CEPHALOSPORIN 3'-PHLOROGLUCIDE ESTERS AND 7-(PHLOROGLUCIDAMIDO)CEPHALOSPORINS AS NOVEL ANTIBACTERIAL AGENTS

Two series of new phloroglucide derivatives were synthesized that poss essed antibacterial activities. The first series includes cephalospori n 3'-phloroglucide esters 19 and 20, which were obtained by condensati on of cephalosporin 16 with bioactive phloroglucides 14 and 15, respec tively. They exhibited a dual mode of antibacterial action. In compari son with cephalosporins 26 and 27, bearing an acetoxy unit at the C-3' position, the bifunctional cephalosporins 19 and 20 showed a broadene d spectrum of activity. Results from the consistent valence force fiel d (CVFF) calculations indicate that the most stable conformational iso mer of phenolic acid 14, holding a cis-syn-syn geometry, possessed a c avity. It provides an ideal environment to accommodate metal ions of h oloenzymes. Phenolic keto acid 15, however, possessed a trans-anti-syn conformation, which allowed chelation between metal ions and the phen olic hydroxyl groups as well as the carbonyl functionalities. Our biol ogical results show that the cavity formed in phloroglucides plays an important role. The second series includes 7-(phloroglucidamido)cephal osporins 24 and 25, which were synthesized by condensation of cephalos porin 21 with 14 and 15, respectively. Results from the CVFF calculati ons indicate that cephalosporin 24 also possessed a cavity. Unlike cep halosporin 3'-phloroglucide esters 19 and 20, cephalosporins 24 and 25 were found resistant to beta-lactamases from Staphylococcus aureus 95 and Pseudomonas aeruginosa 18S-H. These new compounds, however, showe d notable activities against S. aureus FDA 209P, S. aureus 95, Candida albicans, P. aeruginosa 1101-75, and P. aeruginosa 18S-H.