CEPHALOSPORIN : ANTIBIOTIC

Cephalosporins

• Derived from a fungus Acremonium which word is previously known as Cephalosporium
• Discovered in 1945 by Brotzu
• He observed that the culture produced substances which were effective against Salmonella typhi (an agent causing typhoid)

General Information:

    General Structure:         

    SAR Of Cephalosporins:

    1.  7-Acylamino substituents:

-    Acylation of the amino group generally increases potency against gram positive bacteria, but decrease in gram-negative potency.

-    High antibacterial activity is observed only when the new acyl groups are derived from carboxylic acids for gram-positive bacteria.

-   Substituents on the aromatic ring that increases lipophilicity provide higher gram-positive activity and generally lower gram-negative activity.

-   Phenyl ring in the side-chain can be replaced with other heterocycles with an improved spectrum of activity and pharmacokinetic properties and these include thiophene, tetrazole, furan, pyridine, and aminothiazoles

     2.  C-3 Substituents:

- The nature of C-3 substituents influences pharmacokinetic and pharmacological properties as well as antibacterial activity.

-  Modification at C-3 position has been made to reduce the degradation   (lactone of diacetyl cephalosporin) of cephalosporins.

-   Pyridine and imidazole replaced -ACo (Acetoxy) group show improved activity against aeruginosa.

-   Displacement of -ACo group by azide ion yields derivatives with relatively low gram-negative activity.

-   Displacement with aromatic thiols of -ACo group results in an enhancement of activity against gram-negative bacteria with improved pharmacokinetic properties.

-  Replacement of -ACo group at C-3 position with -CH3, -Cl has resulted in orally-active compounds.

     3.  1st Position (S-Position):

-  Oxidation of ring sulphur to sulfoxide or sulfone greatly diminishes or destroys the antibacterial activity.

-  Replacement of sulphur(S) with oxygen(O) leads to Oxazepam (Latamoxef) with increased antibacterial activity, because of its enhanced acylating power & replacement of sulphur(S) with -CH3 group (Loracarbef) has greater chemical stability and a longer half-life.

    4.  C-4 Position:

-   Carboxyl group of 4^th the position has been converted into ester prodrugs to increase bioavailability, and these can be given orally as well (Cefuroxime Axetil and Cefpodoxime Proxetil).

    5.  C-7 Position:

-   Introduction of α-methoxy group (-OCH3), shows higher resistance

to hydrolysis by β- Lactamase enzyme (Cephamycin).

     6.  Olefinic/Alkene Linkage:

 - Compounds that contain only hydrogen and carbon and at least one double or triple bond is known as Olefinic Linkage.

-  This linkage between C3 & C4 is essential for antibacterial activity.

-  Isomerization or transfer of olefinic bond from C3=C4 to C3=C2 leads to great loss in antibacterial activity.

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