S-Aminosulfeniminopenicillins:  Multimode β-Lactamase Inhibitors and Template Structures for Penicillin-Based β-Lactamase Substrates as Prodrugs

A series of novel penicillins, bearing an S- aminosulfenimine (R‘(R‘ ‘)NSN ) side chain at the 6-position, have been prepared by direct reaction of a penicillin ester with sulfur diimides. A set of these structures, with the thiazolidine-ring sulfur in the sulfide oxidation state, exhibited a pattern of reactivity not previously encountered in penicillin chemistry, viz., cleavage of the β-lactam ring resulted in a rapid intramolecular displacement of the S- amino moiety as R‘(R‘ ‘)NH. This was found to be the exclusive reaction occurring consequent on cleavage of the β-lactam ring. The mechanism of this process was delineated in a detailed study in basic methanol. That a similar reactivity pattern held for a penicillin salt in aqueous solution was also verified. Thus the salt 5bm (R‘ = CH 3, R‘ ‘ = p- CH 3 C 6 H 4 SO 2 ) behaved as a moderate substrate for β-lactamase type I from Bacillus cereus ( k cat / K m = 6.26 × 10 5 M - 1 min - 1 ). On enzyme-catalyzed hydrolysis of this compound, displacement of N- methyl- p -toluenesulfonamide (R‘(R‘ ‘)NH) was directly observed ( 1 H NMR) and found to occur faster than displacement of this group from (intact) 5bm in aqueous buffer, by a factor of at least 600. These findings identified the potential of the S- aminosulfeniminopenicillin structure type to be developed as β-lactamase substrates for use as site-specific-release prodrugs. A degree of enzyme inhibition was also observed with this set of thiazolidine-ring-sulfide structures with the most potent inhibitor having the most nucleofugic S- amino moiety p -ClC 6 H 4 SO 2 N(CH 3 ), indicating that displacement of this group, at the enzyme active site, played a role in their mode of inhibition. Structures with the thiazolidine-ring sulfur in the sulfone oxidation state were considerably more potent as inhibitors, with the structure 5a 2 being the most active. As this compound bore the least nucleofugic S- amino moiety C 2 H 5 OC(O)NH, it indicated that the mode of inhibition of the sulfones was distinct from that of the thiazolidine-ring sulfides; it is probable that the sulfones reacted in a manner similar to that shown by sulbactam viz., rapid scission of the thiazolidine-sulfone ring after cleavage of the β-lactam ring. Synergy of action was observed with 5a 2 at high concentration (78 μg/mL) against Escherichia coli when combined 1:1 with penicillin G; no synergy was observed at low concentration (4 μg/mL) when combined with pipericillin, indicating poor permeation characteristics.