Study of Iron Piperazine-Based Chelators as Potential Siderophore Mimetics

Abstract

Gram-negative bacteria's resistance such as Pseudomonas aeruginosa and the Burkholderia group to conventional antibiotics leads to therapeutic failure. Use of siderophores as Trojan horses to internalize antibacterial agents or toxic metals within bacteria is a promising strategy to overcome resistance phenomenon. To combat the Pseudomonas sp, we have synthesized and studied two piperazine-based siderophore mimetics carrying either catecholate moieties (1) or hydroxypyridinone groups (2) as iron chelators. These siderophore-like molecules were prepared in no more than four steps with good global yields. The physicochemical study has highlighted a strong iron affinity since their pFe values were higher than 20. 1 possesses even a pFe value superior than those of pyoverdine, the P. aeruginosa endogenous siderophore, suggesting its potential ability to compete with it. At physiological pH, 1 forms mainly a 2:3 complex with iron, whereas two species are observed for 2. Unfortunately, the corresponding Ga(III)-1 and 2 complexes showed no antibacterial activity against P. aeruginosa DSM 1117 strain. The evaluation of their siderophore-like activity showed that 1 and 2 could be internalized by the bacteria.

Design and Synthesis of Novel Antimicrobial Agents

“…The conjugates also take advantage of the bacterial ferri-siderophore uptake transporters for efficient passage through the outer membrane. To tackle P. aeruginosa species, Loupias et al [ 235 ] created two piperazine-based siderophore mimics with catechol or hydroxypyridone chelating groups ( 153 , 154 , Figure 15 ). Unfortunately, the complexes exhibited no antibacterial action, although they could be employed as antibiotic transporters against Pseudomonas species.…”

Discovery, synthesis, and cytotoxic evaluation of isoquinolinequinones produced by Streptomyces albidoflavus derived from lichen

“…It could improve the lipid-water partition coefficient of compound and stimulate their bioactive potential. 17,18 Therefore, we designed a series of derivatives 1a-1w by introducing the different piperazinyl acetic acid fragments on the amino group at C-7 of scaffold (Scheme 3). Using a similar approach of synthesizing compound 1, analogs 1a-1w were obtained.…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6

“…Designing siderophore mimetics ( Figure 1) is expected to combat bacteria and fungi by introducing either toxic metals or antibiotics into the organism. This strategy has been recently exploited by the team of P. Sonnet [1] in order to evaluate the antipseudomonal activities and cytotoxicity of conjugates bearing a piperazine moiety and a catechol (1) or an hydroxypyridone (2) chelating group.…”

“…The development of new and effective inhibitors is driven by the specific targeting of hCA IX / hCA XII over the ubiquitous cytosolic offtarget isoforms hCA I and hCA II [33]. Bua and colleagues investigated a new cyclic ureidosulfonamide chemotype based on a 2H-benzo[e] [1,2,4]thiadiazin-3(4H)-one 1,1-dioxide scaffold, and resulting from the combination design of the structure of saccharin and acesulfame K [2]. Many derivatives showed enhanced inhibitory activity and selectivity against hCA IX / hCA XII isoforms.…”