Syntheses and Antibacterial Activity of N-Acylated Ciprofloxacin Derivatives Based on the Trimethyl Lock

Abstract

Several N-acyl ciprofloxacin quinone derivatives based on a trimethyl lock structure were synthesized, and their in vitro antibacterial activity against a panel of clinically relevant bacteria was evaluated. A few new analogues displayed enhanced activity against Gram-positive species compared to the parent drug. Additionally, studies of 8-Cip, which was the most potent compound tested, indicate that it may act through a dual-action mechanism.KEYWORDS: Ciprofloxacin, trimethyl lock, drug release, antibacterial S ince their discovery in 1970s, fluoroquinolone antibiotics have played an important role in treatment of bacterial infections and have saved countless millions of lives. Targeting bacterial DNA gyrase and topoisomerase, fluoroquinolones exhibit their significant bactericidal activity by forming ternary complexes of enzyme−DNA−drug and consequently blocking bacterial replication. 1,2 Their notable antimicrobial activity, excellent pharmacokinetic properties, and few side effects have led to the widespread use of fluoroquinolones and, unfortunately, thus also the development of bacterial resistance. 3 Therefore, although many advances in the search for new fluoroquinolones have been already made, there is a sense of urgency for new and more effective derivatives.Recently, in our development of linkers to incorporate a drug release function in iron transport-mediated drug delivery, a series of carboxylic acids with a quinone "trimethyl lock" structure and their methyl esters were obtained as synthetic intermediates. 4,5 The chemical nature of the trimethyl lock is an o-hydroxylcinnamic acid derivative. 6 Reduction of the quinone trimethyl lock system generalized by structure 1 would lead to the corresponding hydroquinones 2 in which severe steric repulsion between three methyl groups promotes rapid lactonization with concomitant release of an alcohol or amine (Scheme 1). 7,8 Several quinone trimethyl lock compounds have been investigated for reductase-activated prodrugs such as those based on mustard 9 and oxindoles 10 for anticancer therapy. In ciprofloxacin, one of the best known fluoroquinolones, it has been demonstrated that chemical modification of the secondary amine in the piperazinyl ring by acylation does not always alter the effect of these molecules toward their bacterial target. 11 With the aim of probing the effects of the quinone trimethyl lock on antibacterial activity of fluoroquinonlones, we herein describe the syntheses of several ciprofloxacin derivatives with quinone trimethyl lock precursors as N-acyl substituents and studies of their in vitro antibacterial activity.The syntheses of trimethyl locks with different substituents on the quinone are shown in Scheme 2. Both forms 5H and 8H were derived from lactone 4 by oxidative ring opening of the

Modifications of quinolones and fluoroquinolones: hybrid compounds and dual-action molecules

“…The most active conjugate was found to be compound 31n with MIC values against Gram-positive S. aureus and M. luteus superior to these determined for ciprofloxacin. This result suggests that compound 31n may act through a dual-action mechanism presented in Scheme 17 by serving as a prodrug and covalent thiol-containing enzyme inhibitor [93].

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Trimethyl Lock: A Multifunctional Molecular Tool for Drug Delivery, Cellular Imaging, and Stimuli‐Responsive Materials

“…[37,123] They reported desferrioxamin B-ciprofloxacin conjugates 85 as well as agrobactin-derived synthetic siderophore-ciprofloxacin conjugate 86,b earing both quinone-based and urea-substituted TML cores as oxidoreductase sensitive linkers (Scheme 17). [37,123] They reported desferrioxamin B-ciprofloxacin conjugates 85 as well as agrobactin-derived synthetic siderophore-ciprofloxacin conjugate 86,b earing both quinone-based and urea-substituted TML cores as oxidoreductase sensitive linkers (Scheme 17).…”

“…[37,123] They reported desferrioxamin B-ciprofloxacin conjugates 85 as well as agrobactin-derived synthetic siderophore-ciprofloxacin conjugate 86,b earing both quinone-based and urea-substituted TML cores as oxidoreductase sensitive linkers (Scheme 17). [123] Interestingly, Scheme16. [37] In addition, Miller and co-workers have investigated the ability of the novel TML-ciprofloxacin derivatives synthesized in these studies to serve as antibiotic prodrugs.…”

Ciprofloxacin/Gatifloxacin‐1,2,3‐triazole‐isatin Hybrids and Their In Vitro Anticancer Activity

“…The previous research results indicated 1,2,3-triazole as the linker between fluoroquinolone and isatin motifs could improve the biological activity [18][19][20]. Meanwhile, N-acylated fluoroquinolone derivatives showed enhanced activity and reduced cytotoxicity when compared with the parent, suggesting acetyl might also be an excellent linker [21,22].…”