Conformational, Spectroscopic, and Molecular Dynamics DFT Study of Precursors for New Potential Antibacterial Fluoroquinolone Drugs

Biological activity, functionality,
and synthesis of (fluoro)­quinolones
is closely related to their precursors (for instance 3-fluoroanilinoethylene
derivatives) (i.e., their functional groups, conformational behavior,
and/or electronic structure). Herein, the theoretical study of 3-fluoroanilinoethylene
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.