Semisynthetic cephalosporins

Other Reactions. The reaction of Thydioxybenzaldehyde with sodium cyanide and ammonium chloride, Strecker synthesis, yields /J-hydroxyphenylglycine [938-97-6] a key intermediate in the manufacture of semisynthetic penicillins and cephalosporins (see Antibiotics, p-LACTAMs). 

Pharmaceuticals. -Hydroxybenzaldehyde is often a convenient intermediate in the manufacture of pharmaceuticals (qv). For example, 2-(p-hydroxyphenyl)glycine can be prepared in a two-step synthesis starting with -hydroxybenzaldehyde (86). This amino acid is an important commercial intermediate in the preparation of the semisynthetic penicillin, amoxicillin (see ANTIBIOTICS, P-LACTAMs). Many cephalosporin-type antibiotics can be made by this route as well (87). The antiemetic trimethobenzamide [138-56-7] is convenientiy prepared from -hydroxybenzaldehyde (88) (see Gastrointestinal agents). 

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. 

Pharmacologically useful isoxazoles (B-82MI41600) include antibacterial sulfonamides (614), (615) and (616), semisynthetic penicillins (617), (618), (619) and (620), semisynthetic cephalosporin (621), anabolic steroid (622), the monoamine oxidase inhibitor (623) (used in psychotherapy), antiinflammatory agent (624) and antitumor agent (625). 

It is possible to convert penicillin V or benzylpenieillin to a cephalosporin by chemical ring expansion. The first-generation cephalosporin cephalexin, for example, can be made in this way. Most cephalosporins used in clinical practice, however, are semisynthetics produced from the fermentation product cephalosporin C. 

The ancestral strain of Acremonium chrysogenum (at that time called Cephalosporium acremonium) was isolated on the Sardinian coast in 1945 following an observation that the local sewage outlet into the sea cleared at a quite remarkable rate. Advances were slow because the activity was associated with a number of different types of compound. Cephalosporin C was first isolated in 1952, but it was a further decade before clinically usefiil semisynthetic cephalosporins became available. 

As streptococcal cellulitis is indistinguishable clinically from staphylococcal cellulitis, administration of a semisynthetic penicillin (nafrillin or oxacillin) or first-generation cephalosporin (cefazolin) is recommended until a definitive diagnosis, by skin or blood cultures, can be made (Table 47-4). If documented to be a mild cellulitis secondary to streptococci, oral penicillin VK, or intramuscular procaine penicillin may be administered. More severe streptococcal infections should be treated with IV antibiotics (such as ceftriaxone 50 to 100 mg/kg as a single dose). 

Scheme 6.7). Penicillin G amidase from Mcaligenes faecalis, which is used in the manufacture of semisynthetic penicillins and cephalosporins, was used in both steps to afford a one-pot cascade process [21]. The acylation was performed in an aqueous medium at pH 10-11 and, after separation of the remaining amine enantiomer, the acylated amine was hydrolyzed with the same enzyme by lowering the pH to 7. 

Chemical or enzymatic hydrolysis of this compound allows to obtain large quantities of 7-aminocephalosporanic acid. A number of semisynthetic beta-lactam cephalosporin antibiotics were created by acylating the amino group of the last with various acid derivatives (analogous to the semisynthetic penicillin series) and currently there are about 25,000 of them, of which about 100 are used in medicine. Unlike penicillins, semisynthetic cephalosporins are synthesized not only by expanding the spectrum of various acids by which 7-aminocephalosporanic acid is acylated, but also by internal modifications of aminocephalosporanic nucleus (Rj and Rj). 

The cephalosporins are semisynthetic antibiotics derived from products of various microorganisms, including Cephalosporium and Streptomyces. All cephalosporins... 

It is a semisynthetic potent cephalosporin for parenteral administration. It can be administered less frequently because of its long half life. It is used in infections of genitourinary tract, bone, joint and soft tissue infections, septicaemia, endocarditis, gonorrhoea, postoperative chest infections, biliary tract infection and surgical prophylaxis. 

It is a parenteral, semisynthetic third generation cephalosporin. It is not metabolised and approximately 90 percent of drug is excreted by the kidney in unchanged form. It is indicated in lower respiratory tract, skin and soft tissue infection, septicaemia, urinary tract infection and gonorrhoea. 

The cephalosporins are semisynthetic -lactams derived from cephalosporin C, a natural antibiotic. Their active basic nucleus consists of a six-membered dihydrothiazine ring fused to a -lactam ring (Fig. 3.3.2). Cephalosporins have some desirable quality characteristics that are generally deficient in penicillins. The popularity and usefulness of cephalosporins results from their resistance to many... 

Lactam antibiotics are natural or semisynthetic compounds whose basic nuclear structure consists of a -lactam ring coupled to a thiazolidine (five-membered) or a dihydrothiazine (six-membered) ring to form the penicillin or cephalosporin nucleus, respectively. To those nuclei, various side chains that determine most of the properties of the different -lactams are attached. All members of this group of antibiotics are readily attacked at the -lactam nitrogen by nucleophilic reagents such as hydroxyl ions, alcohols, and primary amines, as well as by secondary amines. They are also susceptible to electrophilic attack at both the... 

Closely related to penicillin is the antibiotic cephalosporin C. It contains a D-a-aminoadipoyl side chain, which can be replaced to form various semisynthetic cephalosporins. Carbapenems have similar structures but with CH2 replacing S and often a different chirality in the lactam ring. 

Semisynthetic products, b First oral cephalosporins. c First commercial cephamycin. dFirst -lactamase inhibitor combination, e First monobaclam and a synthetic product. f First carbapenem. 

Both the cephalosporins and the penicillins owe their antibacterial action to their ability to block bacterial cell-wall biosynthesis. Cephalosporin C is less active than the penicillins, but is less susceptible to enzymatic destruction by /3-lactamases, which are enzymes that cleave the lactam ring. In fact, the so-called resistance of staph bacteria to penicillins is attributed to the propagation of strains that produce /3-lactamase. Numerous semisynthetic penicillins and cephalosporins have been made in the hope of finding new broad-spectrum antibiotics with high activity but with greater /3-lactam stability. Several of these are in clinical use. 

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