- S-aminosulfeniminopenicillins: Multimode β-lactamase inhibitors and template structures for penicillin-based β-lactamase substrates as prodrugs
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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.
- Smyth, Timothy P.,O'Donnell, Michael E.,O'Connor, Michael J.,St Ledger, James O.
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p. 7600 - 7618
(2007/10/03)
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- Preparation and characterization of methyl 11-amino-(N-P-toluenesulfonyl)-9-E-octadecenoate and methyl 8-amino-(N-P-toluenesulfonyl)-9-E-octadecenoate
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Allylic amination of methyl oleate with bis(N-p- toluenesulfonyl) sulfodiimide results in a mixture of methyl 11- amino-(N-p-toluenesulfonyl)-9-E-octadecenoate and methyl 8- amino-(N-p-toluerfesulfonyl)-9-E-octadecenoate in 58% yield. These novel products were isolated and characterized by nuclear magnetic resonance, infrared spectroscopy, mass spectrometry, and melting point. The reaction was analyzed by high- performance liquid chromatography and thin-layer chromatography.
- Herron, Barry F.,Bagby, Marvin O.,Isbell, Terry A.,Byrdwell, Wm Craig,Plattner, Ron,Weisleder, David
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p. 229 - 234
(2007/10/03)
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- DERIVATIVES OF SULFOXYLIC DIAMIDE
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N,N'-Disubstituted sulfur diimides are reduced by the action of thiophenols to N,N'-disubstituted sulfoxylic diamides R1NHSNHR2.Compounds where R1 = R2 = SO2Ar, COPh enter readily into reaction both with retention and with cleavage of the S-N bond.In reaction with secondary amines and CH acids they are "carriers of sulfur." 2,5-Diaroyl-1,2,5-thiadiazolidine-3,4-diones are formed by the successive action of trimethylchlorosilane and oxalyl chloride on the compounds where R1 = R2 = COPh, COC6H4Cl-p.
- Pel'kis, N. P.,Levchenko, E. S.
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p. 1963 - 1967
(2007/10/02)
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- Stereocontrolled Synthesis of Unsaturated Vicinal Diamines from Diels-Alder Adducts of Sulfur Dioxide Bis(imides)
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As an extension of methodology previously developed for the synthesis of vicinal amino alcohols, stereocontrolled synthesis of unsaturated vicinal diamines from Diels-Alder adducts of sulfur dioxide bis(imides) (1a, 1b) and various 1,3-dienes was investig
- Natsugari, Hideaki,Whittle, Robert R.,Weinreb, Steven M.
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p. 7867 - 7872
(2007/10/02)
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- The Chemistry of Sulfur Diimides, 8. - Ene Reactions with Sulfur Diimides - Structure of the Ene Components and Reactivity in the Reaction with Ditosyl Sulfur Diimide
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N,N'-Ditosyl sulfur diimide (1) is an exceptionally reactive enophilic compound.Its reactions with many allylic derivatives give sulfinamidines 3 or - by sigmatropic rearrangements of 3 - diamino sulfane derivatives 4, respectively, in good yields.Conclus
- Bussas, Reinhard,Kresze, Guenter
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p. 629 - 649
(2007/10/02)
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