Heteroatom-activated beta-lactam antibiotics: considerations of differences in the biological activity of [[3(S)-(acylamino)-2-oxo-1-azetidinyl]oxy]acetic acids (oxamazins) and the corresponding sulfur analogues (thiamazins).
The considerable antibacterial activity of [[3(S)-(acylamino)-2-oxo-1-azetidinyl]oxy]acetic acids (oxamazins) in contrast to the lack of activity of the corresponding sulfur analogues (thiamazins) is examined in terms of physicochemical parameters, including electronegativity, IR carbonyl stretching frequencies, base hydrolysis rates, and three-dimensional molecular geometries. An X-ray structure determination of a protected thiamazin together with molecular graphics and molecular orbital calculations on model structures reveals that thiamazins would not fit as well as oxamazins in the active site of target bacterial transpeptidases. As a result of thiamazins' long N-S and S-C bond lengths, the pharmacophoric beta-lactam ring and carboxylate functionality cannot adopt the spatial relationship they have in penicillins and cephalosporins. The beta-lactam nitrogen of the monocyclic, crystalline thiamazin is 0.18 A out of the plane of its three substituents, and this distance (h) is predicted by computational chemistry methods to be higher in oxamazins. The rates of beta-lactam ring opening of an oxamazin, thiamazin, and aztreonam are comparable, even though the pyramidal character and IR data both indicate the electronegative oxygen analogue has reduced amide resonance. MNDO, AM1, and MINDO/3 correctly give a twofold potential for rotation about the N-S bond in model sulfenamides, with barrier heights ranging up to 12 kcal/mol.
D000085:Acetates / Q000138:chemical synthesis; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis*; D001384:Azetidines / Q000138:chemical synthesis*; D001385:Azetines / Q000138:chemical synthesis*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D047090:beta-Lactams
D000085:Acetates; D000900:Anti-Bacterial Agents; D001384:Azetidines; D001385:Azetines; D007202:Indicators and Reagents; D047090:beta-Lactams