Combinatorial Synthesis through Disulfide Exchange: Discovery of Potent Psammaplin A Type Antibacterial Agents Active against Methicillin-ResistantStaphylococcus aureus (MRSA)

Abstract

Psammaplin A is a symmetrical bromotyrosine-derived disulfide natural product isolated from the Psammaplysilla sponge, which exhibits in vitro antibacterial 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 analogues was developed and applied to the construction of a 3828-membered library starting from 88 homodimeric disulfides. These psammaplin A analogues were 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 be extendable to other types of building blocks bearing thiol groups facilitating the construction of diverse discovery-oriented combinatorial libraries.

The Marine Bromotyrosine Derivatives

“…The antibacterial and antifungal activities of the bromotyrosine alkaloids are summarized in Table IV and Table V Interestingly, Gram-positive bacteria are highly susceptible to purpuramine L when compared to the positive control kanamycin (122). Psammaplin A (152) was found to possess antimicrobial activity (109,254,255). It also selectively inhibited the growth of methicillin-resistant Staphylococcus aureus (MRSA) (256).…”

Total Synthesis of the Marine Bromotyrosine Alkaloid Moloka'iakitamide

“…Introduction of a bromine atom at 5 was carried out by reported method in 2 steps. 15) Di-brominated phenol (6) was treated with iodide (8), which was prepared from N-(3-hydroxyproyl)phthalimide (7), 18) in the presence of potassium carbonate (K 2 CO 3 ) and benzyltriethylammonium chloride (BTAC) provided ether (9) in high yields (Chart 2).…”

“…Because of these interesting activities, a number of synthetic studies on these alkaloids have been reported. [6][7][8][9][10][11][12][13][14][15][16] Moloka'iakitamide (1) 17) has been isolated from the Red Sea sponge Pseudoceratina arabica (Pseudoceratinidae) and shows significant parasympatholytic effects on isolated rabbit heart and jejunum, and weakly antifungal activity, contains one bromotyrosine unit and oxalamide moiety (Fig. 1).…”

Dynamic Combinatorial Chemistry: Ligands for Biomolecules

“…This was fi rst demonstrated with a disulfi debased DCL using the pre -equilibrated approach [65] . Based on studies of the marine natural product psammaplin A, an antibacterial agent potent against methicillin -resistant Staphylococcus aureus ( MRSA ), a very large ditopic library composed of more than 3000 constituents was designed.…”