Extensive Structure–Activity Relationship Study of Albicidin's C‐Terminal Dipeptidic p‐Aminobenzoic Acid Moiety

Abstract

Albicidin is ar ecently described natural product that strongly inhibits bacterial DNA gyrase. The pronounced activity,particularly against Gram-negative bacteria, turns it into ap romising lead structure for an antibacterial drug. Hence, structure-activity relationship studies are key for the in-depth understanding of structuralf eatures/moieties affectingg yrase inhibition, antibacteriala ctivity ando vercomingr esistance. The 27 newly synthesized albicidinsg ive profound insights into possibilities for variations of the C-terminus.F urthermore, in the present study,anovel derivative has been identified as overcoming resistance posed by the Klebsiella-protease AlbD. Structural modifications include, for example,a zahistidine replacing the previous instable cyanoalanine as the central amino acid, as well as at riazole amide bond isostere between building blocks Da nd E.

Synthetic and Biological Studies on New Urea and Triazole Containing Cystobactamid Derivatives

“…Finally, ring A can be modified in various manners without substantial loss of activity. This work provides a first information on future directions of medicinal chemistry programmes on the cystobactamids and matches recent findings on the albicidins …”

“…These first structure activi-ty studies (SAR) for natural methoxyaspartate bearing cystobactamids reveal that the urea functionc an be introduced between rings Aa nd Bb ut not between rings Da nd Ef or preserving antibacterial activity.W ea lso show that the triazole ring can serve as as ubstitute for the amide group in cystobactamids.F inally,r ing Ac an be modified in variousm anners withoutsubstantial loss of activity.This work provides afirst information on future directions of medicinalc hemistry programmes on the cystobactamids and matches recent findings on the albicidins. [10]…”

Bacterial pathogens: threat or treat (a review on bioactive natural products from bacterial pathogens)

“…265 Structural modications of 40 such as the substitution of the central amino acid b-cyanoalanine with polar threonine residue 266 or azahistidine leads to analogues with increased bioactivity over the natural albicidin. 267 Replacement of the Nterminal methylcoumaric acid moiety with benzoyl or acyl residues leads to inactivity towards the E. coli gyrase 268,269 whereas carbamoylation of the N-terminus motif, which is most likely a post-NRPS reaction gives rise to a more potent bacterial gyrase inhibitor (IC 50 $ 8 nM). 270 Synthetic azahistidine-albicidin variants with ethoxy group substitution on the C-terminal dipeptide motif exhibits increased potency against Gram-positive B. subtilis, Mycobacterium phlei and ciprooxacin-sensitive (MIC ¼ 0.031 mg mL À1 ) and -resistant S. aureus (MIC ¼ 0.063 mg mL À1 ).…”

“…270 Synthetic azahistidine-albicidin variants with ethoxy group substitution on the C-terminal dipeptide motif exhibits increased potency against Gram-positive B. subtilis, Mycobacterium phlei and ciprooxacin-sensitive (MIC ¼ 0.031 mg mL À1 ) and -resistant S. aureus (MIC ¼ 0.063 mg mL À1 ). 267 Variation in the molecule's stereocenter has minimal effect on the activity as indicated by ent-albicidin containing the D-Cya exhibiting comparable gyrase activity (IC 50 $ 40 nM) with the natural product albicidin. 265 Furthermore, replacing the central amide bond with a triazole moiety leads to a novel albicidin analogue that can overcome the serine endopeptidase AlbD resistance while preserving biological activity.…”

“…265 Furthermore, replacing the central amide bond with a triazole moiety leads to a novel albicidin analogue that can overcome the serine endopeptidase AlbD resistance while preserving biological activity. 267,271 4.3.4 Reutericyclin. Reutericyclin 38a, N-acyl tetramic acid, was initially isolated from the cultures of lactic acid bacteria Lactobacillus reuteri LTH2584 originating from an industrial sourdough isolate ( Fig.…”