Aromatic dienoyl tetramic acids. Novel antibacterial agents with activity against anaerobes and staphylococci

• Published in: Journal of medicinal chemistry 1989-05, Vol.32 (5), p.1062-1069
• Main Authors: Rosen, Terry, Fernandes, Prabhavathi B, Marovich, Mary A, Shen, Linus, Mao, James, Pernet, Andre G
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Bacteria, Anaerobic - drug effects; Chemistry; DNA-Directed RNA Polymerases - antagonists & inhibitors; Drug Resistance, Microbial; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Organic chemistry; Preparations and properties; Pyrrolidinones - chemical synthesis; Pyrrolidinones - pharmacology; Staphylococcus; Staphylococcus - drug effects; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00125a022

Streptolydigin (1) and tirandamycin A (2) are typical members of the naturally occurring class of 3-dienoyl tetramic acids. These compounds, which possess potent antibacterial activity particularly against anaerobes, have been shown to inhibit bacterial RNA polymerase. In contrast, tenuazonic acid (5), which lacks a complex dioxabicyclononane moiety and diene chromophore present in 1 and 2, exhibits essentially no antimicrobial activity and has no effect on bacterial RNA polymerase, suggesting that one or both of these structural features may be critical for antibacterial activity. In this paper, we report on a novel series of synthetic dienoyl tetramic acids that lack a complex dioxabicyclononane unit. Several of these compounds, particularly 8T-W, exhibit potent antimicrobial activity against Gram-positive and Gram-negative anaerobes as well as staphylococci. We will discuss the structure-activity relationship for this series of compounds which, in contrast to their natural counterparts, do not inhibit significantly RNA polymerase. We will also discuss preliminary results on the biochemical and microbiological properties of this series of compounds, several of which moderately inhibit supercoiling by DNA gyrase isolated from E. coli H560, although this enzyme has not been established as their target in whole cells. Compound 8W, which is not cross-resistant with DNA gyrase subunit A or B inhibitors or tirandamycin, has also been demonstrated to be rapidly bactericidal.