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

• Published in: Chemistry : a European journal 2020-04, Vol.26 (19), p.4289-4296
• Main Authors: Planke, Therese, Cirnski, Katarina, Herrmann, Jennifer, Müller, Rolf, Kirschning, Andreas
• Format: Article
• Language: English
• Subjects: amides; Amides - chemistry; Aniline; Aniline Compounds - chemistry; Anti-Bacterial Agents - chemistry; Antibiotics; Antifungal agents; Asparagine - analogs & derivatives; Asparagine - chemistry; Bacteria - drug effects; Benzoates - chemistry; Benzoic acid; Chemical bonds; Chemical synthesis; Chemistry; Derivatives; Hydrolysis; medicinal chemistry; Molecular Structure; Nitro Compounds - chemistry; Triazoles; Triazoles - chemical synthesis; Triazoles - chemistry; Urea; Urea - chemical synthesis; Urea - chemistry; Ureas
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201904073

Cystobactamids belong to the group of arene‐based oligoamides that effectively inhibit bacterial type IIa topoisomerases. Cystobactamid 861‐2 is the most active member of these antibiotics. Most amide bonds present in the cystobactamids link benzoic acids with anilines and it was found that some of these amide bonds undergo chemical and enzymatic hydrolysis, especially the one linking ring C with ring D. This work reports on the chemical synthesis and biological evaluation of thirteen new cystobactamids that still contain the methoxyaspartate hinge. However, we exchanged selected amide bonds either by the urea or the triazole groups and modified ring A in the latter case. While hydrolytic stability could be improved with these structural substitutes, the high antibacterial potency of cystobactamid 861‐2 could only be preserved in selected cases. This includes derivatives, in which the urea group is positioned between rings A and B and where the triazole is found between rings C and D. Fighting Gram‐negative and Gram‐positive bacteria: Thirteen new cystobactamids, derived from cystobactamid 861‐2 are prepared by chemical synthesis. Main modifications are exchange of the amide group by the chemically more stable urea group and the triazole ring as located in ring A. Antibiotic activity against Gram‐negative and ‐positive bacteria including a multidrug‐resistant strain can be preserved, when the urea function is located between rings A and B and the triazole is positioned between rings C and D.