Effects of protonation and deprotonation on the reactivity of quinolone: A theoretical study

Abstract

Quinolones are the subject of much research as antibacterial compounds and as a new class of antitumor agents. The protonation (P) and deprotonation (D) sites and conformations of quinolone were investigated. The proton affinity (PA) on each of the possible sites in 4-oxo-1,4-dihydroquinoline has been calculated by the restricted Hartree-Fock (HF) and density functional theory (DFT) methods with the basis set 6-311G**. The O-site of protonation was found to be strongly favored over the N-site for the studied compound in the gas phase. Deprotonation takes place in quinolone by detachment of the N-H and COOH protons. The PA of the simple quinolone molecule was used to characterize quinolone reactivity with DNA binding sites. The relative stabilities of the syn and anti conformations were investigated at the B3LYP/6-311G** level of theory; the syn form was shown to be slightly more stable. Its conformation seems to be intrastabilized by hydrogen-bonds consisting of a hydroxyl proton with the O10 atom as the acceptor. We computed and discussed the charge-density distribution and electrostatic potential to explain the reactivity of quinolone. Quinolones are well known antibacterial agents, they act by inhibition of DNA replication in bacteria [1]. In the past 16 years, quinolone derivatives have been the subject of much research as a new class of antitumor agents [2][3][4][5][6][7]. The reaction mechanism of quinolone antibacterial activity has been reported [8] to be via intermolecular hydrogen-bonding with the guanine of bacterial DNA in a gyrase-DNA complex (Scheme 1(a)). The carboxylic and hydroxyl groups are capable of intramolecular hydrogen-bond formation (Scheme 1(b)), which decreases the concentration of quinolone capable of specific interaction with DNA. Another factor affecting the behavior of the carboxylic groups is the presence of additional proton acceptors in the quinolone molecule. One of the most important chemical processes is the protonation reaction. It not only plays an important role in general chemistry but is also of high Scheme 1 physiological relevance. Proton affinities (PA's) are important in mechanistic studies of proton-transfer reactions and in reactions involving protonated and deprotonated organic molecules [9][10][11][12]. Therefore, reliable computational predictions of proton affinities are very important. The present work was devoted to investigating quinolone-protonation sites and the relation between acid-base properties

New N -4 piperazinyl derivatives of norfloxacin: design, synthesis, and correlation of calculated physicochemical parameters with antibacterial activity

“…14 Moreover, some reports showed the importance of the steric effect and Gibbs free energy or heat of formation on the binding of quinolones with DNA. 9 Additionally, partitioning of quinolones in 1-octanol/water was found to be an entropy-driving process with absorbing heat and water solvating drug molecules more easily than 1-octanol. The enthalpy changes for quinolone molecules partitioning in 1-octanol/water are all positive, and the degrees of the system decrease.…”

“…Deprotonation of the piperazinyl-NH group greatly affects the charge distribution in the studied compounds. 9 Collectively, optimizing the overall molecular configurations enhances the number of intracellular targets for antimicrobial action and impedes the efficiency of efflux proteins that diminish intracellular penetration. 10 Based on the above findings and in continuation of our research to explore the effect of N-4 piperazinyl substitution on antibacterial activity, 11 a number of different N-4 piperazinyl substituents are designed.…”