Quantitative structure-activity relationships for the toxicity of chlorophenols to mammalian submitochondrial particles

The toxicity of a series of chlorophenols, determined by a short-term in vi tro assay utilizing mammalian submitochondrial particles, was related to th e physicochemical and structural properties of these compounds. Quantitativ e Structure-Activity Relationships were defined by correlating EC50 values with six molecular descriptors, chosen to represent lipophilic, electronic and steric effects: the n-octanol/water partition coefficient (log K-ow), t he constant of Hammea (Sigma sigma), the acid dissociation constant (pK(a)) , the first order valence molecular connectivity index ((1)chi(v)), the per imeter of the efficacious section (CD) and the melting point (m.p.). The re sults of regression analysis showed that log K-ow is rile most successful d escriptor, indicating that the ability of chlorophenols to partition into t he lipid bilayer of the mitochondrial membrane has an important role in det ermining their toxic effects. These results are consistent with a molecular mechanism of uncoupling action based on the chemiosmotic theory and on the protonophoric properties of chlorophenols. The quality of the QSAR models confirms the suitability of the SMP assay as a short-term prediction tool f or aquatic toxicity of environmental pollutants acting on respiratory funct ions. (C) 1999 Elsevier Science Ltd. All rights reserved.