Co(II) and Cu(II) pyrophosphate complexes have selectivity and potency against Mycobacteria including Mycobacterium tuberculosis

• Published in: European journal of medicinal chemistry Vol. 70; pp. 589 - 593
• Main Authors: Hoffman, Amanda E., DeStefano, Michelle, Shoen, Carolyn, Gopinath, Krishnamoorthy, Warner, Digby F., Cynamon, Michael, Doyle, Robert P.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.12.2013
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacteriocidal; Cobalt; Cobalt - chemistry; Copper; Copper - chemistry; Diphosphates - chemistry; Dose-Response Relationship, Drug; MDR-TB; Microbial Sensitivity Tests; Models, Molecular; Mycobacterium - drug effects; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Pyrophosphate; Structure-Activity Relationship; INH; Bacteriocidal; MOTT; MIC; Pyrophosphate; MDR-TB; XDR-TB; Copper; Cobalt; TB; isoniazid; tuberculosis; extensively drug-resistant TB; multidrug-resistant TB; Mycobacteria other than TB; minimum inhibitory concentration
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2013.10.044

Tuberculosis (TB) causes up to 10 million incident cases worldwide per annum. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains are leading factors in the resurgence of TB cases and the need to produce new agents to combat such infection. Herein, we describe Co(II) and Cu(II) metal based complexes that feature the pyrophosphate ligand with notable selectivity and marked potency against Mycobacterium tuberculosis, including MDR strains. Such complexes are confirmed to be bacteriocidal and not affected by efflux inhibitors. Finally, while susceptibility to copper has recently been established for M. tuberculosis, the greater efficacy of cobalt observed herein is of considerable note and in line with the discovery of a copper metallothionein in M. tuberculosis. [Display omitted] •Cobalt and copper pyrophosphate complexes have potency and selectivity against TB.•Cobalt is more effective than copper with lower Human lung cell toxicity.•Resistance, even at 2× MIC, is not observed in wild-type TB or a TB transposon library.