Acetylenic Replacement of Albicidin's Methacrylamide Residue Circumvents Detrimental E/Z Photoisomerization and Preserves Antibacterial Activity

Abstract

The natural product albicidin is a highly potent inhibitor of bacterial DNA gyrase. Its outstanding activity, particularly against Gram-negative pathogens, qualifies it as a promising lead structure in the search for new antibacterial drugs. However, as we show here, the N-terminal cinnamoyl moiety of albicidin is susceptible to photochemical E/Z isomerization. Moreover, the newly formed Z isomer exhibits significantly reduced antibacterial activity, which hampers the development and biological evaluation of albicidin and potent derivatives thereof. Hence, we synthesized 13 different variants of albicidin in which the vulnerable para-coumaric acid moiety was replaced; this yielded photostable analogues. Biological activity assays revealed that diaryl alkyne analogues exhibited virtually undiminished antibacterial efficacy. This promising scaffold will therefore serve as a blueprint for the design of a potent albicidin-based drug.

Overcoming AlbD Protease Resistance and Improving Potency: Synthesis and Bioactivity of Antibacterial Albicidin Analogues with Amide Bond Isosteres

“…In summary, we have shown that replacement of the D–E amide bond of albicidin resists protease AlbD cleavage, and at the same time, potency against both G+ve and G–ve bacteria can be increased. Our study on amide bond replacements encourages the application of these isosteres to replace not only other amides of albicidin or related cystobactamide structures − but also other peptide structures or aromatic oligoamides. , Whereas the ( Z )-fluoroalkene ( 7 ) is a state-of-the-art well-known isostere, to our knowledge, we report one of the very few examples of an alkyne ( 5 ) considered to act as an amide isostere . This Letter is a further important step in understanding the SARs of albicidin.…”

“…Both the structure elucidation and the first total synthesis were accomplished by our group . This led to the reporting of a number of albicidin structure–activity relationship (SAR) studies describing building block replacements. , …”

“…When we tried to couple 31f to the AB-PCP ( 32 ), no desired product was formed. So, we used AB-PCP ester 33 (see the SI) as an alternative highly potent AB motif . Target compounds were purified by reverse-phase high-performance liquid chromatography (HPLC).…”

“…5 This led to the reporting of a number of albicidin structure−activity relationship (SAR) studies describing building block replacements. 6,7 Albicidin (1) is naturally synthesized according to a nonribosomal biosynthesis mechanism and has an unusual structure (Figure 1). It consists of six buildings blocks (A: methylcoumaric acid (MCA), B: para-aminobenzoic acid (pABA1), C: L-cyanoalanine (Cya), D: para-aminobenzoic acid (pABA2), and E and F: para-amino-2-hydroxy-3-methoxybenzoic acid (pHMBA1 and pHMBA2)) which are linked by five peptide bonds.…”

Improvement of the antimicrobial potency, pharmacokinetic and pharmacodynamic properties of albicidin by incorporation of nitrogen atoms

“…The first total synthesis of albicidin established by our group employed an allyl protecting group strategy 23 and paved the way for initial SAR studies. This included many variations of the cinnamoyl residue (building block A) 24,25 and the incorporation of various α-amino acids at building block C. 26,27 A recent study demonstrated the significance and influence of the hydroxy and methoxy substituents on the E and F building blocks on the antibacterial activity. 28 Furthermore, with an azahistidine we have established a new important modification in the central building block C, which resulted in improved antibacterial activities and prevented hydrolysis.…”