Published: October 13, 2011 r2011 American Chemical Society 13504 dx.doi.org/10.1021/jp201576u | J. Phys. Chem. A 2011, 115, 13504–13512 ARTICLE pubs.acs.org/JPCA Thermal and Solvent Effects On NMR Indirect SpinSpin Coupling Constants of a Prototypical Chagas Disease Drug Teodorico C. Ramalho,* ,† Douglas H. Pereira, † and Walter Thiel ‡ † Department of Chemistry, Federal University of Lavras, 37200-000 Lavras, Minas Gerais, Brazil ‡ Max-Planck-Institut f€ ur Kohlenforschung, Kaiser-Wilhelm-Platz 1, D 45470 M€ ulheim an der Ruhr, Germany 1. INTRODUCTION Depite recent progress, Chagas disease is still one of the most serious health problems facing humanity, causing many deaths and having a great and limiting influence on the quality of life in many countries. 15 To date, no single drug has been developed that is both readily absorbed and effective for an extended period. 1 The most promis- ing drugs available are nitroimidazole and nitrofuran compounds. 6 Therefore, the intracellular generation of free radicals appears to be a strategy that is exploited in the Chagas treatment with nitroimidazole and nitrofuran derivatives. 7 These electrophilic compounds behave as oxygen-mimicking species, affecting the T. cruzi cells and inducing damage to DNA and other molecules. 810 In practice, nitroimidazoles are used most, with metronidazole (1) (Figure 1) being considered a prototypical representative of that class. 18 Recently, 1 H, 31 P, and 19 F NMR imaging 11 of nitroimidazoles has been applied for measuring tumor 12 and tissue oxygenation. 13 Other nitroimidazoles labeled with 19 F or 123 I have been investi- gated as possible noninvasive markers of hypoxia. 1214 In solution, the bioactive conformation of these drugs is most frequently studied by NMR spectroscopy through analysis of homo- and heteronuclear NMR spinspin coupling constants (SSCC). 15,16 The theoretical calculation of SSCC values is chal- lenging because the results may strongly depend on the molecular structure as well as on dynamics and solvent effects. 17,18 It is well- known that nonbonded electrons can strongly influence the SSCC values. 19 Experimentally, spinspin coupling is crucial for indirect NMR detection techniques that are based on the transfer of magnetization from a more sensitive nucleus (usually a proton) to a heteronucleus. 20 Thermal and solvent effects on the SSCC of drugs such as 1 have not yet been measured, and surprisingly little computational work on the subject has appeared. Given the size of these systems, the most promising computational approach is to use density functional theory (DFT), which has been employed with success to reliably predict the chemical shifts of large compounds and complexes 21 because of the efficient incorpora- tion of electronic correlation and relativistic effects. 22 In fact, NMR signals primarily reflect local perturbations to electronic shielding (chemical shifts), short-range through-bond interactions (J-coupling), and medium-range through-space in- teractions (nuclear Overhauser effect). Hence, NMR spectros- copy is a technique sensitive to local conformation 2329 that can be used for structure determination. 3033 Our previous studies addressed 1 H, 13 C, and 15 N chemical shift calculations Figure 1. Structure and numbering of metronidazole. Received: February 17, 2011 Revised: October 9, 2011 ABSTRACT: NMR J-couplings across hydrogen bonds reflect the static and dynamic character of hydrogen bonding. They are affected by thermal and solvent effects and can therefore be used to probe such effects. We have applied density functional theory (DFT) to compute the NMR n J(N,H) scalar couplings of a prototypical Chagas disease drug (metronidazole). The calculations were done for the molecule in vacuo, in microsolvated cluster models with one or few water molecules, in snapshots obtained from molecular dynamics simulations with explicit water solvent, and in a polariz- able dielectric continuum. Hyperconjugative and electrostatic effects on spinspin coupling constants were assessed through DFT calculations using natural bond orbital (NBO) analysis and atoms in molecules (AIM) theory. In the calculations with explicit solvent molecules, special attention was given to the nature of the hydrogen bonds formed with the solvent molecules. The results highlight the importance of properly incorporating thermal and solvent effects into NMR calculations in the condensed phase.