β-Lactams: variations on a chemical theme, with some surprising biological results

Until the middle of the 1970s virtually all the significant developments in β-lactam antibiotics had been achieved by adding different side chains to the classical penam and cephem nuclei.1 Notwithstanding the fact that, in earlier decades, manipulation of the penicillin nucleus had failed to produce any novel drugs of interest,2 the second half of the 1970s saw huge progress in useful alterations to the basic penam and cephem ring structures. Penems (Ia) were synthesized,3 naturally occurring carbapenems (Ib, e.g. olivanic acids), oxapenams and monocyclic β-lactams (nocardicins and monobactams) were discovered,4,5,6,7 and penam sulphones (II) were found to be inhibitors of some β-lactamases.8 The cephalosporin nucleus was modified to produce microbiologically active oxacephems9 (IIIa) and carbacephems (IIIb).10 Not all changes were advantageous: for example, oxocephems (IV),11 cephams (V)12 and cephems with the double bond in the 2,3 instead of the 3,4 position13,14 had little or no activity. Many of the active structures mentioned above, as such or after suitable modification, have found their way into clinical practice, for example, imipenem, clavulanate, aztreonam, sulbactam, latamoxef and loracarbef. Many other related compounds have been intensively studied but have either been abandoned as clinical candidates or have not yet been fully developed. Iso-oxacephems (VIa), also reported12 during the ‘fertile’ period mentioned above, have been reinvestigated recently as possible oral15 or parenteral16 antibiotics. Other similar compounds, synthesized later, also show good antibacterial activity, e.g. isocephems (VIb),17 iso-azacephems18 (VIc) and isopenams (VII).17 penems are still under development as potential therapeutic agents.19