851-07-0Relevant academic research and scientific papers
S-aminosulfeniminopenicillins: Multimode β-lactamase inhibitors and template structures for penicillin-based β-lactamase substrates as prodrugs
Smyth, Timothy P.,O'Donnell, Michael E.,O'Connor, Michael J.,St Ledger, James O.
, p. 7600 - 7618 (2007/10/03)
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' = CH3, R'' = p-CH3C6H4SO2) behaved as a moderate substrate for β- lactamase type I from Bacillus cereus (k(cat)/K(m) = 6.26 x 105 M-1 min- 1). On enzyme-catalyzed hydrolysis of this compound, displacement of N- methyl-p-toluenesulfonamide (R'(R'')NH) was directly observed (1H 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-ClC6H4SO2N(CH3), 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 5a2 being the most active. As this compound bore the least nucleofugic S-amino moiety C2H5OC(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 5a2 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.
