Burton H. Jaynes

Synthesis and vitro antibacterial activity of hygromycin a analogs modified at the C4′ aryl position

Abstract A variety of hygromycin A analogs are described which contain modifications of or replacements for the natural sugar. Antibacterial activities against Serpulina (Treponema) hyodysenteriae , an important animal health pathogen, are reported and indicate that small lipophilic C 4′ substituents serve as useful sugar surrogates in the hygromycin A class.

Comparative structure–activity relationship studies of 1-(5-methylsulfonylpyrid-2-yl)-5-alkyl and (hetero)aryl triazoles and pyrazoles in canine COX inhibition

Structure-activity relationship (SAR) studies of novel 5-alkyl and 5-aryl/heteroaryl substituted 1,2,4-triazoles are described. The in vitro activity is compared to the pyrazole class of compounds with analogous side chains to delineate the contribution of the triazole ring nitrogen in binding to the active site. Both series are quite potent and selective in the canine whole blood (CWB) COX-2 assay, suggesting the increased binding contribution of the hydrophobic side chains.

Chapter 13. Antibacterial Agents

Publisher Summary This chapter discusses the recent important developments of research that has focused on finding new analogs of existing classes of anti-bacterial agents, novel classes lacking cross-resistance, and novel anti-bacterial screening targets. The chapter discusses the important developments of the past year related to β-lactams, macrolides, quinolones, oxazolidinones, and tetracyclines, in addition to several less-developed or new areas that offer exciting potential, including novel screening targets. Recently, β-lactam permeation and transport mechanisms have been reviewed. In the cephalosporin area, pharmacokinetic studies of newer compounds and new information on agents, including S-1090, E1100, and “dual-action” cephalosporin-quinolone conjugates RU-59863 and 2-oxaisocephems, have appeared. New broad spectrum cephalosporins have also been described in the chapter. Several new examples of cephalosporins, containing a catechol moiety to enhance uptake into the gram-negative bacteria, have appeared. Two of these reports contain results of extensive evaluation in vitro . New carbapenems have also been reported with potent anti-pseudomonal activity. Having now witnessed the commercial introduction of several second generation macrolides, pharmaceutical scientists are poised to develop the next wave of improved macrolides. The anti-microbial and pharmacokinetic properties of most of the quinolones under development, that include a number of very promising candidates, have been discussed in the chapter. New information pertaining to the mechanisms of quinolone activity has appeared and the toxicity of this class has been reviewed. Several reviews of tetracycline antibiotics have appeared, including an account of the newest generation of tetracyclines, the glycylcyclines. Additional biological data have been reported on the two most widely profiled glycylcyclines, DMG-MINO, and DMG-DMDOT.

Chapter 11. Antibacterial Agents

Publisher Summary Research continues to search within known antibiotic classes for improved agents, look for novel classes lacking cross-resistance, and study resistance mechanisms to approach the problem of resistant bacteria and the possible consequences. This chapter discusses the important developments of the recent times related to β-lactams, quinolones, tetracyclines, and macrolides, in addition to several less-developed areas that offer potential improvements in therapeutic options. New information, pertaining to the mechanisms of quinolone activity and toxicity, has also appeared. Topoisomerase IV may be a target for the quinolones in intact bacteria, and the accumulation of quinolones is significantly increased in post-antibiotic effect (PAE) phase cells relative to the actively growing cells. The potency of quinolones against mammalian topoisomerase II is, to a large extent, dependent on the structure of the C-7 substituent. A number β-lactams, with unusual structures, has been recognized. E1101, the isopropoxycarbonyloxymethyl ester prodrug of E1100 exhibits in effect oral absorption in laboratory animals and humans and has been the subject of an extensive chemistry and structure–activity relationship (SAR) study. The increased need for new agents for combating antibiotic-resistant bacteria has rejuvenated interest in the tetracycline class. Two common mechanisms of resistance to tetracyclines exist. The first is the removal of drug from the bacterial cell by membrane-bound efflux proteins and the second is the ribosomal protection that prevents tetracyclines from interrupting polypeptide chain elongation. The well-precedented ability of macrolides to penetrate and accumulate in various host cells has led to: (1) studies of the utility of macrolides versus infections, caused by intracellular pathogens (for example, chlamydia and enteric bacteria) and (2) further studies on uptake and effect on macrophages, neutrophils, and T-lymphocytes.