Article

Tethered thiazolidinone dimers as inhibitors of the bacterial type III secretion system.

Department of Immunology, University of Washington, Seattle, WA 98195, USA.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.65). 02/2009; 19(5):1340-3. DOI: 10.1016/j.bmcl.2009.01.047
Source: PubMed

ABSTRACT Disruption of protein-protein interactions by small molecules is achievable but presents significant hurdles for effective compound design. In earlier work we identified a series of thiazolidinone inhibitors of the bacterial type III secretion system (T3SS) and demonstrated that this scaffold had the potential to be expanded into molecules with broad-spectrum anti-Gram negative activity. We now report on one series of thiazolidinone analogs in which the heterocycle is presented as a dimer at the termini of a series of linkers. Many of these dimers inhibited the T3SS-dependent secretion of a virulence protein at concentrations lower than that of the original monomeric compound identified in our screen.

0 Bookmarks
 · 
113 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: With reports of pandrug-resistant bacteria causing untreatable infections, the need for new antibacterial therapies is more pressing than ever. Alkaloids are a large and structurally diverse group of compounds that have served as scaffolds for important antibacterial drugs such as metronidazole and the quinolones. In this review, we highlight other alkaloids with development potential. Natural, semisynthetic and synthetic alkaloids of all classes are considered, looking first at those with direct antibacterial activity and those with antibiotic-enhancing activity. Potent examples include CJ-13,136, a novel actinomycete-derived quinolone alkaloid with a minimum inhibitory concentration of 0.1 ng/mL against Helicobacter pylori, and squalamine, a polyamine alkaloid from the dogfish shark that renders Gram-negative pathogens 16- to >32-fold more susceptible to ciprofloxacin. Where available, information on toxicity, structure–activity relationships, mechanisms of action and in vivo activity is presented. The effects of alkaloids on virulence gene regulatory systems such as quorum sensing and virulence factors such as sortases, adhesins and secretion systems are also described. The synthetic isoquinoline alkaloid virstatin, for example, inhibits the transcriptional regulator ToxT in Vibrio cholerae, preventing expression of cholera toxin and fimbriae and conferring in vivo protection against intestinal colonisation. The review concludes with implications and limitations of the described research and directions for future research.
    International Journal of Antimicrobial Agents 11/2014; · 4.42 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The diversity in the biological response of 4-thiazolidinones has attracted the attention of many researchers to explore this framework for its potential. It is, therefore, of prime importance that the study of this topic and the development of new synthetic strategies should be based on the most recent knowledge, emerging from the latest research. This review is an endeavor to highlight the progress in the chemistry and biological activity of the 4-thiazolidinones, predominantly after 2006. The last section of the review encompasses the various patents granted on 4-thiazolidinone analogs/derivatives with World Intellectual Proprietary Organization (WIPO) and United State Patent Trademark Office (USPTO), particularly in the duration of the year 2000 to the year 2012.
    European Journal of Medicinal Chemistry 11/2013; 72C:52-77. · 3.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A facile and convenient protocol was developed for the synthesis of 5-arylidene-2-imino-4-thiazolidinones using solid basic catalyst immobilized onto supported ionic liquid-like phase (SILLP) in high yields (80–95%). The X-ray analysis of the representative compound established the Z configuration of the product at the chiral axis.
    Journal of the Iranian Chemical Society 02/2012; 9(1). · 1.47 Impact Factor

Full-text

Download
0 Downloads
Available from