J. Med. Chem. 1993,36, zyxwvu 1007-1016 1007 Mechanistic Interpretation of the Genotoxicity of Nitrofurans (Antibacterial Agents) Using Quantitative Structure-Activity Relationships and Comparative Molecular Field Analysis h i m Kumar Debnatht and Corwin Hansch’ Department of Chemistry, Pomona College, Claremont, California 91 71 1 Ki H. Kim’ and Yvonne C. Martin Computer Assisted Molecular Design Project, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064 Received October 26, 1992 Quantitative structureactivity relationship (QSAR) and comparative molecular field analysis (CoMFA) have been applied to elucidate the mechanisms of genotoxicity (SOSIP) of nitrofuran derivatives on Escherichia coli PQ37. The following equation was developed log SOSIP zyx = -33.1qc2 + 1.00 log P - 1.5OImt - 1.19MR - 0.7615s - 3.76; n = 40, r = zyxw 0.900, s = 0.475. The QSAR model clearly reveals three important factors, namely, electronic zyxwv (q,~), hydrophobic (log zyx P) and steric (MR, Imt, 15,6) contributing toward the genotoxic activity of this class of compounds. zyx qc2, the charge on the c2 atom attached to the NO2 group, supports a furan ring opening mechanism in explaining the genotoxicity. The finding of the coefficient of 1 with log P conforms to our previous findings with several different classes of mutagens acting on different systems. CoMFA analysis clearly demonstrates ita potential in unraveling the steric features of the molecules through contour maps. The CoMFA cross-validated model also supports the importance of the electronic factor. It could not reveal any hydrophobic influence because the interaction energies of the CH3 and HzO probes are collinear. QSAR (classical) and CoMFA, if used judiciously, may complement each other and enhance the applicability of SAR in drug design. Introduction Nitrofurans are an important class of chemicals in that they are used as antimicrobial agents in human and veterinary medi~inesl-~ despite their mutagenic415 and carcinogenic6J activities. Nitrofurantoin is still on the market and used as a urinary tract disinfectant and furazolidone is used in poultry food to prevent intestinal infection. But the toxicities of nitrofuran derivatives definitely restrict their developmentand use as agents in clinical medicine or as food preservatives. In fact, AF-2 [2-(2-furyl)-3-(5-nitro-2-furyl)acrylamidel, used as food preservative in Japan, was banned in 1974 and 3-(5-nitro- 2-fury1)acrylicacid, used as wine preservative in Czech- oslovakia, was banned in 1978. Nitrofurans and their analogs are “direct acting mutagen^"^^^^^^^ as they do not require exogenous acti- vating systems. The nitro group is reduced by the bacterial reductase to the hydroxylamine which appears to attack DNA via the nitrenium ion. The best characterized metabolites so far reported are aminofurans and their isomeric open chain nitriles, but these do not appear to be mutagenic or toxic.1s18 Recently, Lambert et al.19 proposed a hypothetical pathway of adduct formation of nitrofurans. In trying to gain a deeper understanding of the mech- anism of mutagenicity, we have been developing quan- titative structureactivity relationships (QSAR) for various kinds of mutagens including aromatic nitro compounds. There is a large amount of experimental work on nitro compounds, but these studies were not structured with the thought of doing QSAR. Thus, the data available are not well structured families of compounds which can be +New York Blood Center, 310 East 67th Street, New York, NY 10021. 0022-2623/93/1836-1007$04.00/0 treated by the classical approachusing Hammett constants to account for the electronic effect of structural changes on the properties of the nitro group. To circumvent this difficulty, we have used molecular orbital calculations (AM1methodology) to cope with these effects. While we have found that in comparing Hammett and MO param- eters the former give better results,20 the latter allow one to include a vastly larger range of chemicals in a QSAR. Bringing in such a wide array of structures magnifies the difficulties of accounting for steric effects molecules of greatly different shape encounter in reacting with biore- ceptors. In the case of nitro mutagens, this would be cellular reductases, and, in the end, DNA. Equations 1 and 2 illustrate our results. Aromatic nitro compounds acting on Salmonella typhimurium TA98:” log TA98 = 0.65 log P - 2.90 log (0.10 log‘ + 1) - 1.38CLUMO + 1.88lL - 2.891, - 4.15 (1) n = 188, r = 0.900, s = 0.886, log Po = 4.93 Aromatic nitro compounds acting on S. typhimurium TA100:” log TAl00 = 1.20 log P - 3.40 log (8.10 IOgp + 1) - 2.05eLuMo - 3.501, + 1.86Zind - 6.39 (2) n = 117, r = 0.886, s 0.835, log Po 5.44 In these equations, P is the octanol-water partition coefficient, CLUMO is the energy of the lowest unoccupied 0 1993 American Chemical Society