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

Abstract

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.

Effects of Magnesium, Calcium, and Aluminum Chelation on Fluoroquinolone Absorption Rate and Bioavailability: A Computational Study

“…Variable patient compliance with FQ spacing regimens coupled with the need for new structures for applications to FQ-resistant bacteria [ 39 , 40 , 41 ] points to the utility for continued studies of chelation interactions between FQs and commonly encountered multivalent cations found in diet and medication. Reports of aluminum salts and their effect on bioavailability indicate a higher magnitude of effect compared to other multivalent metals, but thus far computational studies of FQ interactions with aluminum ion remain more limited.…”

Computational study of fluoroquinolone binding to Mg(H2O)N2+ and its applicability to future drug design

“…Musa and Eriksson explored the protonation states and photochemistry of norfloxacin using DFT. Dorotíková et al recently performed a computational study of substituent effects on the structures of “push‐pull ethylene” fluoroquinolone precursors. Most pertinent to the present study, Li et al have published several studies on quantitative structure–activity relationships of various fluoroquinolones.…”

Computational studies of 2-(4-oxo-3-phenylthiazolidin-2-ylidene)malononitrile

“…In compounds that have aromaticity, the C=C stretching vibrations is mostly present at 1600–1500 cm −1 [63, 73]. In the current system, these stretching vibrations are predicted at 1587–1438 cm −1 while experimentally observed at 1597–1461 cm −1 [10].…”