Harnessing Transition Metal Scaffolds for Targeted Antibacterial Therapy.

Antimicrobial resistance, caused by persistent adaptation and growing resistance of pathogenic bacteria to overprescribed antibiotics, poses one of the most serious and urgent threats to global public health. The limited pipeline of experimental antibiotics in development further exacerbates this looming crisis and new drugs with alternative modes of action are needed to tackle evolving pathogenic adaptation. Transition metal complexes can replenish this diminishing stockpile of drug candidates by providing compounds with unique properties that are not easily accessible using pure organic scaffolds. We spotlight four emerging strategies to harness these unique properties to develop new targeted antibacterial agents.

Ferrocenyl catechols: synthesis, oxidation chemistry and anti-proliferative effects on MDA-MB-231 breast cancer cells.

The synthesis and anti-tumoral properties of a series of compounds possessing a ferrocenyl group tethered to a catechol via a conjugated system is presented. On MDA-MB-231 breast cancer cell lines, the catechol compounds display a similar or greater anti-proliferative potency (IC(50) values ranging from 0.48-1.21 µM) than their corresponding phenolic analogues (0.57-12.7 µM), with the highest activity found for species incorporating the [3]ferrocenophane motif. On the electrochemical timescale, phenolic compounds appear to oxidize to the quinone methide, while catechol moieties form the o-quinone by a similar mechanism. Chemical oxidation of selected compounds with Ag(2)O confirms this interpretation and demonstrates the probable involvement of such oxidative metabolites in the in vitro activity of these species.

Synthesis, oxidation chemistry and cytotoxicity studies on ferrocene derivatives of diethylstilbestrol.

A series of compounds is described in which one of the ethyl groups in diethylstilbestrol has been replaced by a ferrocenyl substituent. Only those derivatives incorporating phenol moieties underwent isomerisation from the Z to the E form, and some of them could be chemically oxidized to a quinone species. The compounds were less cytotoxic against hormone-independent MDA-MB-231 breast cancer cell lines than their corresponding ferrocenyl phenyl or phenol isomers in which the ferrocene and ethyl moieties are linked to the same carbon atom. The biochemical results were evaluated in conjunction with information obtained from electrochemical and chemical oxidation experiments.