Synthesis and turbeculostatic activity of podands with fluoroquinolone fragments

Abstract

Fluorine-substituted quinolonecarboxylic acids are known as synthetic antibacterial drugs with a broad spectrum of activity, which are successfully used for the therapy of various bacterial diseases, including tuberculosis [1 ]. Nevertheless, problems pertaining to the appearance of bacterial strains resistant to quinolones stimulate researchers to continue investigations aimed at a modification of the known fluroquinolones [2].We have attempted to modify a fluoroquinolone fragment responsible for penetration into bacterial ceils, with the pttrpose of increasing the transport function of the molecule, since it is known that fluoroquinolones (in particular, pefloxacin) penetrate into bacterial cells by a simple diffusion mechanism [3].In order to find reaction pathways to fluoroquinolones possessing increased penetrating ability with respect to the cell membranes, we have synthesized compounds containing podand residues that are known [4] to readily pass through the cellular barriers.Because of the low nucleophilicity of glycols, the oxygen-containing podands IV were obtained under rigid conditions from the ethyl ester of 1-ethyl-6,7-difluoro-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid (Ib), in which the mobility of a fluorine atom in position 7 is somewhat higher than in the acid (Ia).Podands V and VI were obtained by direct interaction of acid Ia with polyethylene polyamines. Potassium carbonate was used as the acceptor of hydrogen chloride in the synthesis of compounds IV and VI, whereas triethylamine was used for the same purpose in the synthesis of compounds V known to form strong complexes with potassium cations.Podands-hydrazones VII were obtained by heating formylpodands III with 7-hydrazino-4-oxo-6-ftor-l-ethyl-l,4-dihydro-3-quinolinecarboxylic acid (II) in DMF.

Recent updates of fluoroquinolones as antibacterial agents

“…Another research study revealed that dimers of the same fluoroquinolones or two different fluoroquinolones linked by a linker at C‐7 exhibited highly promising antibacterial activity against tested bacterial strains . From the results, it is clear that derivatives with a bulky C‐7 side chain are more potent against efflux mutants .…”

Fluorinated benzazoles and benzazines

“…In order to improve the pharmacokinetic properties of fluoroquinolones, they were modified with aminoether or polyethyleneamine podand fragments, which are able to penetrate through cell membranes (Scheme 20) [60]. This modification gave derivatives 63 that proved to be specifically active against micobacteria under a low toxicity.…”

4‐Quinolone Derivatives and Their Activities Against Gram‐negative Pathogens

“…Many other biological pharmacophores such as azole/hydrozone , benzofuroxan , bisphosphonate , catecholate , citrate , glycoside , isoniazid , kanamycin , kojic acid , β ‐lactams , lactone , imidazole , sideromycins , peptide , phenothiazinium , pyochelin , pyoverdin , pyrazine , pyridyl , pyrimidine , pyrrazole , quinolone , sulfonamide , siderophore , tetrahydroquinoline , 1,3,4‐thiadiazol/oxadiazol , thiazole , triazine , and trifluoroacetimidoyl have been introduced into the piperazinyl subunit of FQs; although some of them such as lactone‐CPFX hybrid 23 (MIC of 0.11 μg/mL against multidrug‐resistant E . coli , which was 50 times more potent than the parent CPFX ) showed promising activity against Gram‐negative pathogens, the majority of them were less active than the parents.…”