ORIGINAL PAPER Global and local chemical reactivities of mutagen X and simple derivatives Elizabeth Rincon & Francisco Zuloaga & Eduardo Chamorro Received: 25 August 2012 / Accepted: 6 February 2013 / Published online: 6 March 2013 # Springer-Verlag Berlin Heidelberg 2013 Abstract Registered by the World Health Organization (WHO), 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)- furanone (MX) is one of the strongest bacterial mutagens ever tested, as highlighted by the Ames Salmonella typhimurium TA100 assay. We provide new insights concerning this mutagenic activity on the basis of global and local theoretically defined electrophilicity indices. Our results further support the idea that mutagenicity of MX and its analogues is related more closely to one-electron transfer processes from the electron-rich biological environment than to adduct formation processes. We also stress that, although the Z-open tautomers are intrinsically more electro- philic than furanone ring analogues, the observed mutagenic activity is significantly correlated only to the electrophilicity response of the ring forms. In that context, we also emphasize that it is electrophilicity at the C α in the α–β unsaturated carbonyl moiety that exhibits a strong correlation with the observed mutagenic activity. Keywords MX . Electrophilicity . TA100 assay . Global and local indices . Conceptual DFT Introduction 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX, Mutagen-X) 1 and analogue compounds 2–24 (see Fig. 1) belong to a group of direct-acting genotoxic disin- fection by-products of chlorinated drinking water. MX is formed from the reaction of chlorine with organic com- pounds (e.g., humic and fulvic acids) present in the raw water [1]. Chlorinated hydroxyfuranones generate mutage- nicity in a variety of bacterial strains as evidenced in several short-term assays. These facts have been related (at least partly) to cancer risks associated with chorinated drinking water [2]. In fact, MX has been identified as one of the most potent bacterial mutagens, with mutagenicity values reported in the range of 2,800 to 10,000 revertants/nmol in the Ames Salmonella typhimurium TA100 assay [3, 4]. This bacterial reverse mutation assay evaluates the mutagenic properties of compounds. Amino acid-dependent strains of the simplest bacteria are employed. In the absence of an external histidine source, the cells cannot grow in colonies. When reversion of the mutation occurs, colony growth continues due to the production of histidine. Mutagenic compounds thus yield an increased number of revertant colonies in relation to the background level (i.e., spontane- ous revertants) [4]. However, analytical difficulties in mea- suring the low doses of MX encountered in drinking-water lead to uncertainty over whether this species would be genotoxic in vivo. The World Health Organization (WHO) guidelines for drinking water maintain an updated register regarding MX, considering it unnecessary at present to propose a formal guideline value for MX in drinking water [5, 6]. Benigni and co-workers [7, 8], have emphasized the usefulness of quantitative structure-activity relationships (QSAR) for the evaluation/prediction of mutagenicity and carcinogenicity of α–β unsaturated compounds. In the Electronic supplementary material The online version of this article (doi:10.1007/s00894-013-1799-7) contains supplementary material, which is available to authorized users. E. Rincon (*) : F. Zuloaga Instituto de Ciencias Quimicas, Facultad de Ciencias, Universidad Austral de Chile, Las encinas 220, Valdivia, Chile e-mail: elizabethrincon@uach.cl E. Chamorro Departamento de Ciencias Quimicas, Facultad de Ciencias, Universidad Andres Bello, Av. Republica 275, 8370146 Santiago, Chile e-mail: echamorro@unab.cl J Mol Model (2013) 19:2573–2582 DOI 10.1007/s00894-013-1799-7