摘要:

Introductionβ-Lactams have gained substantial interest in the scientific community not only due to their antibiotic properties1–3but also as reactive intermediates and as starting materials in a wide range of synthetic settings.4,5The heavy use of antibiotics during the second half of the last century has resulted in an increasing number of bacteria being resistant to the drugs available today.6,7One way of overcoming this problem involves development of antibacterial agents against novel targets in the microorganism.8A large number of infectious Gram negative bacteria produce pili, which are a family of extracellular, supramolecular protein organelles that mediate attachment to host tissue.9Pilus assembly is performed by periplasmic chaperones that fold and transport the subunits to the outer cell membrane where they are incorporated into a growing pilus.10Thus, if the chaperone-subunit complex can be prevented from being formed, colonization of host tissue cannot occur.11,12Moreover, periplasmic chaperones constitute a highly conserved structure, which can be found in a large number of pathogenic bacteria such asB. pertussis, S. typhimuriumandH. influenzaeresponsible for the diseases whooping cough, gastrointestinal disorder and meningitis respectively.9,13In addition, the structures of the chaperone-subunit complexes are well studied and it has been shown, both by NMR14,15and X-ray crystallography,16,17that the pili-subunits bind to the chaperone by anchoring of the carboxy terminus to the side chains of Arg 8 and Lys 112. Previously, we reported a stereoselective synthesis of optically active β-lactams, which were designed to be a suitable scaffold for the development of compounds (termed pilicides) that inhibit pilus formation in uropathogenicE. coli.18Bicyclic β-lactam methyl esters3were synthesized in yields as high as 93% by reacting the two key intermediates, the acyl Meldrum's acids1and 2-H-Δ2-thiazoline methyl ester2(Fig. 1). These esters could then be selectively reduced to the corresponding aldehydes4by DIBAL-H, which would have potential to form imines with Lys 112.18Original procedure for the formation of the β-lactam methyl esters3and their corresponding aldehydes4.The stereochemistry of the β-lactams synthesized by this method is different compared to the original penicillin's, thus having a chance to withstand enzymatic degradation by penicillin-resistant bacteria. Other compounds such as bicyclic 2-pyridinones5and amino acid derivatives6(Fig. 2) are known to bind to chaperones as free carboxylic acids19or as their corresponding Li-salts.20This article describes the synthesis of β-lactam carboxylic acids and the study of their binding affinity to the periplasmic chaperone PapD by the surface plasmon resonance technique. Moreover, a new practical and efficient procedure for the synthesis of the important intermediate, 2-H-Δ2-thiazolinecarboxylic acid methyl ester2, was developed.Bicyclic 2-pyridinone5, amino acid derivative6and the heptapeptide8, corresponding to theC-terminus of the pilus adhesion protein PapG, have shown chaperone binding and chaperone/subunit inhibitor activity.19Novel bicyclic β-lactam carboxylic acids7targeted in this article are also designed to have corresponding biological activity.

ISSN:1477-0520    

DOI:10.1039/b210551a

出版商:RSC    

年代:2002

数据来源: RSC