Unique Bidentate Chelators of Functionalized Heterocyclic Fluoroquinolones with Dual Anti-Inflammatory and Selective...

In the context of repurposing antimicrobial fluoroquinolones (FQs), we propose that their increased efficacy is attributable to the lipophilic properties of the newly developed FQs.

This study involved the synthesis of 21 lipophilic-acid chelating fluoroquinolones (FQs) and their subsequent screening approaches for selective antiproliferative, antioxidant, and anti-inflammatory activities.

Notably, the reduced FQ series, specifically 14c, demonstrated radical scavenging activities for NO and DPPH that were comparable to the referencing agents. In contrast to the others, the reduced 10a, 10b, and 14b FQs exhibited significant antioxidant effects. Predominantly, MCF7, HT29, T47D, and SW480 were the best target cell lines for the new FQs to exhibit their antiproliferative activities. In fact, many FQ derivatives have revealed IC50 values below 10 µM, mainly with MCF7 and HT29cell lines. Among the three synthesized series (nitro, reduced, and triazolo), the compounds (10a-d and 14a-d) of the reduced series exhibited the highest activities (lowest IC50) against the strongest four cell lines. All reduced series of hexyl phenyl 14a, 14c, and 14d with para-halogens were stronger than their hexyl amine counterparts 10a, 10c, and 10d. The selectivity indices for the new FQs were either equipotent or more potent than the reference cisplatin.

The remarkable effects of the reduced series 14a, 14b, 14c, 10a, 10c, and 10d stemmed from metal chelation within the C8-C7 ethylene diamine bridge. Furthermore, the spatial and steric constraints introduced by the N1 substituent ultimately influenced the chelation geometry. Complexation studies revealed that central iron chelation is the predominant intracellular mechanism, whereas zinc chelation is the primary mode of interaction with the zinc-dependent metalloenzyme Glo-I. Mechanistically, nitroFQs 9d, 13a, and 13d and their respective reduced FQs 14a and 14d were shown to exhibit unprecedentedly equipotent Glo-I enzymatic inhibition, matching the IC50 value of myricetin (3.5 µM). Appreciably significant GLo-I inhibition with IC50 values ranging from 24-52 µM was obtained for nitroFQs and their reduced FQs in the ascending order of 9c < 9b < 13b < 14b < 10b < 10c < 10d.

The mechanism of action of the FQs involved acidic functional groups and a C7-C8 ethylenediamine chelation bridge, with iron chelation being the predominant pathway.