Conformational, Spectroscopic, and Molecular Dynamics DFT Study of Precursors for New Potential Antibacterial Fluoroquinolone Drugs Sandra Dorotíkova ́ , † Kristína Plevova ́ , ‡ Luka ́ s ̌ Buc ̌ insky ́ ,* ,† Michal Malc ̌ ek, † Peter Herich, † Lenka Kuckova ́ , † Miroslava Bobenic ̌ ova ́ , † Stanislava S ̌ oralova ́ , § Jozef Koz ̌ ís ̌ ek, † Marek Fronc, † Viktor Milata, ‡ and Dana Dvoranova ́ † † Institute of Physical Chemistry and Chemical Physics, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinske ́ ho 9, SK-812 37 Bratislava, Slovak Republic ‡ Institute of Organic Chemistry, Catalysis and Petrochemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinske ́ ho 9, SK-812 37 Bratislava, Slovak Republic § Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University in Bratislava, Odboja ́ rov 10, SK-832 32 Bratislava, Slovak Republic * S Supporting Information ABSTRACT: Biological activity, functionality, and synthesis of (fluoro)- quinolones is closely related to their precursors (for instance 3-fluoroanilino- ethylene derivatives) (i.e., their functional groups, conformational behavior, and/or electronic structure). Herein, the theoretical study of 3-fluoroanilino- ethylene derivatives is presented. Impact of substituents (acetyl, methyl ester, and ethyl ester) on the conformational analysis and the spectral behavior is investigated. The B3LYP/6-311++G** computational protocol is utilized. It is found that the intramolecular hydrogen bond N-H···O is responsible for the energetic preference of anti (a) conformer (anti position of 3-fluoroanilino group with respect to the CC double bond). The Boltzmann ratios of the conformers are related to the differences of the particular dipole moments and/ or their dependence on the solvent polarity. The studied acetyl, ethyl ester, and methyl ester substituted fluoroquinolone precursors prefer in the solvent either EZa, ZZa, or both conformers equally, respectively. In order to understand the degree of freedom of rotation of the trans ethyl ester group, B3LYP/6-311G** molecular dynamic simulations were carried out. Vibrational frequencies, electron transitions, as well as NMR spectra are analyzed with respect to conformational analysis, including the effect of the substituent. X-ray structures of the precursors are presented and compared with the results of the conformational analysis. ■ INTRODUCTION 3-Fluoroanilinoethylene derivatives belong to precursors of quinolones. Quinolones possess a variety of biological activities, including antimicrobial, 1 antiviral (anti-HIV), 2,3 and antima- larial effects. 4 Nowadays, the fluoroquinolones play a specific role in medicine, being widely used for the treatment of infections caused by both Gram-positive 5,6 or Gram-nega- tive 6-8 pathogens. Moreover, fluoroquinolones have been demonstrated to possess antitumor activity, 9,10 hand-in-hand with interesting mechanical effect on the DNA molecule. 11-14 DNA gyrase and DNA topoisomerase IV are both sensitive to the 4-quinolone class of antibacterial compounds in vitro. This activity of quinolones is the result of the inhibition of the supercoiling of DNA catalyzed by the enzyme DNA gyrase. Emami et al. 15 and Shen 16 have proposed drug-DNA models which imply hydrogen-bond type interactions between the DNA unpaired bases and the quinolone, as well as a stacked dimerization of the drug. Stereochemistry is becoming very important in such interactions (i.e., the orientation of the substituents can be critical for the activity of the agents). Manipulations of the basic molecule, including replacement of hydrogen with fluorine, substitution on the cyclic amine residue, and the addition of new residues on the quinolone ring, have led to improved breadth and potency of antibacterial activity and pharmacokinetics. Thus, the primary attention was foremostly focused on the investigations of structure-activity relationships of fluoroquinolones. Nowadays, the attention turns to innovative novel reaction pathways which lead to the synthesis of novel derivatives, emphasizing the role of the precursors from which the substances are mainly prepared using the modified Gould-Jacobs reaction. 17,18 Newly synthe- sized 3-fluoroquinolones have been prepared from precursors bounded with different substituents R 1 and R 2 , such as -COOC 2 H 5 , -COOCH 3 , and -COCH 3 . 19 The structure of these precursors of fluoroquinolones is summarized in Table 1. Received: June 26, 2014 Revised: September 4, 2014 Article pubs.acs.org/JPCA © XXXX American Chemical Society A dx.doi.org/10.1021/jp506355f | J. Phys. Chem. A XXXX, XXX, XXX-XXX