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

• Published in: Journal of organic chemistry Vol. 63; no. 22; pp. 7600 - 7618
• Main Authors: Smyth, Timothy P, O'Donnell, Michael E, O'Conno, Michael J, St Ledger, James O
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 30.10.1998; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; INACTIVATION; EVOLUTION; HETEROCYCLES; ENZYME MECHANISM; ESCHERICHIA-COLI; REACTIVITY; HYDROLYSIS; PORIN CHANNELS; DUAL-ACTION CEPHALOSPORINS; DERIVATIVES
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo970737f

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 × 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 5a 2 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 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.