Structure activity relationship studies on rhodanines and derived enethiol inhibitors of metallo-ß-lactamases.

Metallo-ß-lactamases (MBLs) enable bacterial resistance to almost all classes of ß-lactam antibiotics. We report studies on enethiol containing MBL inhibitors, which were prepared by rhodanine hydrolysis. The enethiols inhibit MBLs from different subclasses. Crystallographic analyses reveal that the enethiol sulphur displaces the di-Zn(II) ion bridging 'hydrolytic' water. In some, but not all, cases biophysical analyses provide evidence that rhodanine/enethiol inhibition involves formation of a ternary MBL enethiol rhodanine complex. The results demonstrate how low molecular weight active site Zn(II) chelating compounds can inhibit a range of clinically relevant MBLs and provide additional evidence for the potential of rhodanines to be hydrolysed to potent inhibitors of MBL protein fold and, maybe, other metallo-enzymes, perhaps contributing to the complex biological effects of rhodanines. The results imply that any medicinal chemistry studies employing rhodanines (and related scaffolds) as inhibitors should as a matter of course include testing of their hydrolysis products.

Synthesis of a phosphinate analogue of the anti-tumour phosphate di-ester perifosine via sequential radical processes.

An efficient synthesis of a phosphinate analogue of the anti-tumour phosphate di-ester perifosine is described (6 steps and 50% overall yield). The two phosphorus-carbon bonds in the perifosine analogue were prepared by sequential double radical hydrophosphinylation processes. This is the first example of a phosphinate analogue of perifosine, designed to be resistant to hydrolysis by phospholipid-metabolizing enzymes.

A highly porous interpenetrated metal-organic framework from the use of a novel nanosized organic linker.

The initial use of a novel elongated tricarboxylic acid H(3)hmpib in metal-organic framework (MOF) chemistry resulted in a [Zn(4)O(hmpib)(2)] MOF (UCY-1) with pyrite topology. The compound displays a remarkably high internal surface area despite its double-interpenetrated structure as well as high CO(2) uptake and selective adsorption for it over CH(4).

The road to avibactam: the first clinically useful non-ß-lactam working somewhat like a ß-lactam.

Avibactam, which is the first non-ß-lactam ß-lactamase inhibitor to be introduced for clinical use, is a broad-spectrum serine ß-lactamase inhibitor with activity against class A, class C, and, some, class D ß-lactamases. We provide an overview of efforts, which extend to the period soon after the discovery of the penicillins, to develop clinically useful non-ß-lactam compounds as antibacterials, and, subsequently, penicillin-binding protein and ß-lactamase inhibitors. Like the ß-lactam inhibitors, avibactam works via a mechanism involving covalent modification of a catalytically important nucleophilic serine residue. However, unlike the ß-lactam inhibitors, avibactam reacts reversibly with its ß-lactamase targets. We discuss chemical factors that may account for the apparently special nature of ß-lactams and related compounds as antibacterials and ß-lactamase inhibitors, including with respect to resistance. Avenues for future research including non-ß-lactam antibacterials acting similarly to ß-lactams are discussed.

One-pot regioselective synthesis and X-ray crystal structure of a stable [60]fullerene trisadduct with the e(edge),e(face),trans-1 addition pattern.

The Bingel functionalisation of C(60) with a structurally novel tether equipped with three reactive malonate groups afforded a C(2v)-symmetrical e(edge),e(face),trans-1 trisadduct in a complete regioselective manner and in an excellent yield of 65%. The [60]fullerene trisadduct showed pronounced ability to crystallise and gave X-ray quality single crystals for analysis.