Cefodizime, an aminothiazolylcephalosporin. V. Synthesis and structure-activity relationships in the cefodizime series.

Abstract

The synthesis as well as in vitro antibacterial activity and pharmacokinetic behavior of cefodizime (HR 221, la), its analogs and derivatives is described. In this comparison, cefodizime stands out for its balance between its high antibacterial activity, prolonged elimination half-life and high AUCin mice and dogs.In recent years, a number of /3-lactamase stable, highly active broad-spectrum cephalosporins have been developed and introduced into therapy. The first representative of this group was cefotaxime (CTX)1]) , which possesses an aminothiazolyl side chain with a sy/z-methoximino group in the 7-position. This specific side chain, which is responsible for the outstanding microbiological properties of CTX2>3) , was subsequently combined with other cephalosporin parent compounds to also yield highly active cephalosporins such as cefmenoxime4), ceftizoxime5) or ceftriaxone6). The 3'-substituent of these do not substantially alter the antibacterial spectrum compared to that of cefotaxime but affect mainly the pharmacokinetics, /3-lactamase stability and metabolism. Cefodizime (HR 221)7), a derivative of CTXsynthesized in the laboratories of Hoechst AG, contains a mercaptothiazolyl side chain in 3'-position with an additional acid group. As has been demonstrated in our and other laboratories this specific 3'-substituent renders both high antibacterial activity7'8) and prolonged half-life in laboratory animals9) to HR221. As has been found recently10), HR221 markedly stimulates the immune-system of laboratory animals.In this context we were especially interested in howvariations in the 7-side-chain and in the substitution of the mercaptothiazolyl moiety would affect the antibacterial and pharmacokinetic properties.In this paper we wish to describe the synthesis of HR221 derivatives and closely related aminothiazolylcephalosporins.Their microbiological and pharmacokinetic properties will be discussed. ChemistryCompounds la, 2a~2k and 3a~3i were prepared from cefotaxime (CTX) by 3'-acetate displacement with the appropriate 2-mercaptothiazoles in aqueous solution of pH 6.5~7.0 (Scheme 1). In general, the cephalosporanic acids were isolated directly from the reaction mixture by acidification and proved to be sufficiently pure for biological testing.Dedicated to Prof. L. Horner on the occasion of his 75th birthday.

Peptide Targeting of an Antibiotic Prodrug toward Phagosome-Entrapped Mycobacteria

“…EtOAc was rotoevaporated to dryness, resuspended in minimal MeOH, and precipitated in cold ether. Boc-Gly-cephalosporanic acid (18.5 μmol) was reacted with 3-mercaptoproprionic acid (100 μmol, Sigma-Aldrich) to displace the 3′-acetate according to a previously reported method . The reaction was carried out at 60 °C overnight in 500 μL of H 2 O with the addition of a 1 M solution of NaHCO 3 dropwise until a pH of 5 to 6 was achieved.…”

“…Boc-Gly-cephalosporanic acid (18.5 μmol) was reacted with 3-mercaptoproprionic acid (100 μmol, Sigma-Aldrich) to displace the 3′-acetate according to a previously reported method. 24 The reaction was carried out at 60 °C overnight in 500 μL of H 2 O with the addition of a 1 M solution of NaHCO 3 dropwise until a pH of 5 to 6 was achieved. A lower pH was used in this protocol to prevent ring opening of the cephalospoin.…”

Neuere Entwicklungen auf dem Gebiet der β-Lactam-Antibiotica

“…Der folgende irreversible Acylierungsschritt ist von der Natur der Substituenten am P-Lactam abhangig, die durch zusatzliche Bindungsstellen am Enzym stark induzierend wirken konnen. Kiirzlich gelang es, die dreidimensionale Struktur einer D-D-Carboxypeptidase/Transpeptidase aus Streptococcus R. 61 H,N-CH(CH,),--CH,-0-COCH,…”

Synthesis of cefepime‐d3 and cefepime‐d8

“…W Amax (EtOH) nm ( E ) 258 (24300). IH NMR (CDClg,6 in ppm), the N-Me-pyrrolidine moiety 3.55 (4H, m y NCHz), 2.15 (4H, m, CHZCH~), no N-CH3 signal.…”