A QSAR study of acute toxicity of N-substituted fluoroacetamides to rats Ivan O. Juranic ´ a , Branko J. Drakulic ´ b, * , Slobodan D. Petrovic ´ c,d , Dus ˇan Z ˇ . Mijin c , Milena V. Stankovic ´ d a Faculty of Chemistry, University of Belgrade, P.O. Box 151, 11001 Belgrade, Serbia and Montenegro b Department of Chemistry, Institute of Chemistry, Technology and Metallurgy, Njegos ˇeva 12, 11000 Belgrade, Serbia and Montenegro c Faculty of Technology and Metallurgy, University of Belgrade, Karnegijeva 4, P.O. Box 3503, 11001 Belgrade, Serbia and Montenegro d Hemofarm group, Beogradski put b.b., 26300 Vrs ˇac, Serbia and Montenegro Received 22 December 2004; received in revised form 26 April 2005; accepted 1 May 2005 Available online 5 July 2005 Abstract Acute toxicity in vivo toward rats, of nineteen N-alkyl and N-cycloalkyl fluorocetamides [F–CH 2 –C(O)–NH–R] was correlated with their structure-dependent properties. Used descriptors are: molecular weights (M w ) and heat of forma- tion (DH f ) of compounds; molar refractivity (CMR), lipophilicity (Clog P), Broto lipol values, virtual log P, molecular lipophilic potential (MLP), Van der Waals surfaces (VdW SAS) and hydropathicity surface (ILM) of whole molecules; Taft steric parameters (E s ); E s values with Hancock corrections (E CH s ) and Verloop sterimol (B 5 ) and (L) parameters of alkyl and cycloalkyl residues; superdelocalizabilities and electron densities on the [NH–C(O)–CH 2 –F] fragment. Strong quantitative structure–activity relationships were assessed. Obtained correlation suggested that lipophilicity, shape and bulkiness of the alkyl and cycloalkyl substituents, particular nearest vicinity of the amide nitrogen, as well charges on the amide moiety are the main factors that influence on the acute toxicity of studied compounds toward rats. Mecha- nism of toxic action was proposed. Ó 2005 Elsevier Ltd. All rights reserved. Keywords: Acute toxicity; Rats; N-alkyl fluoracetamides; QSAR 1. Introduction One of the current interests in medicinal chemistry and toxicology is the classification of chemical sub- stances with the respect to their toxicity toward living systems. Quantitative structure–activity relationships (QSAR) have provided a valuable tool in research on the toxicity of organic chemicals. The toxicity of derivatives of fluoroacetic acid to insects and rodents is well known (Metcalf, 1966; Zhu et al., 2002). Fluoroacetamide is an active insecticide, but it is less toxic and acts more slowly than sodium fluoro- acetate (Alekseev and Turov, 1967). In addition, various N-substituted and N,N-disubstituted fluoroacetamides (Takeuchi and Ishida, 1962) and N-methylenefluoroace- tamide derivatives (Pianka and Polton, 1965) have been 0045-6535/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.chemosphere.2005.05.005 * Corresponding author. Tel./fax: +381 11 3281867. E-mail address: bdrakuli@helix.chem.bg.ac.yu (B.J. Draku- lic ´). Chemosphere 62 (2006) 641–649 www.elsevier.com/locate/chemosphere