| The carbapenem class of {dollar}beta{dollar}-lactam antibiotics is one of the most promising classes of antimicrobial agents because of its exceptionally high efficacy against a wide range of bacteria. In search of a new carbapenem derivative with an improved profile, studies were conducted towards the syntheses of the 1-substituted carbapenem derivatives (I). Two approaches were employed for the most crucial step in the carbapenem synthesis, the construction of the carbapenem nucleus. One was by the carbene insertion reaction to form a C{dollar}sb3{dollar}-N{dollar}sb4{dollar} connection and another was by a Wittig-type reaction to form a C{dollar}sb2{dollar}-C{dollar}sb3{dollar} connection. Attempts were made to introduce several heterocyclic groups into the 1-position of the carbapenem nucleus, however, no carbapenem derivative with a 1-heterocyclic substituent was successfully synthesized. During these studies, 1-unsubstituted, 1-{dollar}alpha{dollar}-phenyl and 1-{dollar}alpha{dollar}-methyl carbapenem derivatives (I, R=H, {dollar}alpha{dollar}-Ph, {dollar}alpha{dollar}-Me, R{dollar}spprime{dollar}=SPh) were synthesized and their antimicrobial activity was tested. The 1-{dollar}alpha{dollar}-methyl derivative was found to be less active than the unsubstituted derivative and the 1-{dollar}alpha{dollar}-phenyl substituted derivative was found to be even less active than the 1-{dollar}alpha{dollar}-methyl derivative.(UNFORMATTED TABLE OR EQUATION FOLLOWS){dollar}{dollar}vbox{lcub}vskip54pt{rcub}{dollar}{dollar}(TABLE/EQUATION ENDS) As a second part of the research project, penicillin and cephalosporin derivatives with an extra carboxyl group at the C{dollar}sb6{dollar}/C{dollar}sb7{dollar} side chain were synthesized as possible cephalosporinase inhibitors and their biological activity was assessed. In general, the malonamates (n = l) were found to be the strongest inhibitors of the cephalosporinase, the oxamates (n = 0) to be the next strongest and the succinamates (n = 2) to be the weakest inhibitors in both cephalosporin (II) and penicillin derivatives (III). The penicillin derivatives showed stronger inhibition than the corresponding cephalosporin derivatives. Introduction of a dithiolanylidyl group at the methylene position of the penicillin malonamate (IV) resulted in a dramatic increase in cephalosporinase inhibitory activity. Penicillin sulfones (III and IV, m = 2) showed a diminished inhibition compared to the corresponding penams (III and IV, m = 0). All the penicillin and cephalosporin derivatives showed very weak, if any, inhibitory activity against Bacillus cereus penicillinase and TEM2 enzyme. 6-C-Substituted penicillins (V) were also synthesized. Selected compounds were tested against {dollar}beta{dollar}-lactamase-producing intact microbes in combination with ampicillin or cephalothin for the evaluation of their synergism. Synergism was observed for some combinations.(UNFORMATTED TABLE OR EQUATION FOLLOWS){dollar}{dollar}vbox{lcub}vskip108pt{rcub}{dollar}{dollar}(TABLE/EQUATION ENDS)... |
