Natural penicillins

There are four groups of penicillins natural penicillins, penicillinase-resistant penicillins, aminopeni-cillins, and the extended-spectrum penicillins. See the... 

Rx amoxicillin, ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, methicillin, mezlocillin, nafcillin, oxacillin, penicillin G benzathine, penicillin G potassium, penicillin Vpotassium, piperacillin, pivampicillin, pivme-cillinam, ticarcillin Penicillin and beta-lactamase inhibitors amoxicillin/ clavulanate potassium, ampicillin/sulbactam sodium, piperacillin sodium/ tazobactam sodium, ticarcillin disodium/clavulanate potassium Chemical Class Penicillin, natural... 

EP Abraham, GGF Newton, K Crawford, HS Burton, CW Elale. Cephalosporin N a new type of penicillin. Nature 171 343, 1953. 

EP Abraham, E Chain. An enzyme from bacteria able to destroy penicillin. Nature 146 837, 1940. 

Gottlieb NL. Comparative pharmacokinetics of parenteral and oral gold compounds. J Rheumatol 1982 9 (SuppI 8) 99-109. Blocka K. Auranofin versus injectable gold Comparison of pharmacokinetic properties. Am J Med 1983 75(6A) 114-122. Abraham EP, Chain E, Baker W, Robinson R. Penicillamine, a characteristic degradiation product of penicillin. Nature 1943 151 107. 

Doyle, F. P, Nayler, J. H., Smith, H., Stove, E. R. Some novel acid-stable penicillins. Nature 1961, 191, 1091-1092. 

Abraham EP, Chain E, Baker W, Robinson R. Penicillamine, a characteristic degradiation product of penicillin. Nature 1943 ... 

Zugaza and Hidalgo (1965) studied the infrared spectroscopy of a variety of penicillins—natural, biosynthetic, and synthetic—in the form of mulls, pellets, and... 

Under natural conditions various strains of Penicillium fungi produce either penicillin G or free 6-aminopenicillanic add ( = 6-APA). The techniques used to prepare analogues such as the ones given above have been (i) fermentation in the presence of an excess of appropriate adds which may be incorporated as side-chain (ii) chemical acylation of 6-APA with activated acid derivatives. 

Penicillins. Since the discovery of penicillin in 1928 as an antibacterial elaborated by a mold, Penicillium notatum the global search for better antibiotic-producing organism species, radiation-induced mutation, and culture-media modifications have been used to maximize production of the compound. These efforts have resulted in the discovery of a variety of natural penicillins differing in side chains from the basic molecule, 6-aminopenici11anic acid [551-16-6], These chemical variations have produced an assortment of dmgs having diverse pharmacokinetic and antibacterial characteristics (see Antibiotics, P-lactams). 

The penicillins as natural and semisynthetic agents are used primarily against susceptible Pasteurella sp., staphylococci, streptococci, clostridia, and CoTynebacterium sp. Penicillin is widely used for therapeutic purposes against these organisms and in animal feeds as a growth promoter. The latter effect is considered to be a result of subtie and reversible effects on the gastrointestinal microflora. 

In the period up to 1970 most P-lactam research was concerned with the penicillin and cephalosporin group of antibiotics (1). Since that time, however, a wide variety of new mono- and bicychc P-lactam stmctures have been described. The carbapenems, characterized by the presence of the bicychc ting systems (1, X = CH2) originated from natural sources the penem ring (1, X = S) and its derivatives are the products of the chemical synthetic approach to new antibiotics. The chemical names are 7-oxo-(R)-l-a2abicyclo[3.2.0]hept-2-ene-2-carboxyhc acid [78854-41-8] CyH NO, and 7-oxo-(R)-4-thia-l-a2abicyclo[3.2.0]hept-2-ene-2-carboxylic a.cid [69126-94-9], C H NO S, respectively. 

Historically, the development of penems is contemporary with that of the naturally occurring carbapenems and the direction of penem research has clearly been influenced by the stmctures of the closely related natural products. The origins of the two groups of compounds is, however, quite different. Unlike carbapenems, no penems have been found in nature. When first described (84,85) they were viewed as hybrid molecules combining stmctural features of penicillins and cephalosporins. 

AH cephalosporins found in nature (Tables 1 and 2) have the D-a-aminoadipic acid 7-acyl side chain (21). AH of these compounds can be classified as having rather low specific activity. A substantial amount of the early work in the cephalosporin area was unsuccessfiiHy directed toward replacing the aminoadipic acid side chain or modifying it appropriately by fermentation or enzymatic processes (6,22). A milestone ia the development of cephalosporins occurred in 1960 with the discovery of a practical chemical process to remove the side chain to afford 7-ACA (1) (1). Several related processes were subsequendy developed (22,23). The ready avaHabHity of 7-ACA opened the way to thousands of new semisynthetic cephalosporins. The cephalosporin stmcture offers more opportunities for chemical modification than does that of penicillins There are two side chains that especiaHy lend themselves to chemical manipulation the 7-acylamino and 3-acetoxymethyl substituents. 

Isolation. Isolation procedures rely primarily on solubiHty, adsorption, and ionic characteristics of the P-lactam antibiotic to separate it from the large number of other components present in the fermentation mixture. The penicillins ate monobasic catboxyHc acids which lend themselves to solvent extraction techniques (154). Pencillin V, because of its improved acid stabiHty over other penicillins, can be precipitated dkecdy from broth filtrates by addition of dilute sulfuric acid (154,156). The separation process for cephalosporin C is more complex because the amphoteric nature of cephalosporin C precludes dkect extraction into organic solvents. This antibiotic is isolated through the use of a combination of ion-exchange and precipitation procedures (157). The use of neutral, macroporous resins such as XAD-2 or XAD-4, allows for a more rapid elimination of impurities in the initial steps of the isolation (158). The isolation procedure for cephamycin C also involves a series of ion exchange treatments (103). 

Penam Sulfone B-Lactamase Inhibitors. Natural product discoveries stimulated the rational design of p-lactamase inhibitors based on the readily accessible penicillin nucleus. An early success was penicillanic acid sulfone, (2(5)-cis)-3,3-dimethyl-7-oxo-4,4-dioxide-4-thia-l-a2abicyclo [3.2.0]heptane-2-carboxylic acid [68373-14-8] (sulbactam) (25, R = = H, R" = R" = CH ), CgH NO S. The synthesis (118), microbiology (119—121),... 

All of the naturally-occurring monobactams discovered as of this writing have exhibited poor antibacterial activity. However, as in the case of the penicillins and cephalosporins, alteration of the C-3 amide side chain led to many potent new compounds (12). Furthermore, the monobactam nucleus provides a unique opportunity to study the effect of stmctural modifications at the N-1 and C-4 positions of the a2etidinone ring on biological activity. In contrast to the bicycHc P-lactams, these positions on the monocyclic ring system are readily accessible by synthesis. 

The only penicillins used in their natural form are benzylpenicillin (penicillin G) and phenoxymethylpenicillin (penicillin V). The remainder of penicillins in clinical use are derived from 6-APA and most penicillins having useful biological properties have resulted from acylation of 6-APA using standard procedures. 

As many natural and synthetic /3-lactams bear 3-acylamino substituents, the corresponding free amines or protected forms thereof are versatile synthetic intermediates. They may be prepared in several ways, for example by deacylation of the 7-amido group in naturally occurring penicillins by enzymic or chemical means. Chemical degradation usually involves conversion of the amide to a chloroimidate followed by cleavage with aqueous alcohols (75S547 p. 560, 78T1731 p. 1753). 

The early investigations of the reactions of the penicillin class of compounds were largely of a degradative nature, and were primarily associated with structure elucidation. These have been discussed in detail (B-49MI51102) and some of the principal transformations are outlined in Schemes 2, 3 and 4 using benzylpenicillin as an example. Some of these reactions will be discussed in greater detail later in this section. 

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