Structure-activity relationships penicillins

Sobotka P, Safauda J. The epUeptogeuic actiou of penicillins structure-activity relationship. J Mol Med 1976 1 151. 

As can be seen from Table 3, only modifications at the 6/3-amino groups have been successful in producing penicillins of medical significance up to this time. Several reviews have dealt with the structure-activity relationship in this area in considerable detail B-80MI51102, B-77MI51106, B-75MI51102) and should be consulted for the actual effects of structural modification on antibacterial activity. 

Bartlett A, Dearden JC, Sibley PR. Quantitative structure-activity relationships in the prediction of penicillin immunotoxicity. Quant Struct-Act Relat 1995 14 258-63. 

The rate of acid-catalyzed degradation of the penicillins also depends largely on the nature of their acylamido side chain. Structure-activity-relationship studies undertaken for the rational design of orally active penicillins have shown that the stability in gastric juice increases with the sum of Taft s inductive substituent constants (of values) of the 6-amino side chain [95]. 

This process starts with the synthesis of novel chemical compounds. Substances with complex structures may be obtained from various sources, e.g., plants (cardiac glycosides), animal tissues (heparin), microbial cultures (penicillin G), or human cells (urokinase), or by means of gene technology (human insu-Un). As more insight is gained into structure-activity relationships, the search for new agents becomes more clearly focused. 

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. Biological evaluation of penicillins yields information such as in vitro and in vivo antibacterial activities, minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), protective effectiveness in laboratory animals (PD50), and pharmacokinetic characteristics including efficiency of absorption, serum levels, tissue distribution, urinary excretion, recycling, etc. Penicillins are also tested for ability to resist inactivation by (S-lactamase produced by both gram-positive and gram-negative bacteria,... 

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. 

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. 

Topics covered in this b3ok include the partial and total synthesis, biosynthesis, and structure-activity relationships of the principle classes of /3-lactam antibiotics, including penicillins, cepfialosporins, clavulanic acids and olivanic acids, and their interactions with bacteria. 

A range of penicillins have been examined as competitive reversible inhibitors of enkephalinase [119,120]. Carfecillin K = 0.18 M) was the most potent inhibitor in the series, whereas cloxacillin (Aj = 27.5 //M), ampicillin (A = 41 //M), nafcillin (A = 59 //M) and carbenicillin (Aj =158 juM) had moderate potency and benzylpenicillin (A = 885 jUM), mezlocillin (Aj = 437 juM) and azlocillin (Kj = 556 //M) were weak inhibitors. Structure-activity relationships within the series have been rationalized... 

V. Structure-Activity Relationships of 6-Substituted Penicillins and 7-Substi-... 

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 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. 

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