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

• Published in: Journal of molecular structure 1999-12, Vol.513 (1), p.177-199
• Main Authors: Dolmella, A., Gatto, S., Girardi, E., Bandoli, G.
• Format: Article
• Language: English
• Subjects: Anticoagulant rodenticides; SAR investigations; Theoretical calculations; Toxicity; X-ray studies
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/S0022-2860(99)00119-2

Coumatetralyl and chlorophacinone, two substances related to 4-hydroxycoumarin (HC) and to 1,3-indandione (ID), respectively, show activity as anticoagulant rodenticides. In the present study we have investigated the solid-state structures of coumatetralyl and chlorophacinone by means of X-ray single-crystal and powder diffraction, along with thermal analysis. The crystal structures of the two compounds have been used as input geometries for a series of computational chemistry efforts, involving other anticoagulant derivatives as well. Thus, ab initio, semiempirical molecular orbital, molecular mechanics and molecular dynamics/simulated annealing calculations have been performed on thirteen anticoagulant rodenticides. In particular, the annealing calculations have been made to assess the conformational freedom of the compounds under scrutiny. All the generated conformers have been classified 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 latter, we have assessed how the selected parameters affect toxicity. The results seem to be consistent with a three-dimensional biophore model, in which higher toxicity is predicted for the more voluminous rodenticides. We suggest that these compounds better fit the active site of the target enzyme vitamin K 2,3-epoxide reductase (KO-reductase).