Combinatorial synthesis through disulfide exchange: Discovery of potent psammaplin A type antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA)

Psammaplin A is a symmetrical bromotyrosine -derived disulfide natural prod uct isolated from the Psammaplysilla sponge, which exhibits in vitro antiba cterial activity against methicillin-resistant Staphylococcus aureus (MRSA) . Inspired by the structure of this marine natural product, a combinatorial scrambling strategy for the construction of heterodimeric disulfide analog ues was developed and applied to the construction of a 3828-membered librar y starting from 88 homodimeric disulfides. These psammaplin A analogues wer e screened directly against various gram positive bacterial strains leading to the discovery of a series of potent antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA), Among the most active leads derived from these studies are compounds 104. 105, 113, 115, 123, and 128. The present, catalytically-induced. disulfide exchange strategy may b e extendable to other types of building blocks bearing thiol groups facilit ating the construction of diverse discovery-oriented combinatorial librarie s.