dynamics/simulated annealing calculations have be en performed on thirteen anticoagulant rodenticides. In particular, the ann ealing calculations have been made to assess the conformational freedom of the compounds under scrutiny. All the generated conformers have been classi fied into families. The classification has first been made empirically, and then validated by means of a cluster analysis. A number of structural and physico-chemical parameters derived from the calculations has been used in turn for structure-activity relationships (SARs) investigations. In the lat ter, we have assessed how the selected parameters affect toxicity. The resu lts seem to be consistent with a three-dimensional biophore model, in which higher toxicity is predicted for the more voluminous rodenticides. We sugg est that these compounds better fit the active site of the target enzyme vi tamin K 2,3-epoxide reductase (KO-reductase). (C) 1999 Elsevier Science B.V . All rights reserved.