ABSTRACT
A series of biotin-functionalized transition metal complexes was prepared by iClick reaction from the corresponding azido complexes with a novel alkyne-functionalized biotin derivative ([Au(triazolatoR,R')(PPh3)], [Pt(dpb)(triazolatoR,R')], [Pt(triazolatoR,R')(terpy)]PF6, and [Ir(ppy)(triazolatoR,R')(terpy)]PF6 with dpb = 1,3-di(2-pyridyl)benzene, ppy = 2-phenylpyridine, and terpy = 2,2':6',2''-terpyridine and R = C6H5, R' = biotin). The complexes were compared to reference compounds lacking the biotin moiety. The binding affinity toward avidin and streptavidin was evaluated with the HABA assay as well as isothermal titration calorimetry (ITC). All compounds exhibit the same binding stoichiometry of complex-to-avidin of 4:1, but the ITC results show that the octahedral Ir(III) compound exhibits a higher binding affinity than the square-planar Pt(II) complex. The antibacterial activity of the compounds was evaluated on a series of Gram-negative and Gram-positive bacterial strains. In particular, the neutral Au(I) and Pt(II) complexes showed significant antibacterial activity against Staphylococcus aureus and Enterococcus faecium at very low micromolar concentrations. The cytotoxicity against a range of eukaryotic cell lines was studied and revealed that the octahedral Ir(III) complex was non-toxic, while the square-planar Pt(II) and linear Au(I) complexes displayed non-selective micromolar activity.
Subject(s)
Anti-Bacterial Agents , Biotin , Gold , Iridium , Microbial Sensitivity Tests , Platinum , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Biotin/chemistry , Gold/chemistry , Gold/pharmacology , Iridium/chemistry , Iridium/pharmacology , Platinum/chemistry , Platinum/pharmacology , Humans , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemical synthesis , Staphylococcus aureus/drug effects , Molecular Structure , Structure-Activity RelationshipABSTRACT
The mounting burden of antimicrobial resistance (AMR) is one of the most concerning threats to public health worldwide. With low economic incentives and a dwindling supply of new drugs in clinical pipelines, more innovative approaches to novel drug design and development are desperately required. Metal-based compounds are rapidly emerging as an alternative to organic drugs, as they have the ability to kill pathogens via metal-specific modes of action. We herein review recent advances in metal-based antibacterial agents, including metal complexes, metal ions and catalytic metallodrugs. The review concludes with a perspective on the rational design of metal-based antibiotics, and how we can exploit their unique properties to tackle AMR.
Subject(s)
Coordination Complexes , Coordination Complexes/pharmacology , Anti-Bacterial Agents/pharmacology , MetalsABSTRACT
1,3-Oxazinen-4-ones are medicinally important scaffolds which have traditionally been accessed using a hetero-Diels-Alder approach or more recently using a cobalt-catalyzed three-component cycloaddition. Herein we report a novel strategy to access this scaffold which allows for the rapid and high yielding synthesis of 1,3-oxazinen-4-ones under ambient temperature and pressures with improved substrate scope.