Katherine E. Brighty

Chemistry and Mechanism of Action of the Quinolone Antibacterials

Publisher Summary Quinolone agents exhibit a bicyclic aromatic core, containing a carbon at the 8th position, yielding a true quinolone, or a nitrogen, and provide a ring system technically termed as naphthyridone. In common usage, both quinolone and naphthyridone structures are encompassed in the class descriptor “quinolone antibacterial agents.” The first generation quinolone compounds generally displayed increased Gram-negative activity over nalidixic acid, but lacked useful activity against Gram-positive cocci, Pseudomonas aeruginosa, and anaerobes. They were, however, generally well absorbed after oral administration and attained high concentrations in the urinary tract, making them useful therapeutically for treatment of urinary tract infections. In the second-generation quinolones, the piperazine ring remains relatively undisturbed, except for alkylation on the distal nitrogen or, less frequently, on the ring carbons. The second-generation compounds are characterized by good to excellent Gram-negative activity, with ciprofloxacin exhibiting the strongest Gram-negative spectrum. The third- and fourth-generation quinolones are characterized by increased structural novelty and complexity, which has resulted in new and useful characteristics. Clinafloxacin, sitafloxacin, and BAY y 3118, all of which bear a chlorine atom at C-8, are among the most potent broad-spectrum agents that have been in the development, and are the only compounds that exhibit Gram-negative activity superior to that of ciprofloxacin. These compounds, with the exception of pazufloxacin, show improved activity against S. pneumoniae compared to ciprofloxacin. The most potent of these agents are gemifloxacin and BAY y 3118, followed by clinafloxacin, sitafloxacin, moxifloxacin, and trovafloxacin.

In vitro activity of CP-99,219, a novel 7-(3-azabicyclo[3.1.0]hexyl) naphthyridone antimicrobial

The in vitro activity of CP-99,219 was compared with that of ciprofloxacin and sparfloxacin against 814 clinical bacterial isolates using a microdilution method with brain-heart infusion broth. CP-99,219 was the most potent agent tested against methicillin-resistant, ciprofloxacin-susceptible staphylocci (minimum inhibitory concentration [MIC]90 < or = 0.25 microgram/ml). CP-99,219 was 32-fold and fourfold more potent than ciprofloxacin and sparfloxacin, respectively, against Streptococcus pneumoniae, including strains resistant to penicillin G and erythromycin (MIC90 < or = 0.25 microgram/ml). CP-99,219 was also the most potent agent tested against S. pyogenes and Enterococcus faecalis (MIC90 < or = 0.5 microgram/ml). The activity of CP-99,219 against Enterobacteriaceae was comparable to that of sparfloxacin, with 90% of Escherichia coli, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Citrobacter freundii, C. diversus, Helicobacter pylori, and K. oxytoca being inhibited by < or = 0.5 microgram/ml. Serratia marcescens, Morganella morganii, and Pseudomonas aeruginosa were less susceptible, with MIC90 values to CP-99,219 of 4, 2, and 2 micrograms/ml, respectively. The MIC90 for Bacteroides fragilis was 0.39 microgram/ml for CP-99,219 compared with 12.5 micrograms/ml for ciprofloxacin. CP-99,219 was highly bactericidal at 1 x to 4 x MIC against both Gram-positive and Gram-negative organisms; its activity was similar in nutrient, trypticase soy, and cation-supplemented Mueller-Hinton broths. The spectrum and potency observed with CP-99,219 warrant further testing with this novel quinolone.

Novel fragmentation of 3-lithio-3,6-dihydro-1,2-oxazines: Synthesis of 2,5-dihydro-2-furanylamines

N-Cbz or N-Boc protected 3,6-dihydro-1,2-oxazines 1 on treatment with LDA at −78°C undergo a novel rearrangement to provide synthetically useful N-Cbz or N-Boc protected dihydro-2-furanylamines 2.

Chapter 13. Antibacterial Agents

Publisher Summary Antibacterial research has focused on the discovery of agents that exhibit improved activity, particularly against resistant organisms, and have a decreased incidence of side effects. This chapter discusses the mechanisms of resistance and transport for various classes of antibacterial agents. The development of new quinolone compounds has been characterized with an emphasis on structural novelty, improvement of potency versus anaerobic and gram-positive pathogens, incorporation of activity against quinolone-resistant strains, and early assessment of the potential for adverse drug reactions. New β-lactam quinolone hybrids have been reported; the carbamate-linked Ro 24-4383 shows broad spectrum activity and exhibits aqueous solubility much greater than that of the quinolone component alone. A new fluoromethoxyimino parenteral cephalosporin, E1077, shows a two-fold greater activity than cefpirome against methicillin-resistant Staphylococcus aureus (MRSA) and P. aeruginosa. The development of new macrolide antibacterial agents has focused on agents with a broad spectrum of activity, including gram-negative (Haemophilus influenzae) and macrolide-lincosamide-streptogramin (MLS)-resistant bacteria, high oral absorption, acid stability, and minimal gastrointestinal side effects. Magainins composed entirely of d -amino acids have been found to retain antibacterial potency but to resist proteolytic cleavage. RP59500 is a synergistic, water-soluble combination of RP57669 and RP54476, which are semisynthetic derivatives of the two main components of the naturally occurring streptogramins.

An Asymmetric Synthesis of (2S,5S)-5-Substituted Azepane-2-Carboxylate Derivatives

To facilitate a drug discovery project, we needed to develop a robust asymmetric synthesis of (2S,5S)-5-substituted-azepane-2-carboxylate derivatives. Two key requirements for the synthesis were flexibility for elaboration at C5 and suitability for large scale preparation. To this end we have successfully developed a scalable asymmetric synthesis of these derivatives that starts with known hydroxy-ketone 8. The key step features an oxidative cleavage of aza-bicyclo[3.2.2]nonene 14, which simultaneously generates the C2 and C5 substituents in a stereoselective manner.

Synthesis and biological evaluation of novel hygromycin A antibacterial agents

Novel hygromycin A derivatives bearing a variety of functionalized aminocyclitol moieties have been synthesized in an effort to increase the antibacterial activity and drug-like properties of this class of agents. A systematic study of the effect of alkylation and removal of the hydroxyls of the aminocyclitol directed us to a series of alkylated aminocyclitol derivatives with improved gram-positive activity.

Synthesis of Mono N-Substituted Guanylthioureas

Abstract A convenient method for the synthesis of mono N-substituted guanylthioureas in reasonable yields from readily available starting materials has been developed. In contrast to the previously published method, the use of highly noxious hydrogen sulfide is avoided. The method allows the rapid preparation of guanylthioureas since the synthesis of each requires only a single step from a common intermediate, the S-methylated derivative of dithiobiuret.