N-Acyl Ciprofloxacins: Synthesis, Antibacterial Activity and Effects on Molecular Loading of Poly(vinyl benzoate) Nanoparticles

Bacterial infections are becoming progressively more difficult to treat due to antibiotic resistance and the decreasing rate at which new antibiotics are brought to market. The Turos laboratory has attempted to tackle this problem for the last 15 years with the discovery of N-thiolated β-lactams leading to the design of polyacrylate nanoparticles to deliver these and other drugs. Chapter 1 discusses many reported instances of utilizing different types of polymeric nanoparticles to deliver antibiotics. Poly(lactic-co-glycolic acid) (PLGA), poly(alkyl cyanoacrylate) (PACA), poly(styrene-co-butylacrylate), and chitosan are the main polymers used to make nanoparticles. Chapter 2 describes the synthesis, antibacterial activity, and mechanism of action of N-acyl ciprofloxacins, which have demonstrated in vitro bioactivity against Staphyloccocus aureus, methicillin-resistant Staphylococcus aureus, Bacillus anthracis, Enterococcus faecalis, Bartonella, and E. coli. Antimicrobial activity was found to diminish with increasingly lipophilic acyl groups of the derivatives. The N-acyl ciprofloxacins were found to utilize the same mechanism of action as the parent drug, ciprofloxacin, however, several exhibited lower mutation frequencies. Chapter 3 discusses the use of the N-acyl ciprofloxacins as probes for experimentation on the poly(vinyl benzoate) nanoparticles. These compounds were incorporated into poly(vinyl benzoate) nanoparticles, also designed in the Turos laboratory, to determine the effects of the lipophilic acyl groups on drug loading and drug release. N-acyl ciprofloxacins with higher lipophilicities (predicted logP values) experienced higher drug loading than the less lipophilic counterparts. However, the nanoparticles were unable to release large amounts of entrapped drug. N-acyl ciprofloxacins with increased hydrophilicity were found to either not be incorporated at all, or in incredibly small amounts. Drug release studies of these drugs indicate that possible the hydrophobic compounds that were associated with the nanoparticles were done so via adsorption onto the surface resulting in a burst release of drug. The work is concluded in Chapter 4, followed by experimental procedures and spectral data in Chapters 5 and 6