Pharmacophore development and validation for inhibitors of the bacterial NorA efflux pump

Using a series of known inhibitors of the bacterial NorA efflux pump and the pharmacophore generation program CATALYST� the first predictive pharmacophore for inhibitors of this pump has been developed. The pharmacophore consists of 3 hydrophobic features, a ring aromatic feature, 16 excluded volumes and one hydrogen bond acceptor. This pharmacophore was subsequently used to search the NCI database for new compound leads and also for de novo design. Two 1,4-naphthoquinones and an aromatic azo compound were identified as possible leads from the NCI database of compounds. These compounds were tested for NorA efflux inhibition in Staphylococcus aureus and they showed inhibitory activity. The de novo design process identified a number of new biaryl ether and biaryl ketone target compounds as potential inhibitors. A biaryl ether target 2-[3-(3-methoxyphenoxy)phenyl]isoindoline-1,3-dione, was synthesised by a concise three step process. This compound showed moderate NorA pump inhibitory activity in Staphylococcus aureus, using berberine as the antibacterial pump substrate. Thus this biaryl ether could serve as the starting point for a new class of inhibitors.