Structure-activity relationships cephalosporins

Dunn GL. Ceftizoxime and other third-generation cephalosporins Structure activity relationships. J Antimicrob Chemother... 

Snyder NJ, Tabas LB, Berry DM, Duckworth DC, Spry DO and Dantzig AH. Structure-activity relationship of carbacephalosporins and cephalosporins antibacterial activity and interaction with the intestinal proton-dependent dipeptide transport carrier of Caco-2 cells. Antimicrob Agents Chemother 1997 41 1649-57. 

Structure-activity correlations in the P-lactam antibiotic field have required drastic re-evaluation in view of the novel structures described above. Apparently, only the intact P-lactam ring is an absolute requirement for activity. The sulfur atom can be replaced (moxalactam) or omitted (thienamycin), and the entire ring itself is, in fact, unnecessary (nocardicin). The carboxyl group, previously deemed essential, can be replaced by a tetrazolyl ring (as a bioisostere), which results in increased activity and lactamase resistance. The amide side chain, so widely varied in the past, is also unnecessary, as shown in the example of thienamycin. There is a considerable literature analyzing the classical structure-activity relationships of the penicillin and cephalosporin groups. 

Structure-activity relationships can be inferred by comparison of the antibacterial properties of the clinical agents and related compounds. Different acyl side chains can result In significant changes in the antibacterial activity, both with respect to potency and to breadth of spectrum. The highest activities are observed when the aeylaniino side chain at C-7 is a substituted acetic add. Homologation of the acetic add moiety lowers activity dramatically as exemplified by1 the naturally occurring cephalosporins, which all have weak activity. 

Although the literature of the penicillins and cephalosporins has been reviewed from time to time, these derivatives, together with their pharmacological properties, have never been discussed in detail and many of them have appeared only in the patent literature. On the other hand, this field is of more than academic interest, since these data could afford a useful basis for structure-activity relationships of help in the design and further investigation of /3-lactam antibiotics. Comparison of different structural, activity and other data enables us to probe into the question of their mode of action more effectively. 

Tune BM.The nephrotoxicity of cephalosporin antibiotics-structure-activity relationships. Comm Toxicol 1986 1 (2) 145-170. Goldstein RS, Smith PFTarloff, JB, Contardi L, Rush GF, HookJB. Biochemical mechanisms of cephaloridine nephrotoxicity. Life Sell 988 42(19) 1809-1916. 

CGP 9000 (9), a 3-methoxycephem derivative, is somewhat more active than cephalexin in vitro and is efficiently absorbed orally in mice.80 The structure-activity relationship of a series of orally active cephalosporins... 

Many analogues of cephalosporin C have been made and the structure-activity relationship (SAR) conclusions are as follows. 

The P-lactam antibiotics continued to be the cynosure of synthesis. Some structure-activity relationships of peni-cillins O and cephalosporins 2 v/ere discussed. Timely reports aimed primarily toward the evaluation of the newer highly serum-bound penicillins dealt with the controversial relationship of drug-serum protein binding to clinical antimicrobial effectiveness. 3,14... 

Clavulanic acid has only weak antibacterial activity, but is a potent irreversible inhibitor for many clinically important p-lactamases (10—14,57,58) including penases, and Richmond-Sykes types II, III, IV, V, VI (Bacteroides). Type I Cephases are poorly inhibited. Clavulanic acid synergizes the activity of many penicillins and cephalosporins against resistant strains. The chemistry (59—63), microbiology (64,65), structure activity relationships (10,13,60—62,66), biosynthesis (67—69), and mechanism of action (6,26,27,67) have been reviewed. 

These successes did not go unnoticed by industry. Several pharmaceutical companies (1963-1964) became interested in applications of it-electron theory to biochemistry. While it was admittedly premature, it was felt that quantum chemistry was both the wave of the future and the very matrix for rational drug design. Hiickel energies of cephalosporins could be correlated with their biological activities.While companies were applying some mathematical methods of correlation techniques in quantitative structure-activity relationships (QSAR), it was chiefly the Hiickel theory and various forms of semiempirical quantum mechanics that was using a large share of computer time on the IBM 7094 mainframe in 1966. 

Jung, F. Boucherot, D. Delvare, C. Olivier, A. Synthesis and structure-activity relationships of new cephalosporins with aminoimidazoles at C-7. Effect of the pKa of the C-7 aminoimidazole on antibacterial spectmm and 3-lactamase stability. J. Antibiot. 1993, 46, 992-1012. 

Structure-activity relationships for a group of semi-synthetic phenyl-glycine derivatives of 7-aminodesacetoxycephalosporanic acids, including cephalexin, have been compared with those of the corresponding cephalosporins. ... 

Antimicrobial Agents Chemother, 41, 1649 (1997). Structure-Activity Relationship of Carbacephalosporins and Cephalosporins Antibacterial Activity and Interaction with the Intestinal Proton-Dependent Dipeptide Transport Carrier of Caco-2 Cells. 

V. Structure-Activity Relationships of 6-Substituted Peniciliins and 7-Substituted Cephalosporins... 

In 1973, Koppel and his colleagues prepared a series of 7a-methoxy-cephalosporins to obtain some idea of structure-activity relationships within the series. The results (Table IX) show a wide variation in activity with modification of the 7 3-side-chain amide, as well as with changes in the group at C-3. In all cases, large differences are seen with the (3-lactamase-producing Serratia marcescens strain against which the non-methoxylated compounds are relatively inactive. 

Reviews of structure-activity relationships among penicillins (Price, 1977a,b) and cephalosporins (Sassiver and Lewis, 1977 Webber and Ott, 1977) have covered both the earlier as well as some of the more recent developments in the field. This chapter will concentrate on the most recent advances, with some comments on the earlier work for perspective. 

A most interesting scientific discovery in the investigation of structure-activity relationships in cephalosporins was the extremely good in vitro activity found with derivatives bearing the aminothiazolemethoxime side chain (20). First revealed in 1977 by French workers (Bucourt et... 

Yamamoto H, Eikyu Y, Okuda S, Kawabaa K et al (2002) Orally active cephalosporins. Part 4 synthesis, structure-activity relationships andoralabsorptionofnovel3-(4-pyrazolylmethylthio) cephalosporins with various C-7 side chains. Biooig Med Chem 10 1535-1545... 

SEMISYNTHETIC CEPHALOSPORINS. III. SYNTHESIS AND STRUCTURE ACTIVITY RELATIONSHIPS OF NOVEL ORALLY ACTIVE 7-[4-HYDROXY-3-(SUBSTITUTED METHYL)PHENYL]-ACETAMIDO-3-CEPHEM-4-CARBOXYLIC ACIDS... 

A major monograph covering many of the aspects of the biology and chemistry of cephalosporins and penicillins up to 1972 has appeared. The chemical interconversion of the 3-lactam antibiotics has been the subject of one review while a second covers the general synthetic methods for 3-lactams, inclucUng cephalosporins and penicillins. Earlier reviews on the mechanism by which 3-lactams effect their antibacterial activity and the structure-activity relationships of penicillins and cephalosporins" should be noted. 

---