Dual-Action Cephalosporins Incorporating a 3'-Tertiary-Amine-Linked Quinolone

Abstract

We have previously reported that linking quinolones to the cephalosporin 3'-position through an ester bond, a carbamate function, or a bond through a quaternary nitrogen produced cephalosporins with a dual mode of antibacterial action. We now describe a new class of dual-action cephalosporins, with greater chemical stability than those previously reported, in which the basic nitrogen of ciprofloxacin is bonded directly to the 3'-cephalosporin position, i.e., the two moieties are linked through a tertiary amine function. These compounds have demonstrated potent activity against a broad spectrum of Gram-positive and Gram-negative bacteria, including beta-lactam-resistant strains.

The influence of natural products upon drug discovery (Antiquity to late 1999)

“…To give an idea of the value of these patented combinations, in 1997 SKB sold over US$ 1.5 billion of Augmentin ® worldwide and the US patent does not expire until 2002. 18 As yet, a corresponding cephalosporin combination has not been marketed, though from the late 1980s workers at Roche had reported on some interesting combination antibiotics where two different nuclei (b-lactams and quinolones) were linked by esters, 19 carbamates 20 or via a tertiary amine function 21 and reported on their stability to three common Gram-negative b-lactamases, 22 showing that only the compounds that contained the cefotaxime structure were stable to two of the three enzymes used.…”

Dual Action-Based Approaches to Antibacterial Agents

“…The design principle for this series of compounds involved exploiting the expulsion of a group on the C-3 substituent of cephalosporin antibiotics. To this end, they synthesized numerous dual-action antibacterial prodrugs combining a cephalosporin linked to a fluoroquinolone through an ester 14 [22], quaternary nitrogen 15 [23], carbamate 16 [24], or tertiary amine 17 [25] functionalities.…”

“…Potential β-lactam-fluoroquinolone dual action antibacterial prodrugs linked via a methylene group at the piperazine nitrogen N4′ have also been investigated [25]. Synthetically these derivatives, such as 17 , were produced via N-alkylation of the fluoroquinolone, for example ciprofloxacin (10 ), with various β-lactam alkyl halides, including the iodide sulfur substituent, which would then undergo intramolecular nucleophilic attack of the thiolate anion on the amide carbonyl, resulting in liberation of the fluoroquinolone ciprofloxacin (10 ) from the tetrazole linker (Scheme 6).…”

Resolving the Antibiotic Paradox

“…These compounds provide additional insight on the lactam variable. Albrecht et al (1994) reported a similar set of 3° amine-linked quinolonyl cephems derived from ciprofloxacin. Gray et al (1995) described the procedures for making these compounds.…”