Bacterial resistance to antibiotic drugs is a growing problem in antibacterial therapy; and new classes of anti-infectives are desperately needed . Predictions suggested that by 2005 nearly 40% of all Streptococcus strains will be resistant to both penicillin and macrolide antibiotics in the United States . Of special concern is the drug resistance of Gram-positive pathogens such as Streptococcus pneumoniae to penicillin, Staphylococcus aureus (MRSA) to methicillin and in particular Enterococcus faecium (VRE) to vancomycin. The biological activity of natural products is often mediated by their carbohydrate epitopes, which influence the phar-macokinetic properties, targeting and mechanism of action in general. Consequently, diversification of the carbohydrate groups may lead to new therapeutics . With the aid of the Cu(I)-catalyzed process, 15 triazole-linked monoglycosy-lated derivatives of vancomycin were synthesized (Fig. 15.2) . Antibacterial screens of this library revealed that acid derivative 2 (Fig. 15.2; 2) was twice as active as vancomycin against both E. faecium and S. aureus.
Triazole derivatives of natural products.
Triazole derivatives of natural products.
Another approach for modifying natural products was described by Marriott et al., who synthesized a triazole derivative of Kabiramide C in the presence ofa catalytic amount of Cu(I) and NEt3 (Fig. 15.2) . Kabiramide C is a macrolide drug that targets actin, a highly conserved and abundant protein, which plays an essential role in cytokinesis, cell mobility and vesicle transport. Each triazole derivative was shown to tightly bind G-actin with the same stoichiometry as the natural product.
A new class of synthetic antibacterial agents against Gram-positive bacteria, containing the oxazolidinone pharmacophore, targets bacterial protein synthesis. However, growing drug resistance has been observed with E.faecium and S. aureus. Additionally, oxazolidinone antibiotics can cause severe hypertensive crisis, an undesired side-effect caused by the inhibition of monoamine oxidase (MAO). In an effort to address these issues, researchers at AstraZeneca made analogues oflineozolide  by replacing the acetamide functionality with a 1,2,3-triazole and the morpholine ring by a thiapyran sulfone . Both the copper-catalyzed and thermal [3+2]cycloaddi-tion processes were employed to generate triazoles; and vinylsulfones were found to give 1,4-disubstituted triazoles with good selectivities (Scheme 15.4).
SAR studies revealed that 5-substitued triazoles were generally inactive or only marginally active. In contrast, many triazoles with a small substituent in the 4-po-sition showed good antibacterial activities and at the same time displayed significantly reduced inhibition of MAO.
Even though tyrocidine antibiotics are attractive therapeutic agents, they cause lysis of human red blood cells. In an attempt to decrease this toxic side effect, Walsh et al. employed a chemoenzymatic approach to make carbohydrate-modified cyclic peptide tyrocidine (tyc) antibiotics, which are nonribosomal peptides (NRP; Scheme 15.5) . They generated a library of 247 glycopeptides by conducting an enzymatic macrocyclization, followed by Cu(I)-catalyzed triazole for-
Triazole/thiapyran analogs of the oxazolidinone antibiotic linezolid.
Chemoenzymatic approach to glycopeptides via copper-catalyzed triazole formation.
mation with azidoalkyl glycosides in 96-well plates. The excised thioesterase (TE) domain from the tyrocidine synthetase was used to catalyze the formation of the head-to-tail cyclic peptide derivatives from linear, propargylglycine-containing, peptide N-acetyl cystamine (SNAC) thioesters. The cyclization was followed by copper-catalyzed triazole formation, which proceeded cleanly, allowing the crude reaction mixtures to be screened in antibacterial and hemolytic assays. Screening hits were validated by re-testing the purified compounds, leading to the identification of two glucopeptides that displayed a 6-fold better therapeutic index than wild-type tyrocidine while maintaining its high antibacterial potency.
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