SAR of Cephalosporins

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Chapter: Medicinal Chemistry : Antibiotics

The addition of amino group and a hydrogen to α and α1 position produces basic compound, which is protonated under acidic conditions of stomach.

SAR of Cephalosporins

1. 7-Acylamino substitution

a. The addition of amino group and a hydrogen to α and α1 position produces basic compound, which is protonated under acidic conditions of stomach. The ammonium ion improves the stability of β-lactum of cephalosporins and make active orally. Activity against positive bacteria is increased and gram negative is decreased by acylation of amino group.

b. When the new acyl groups are derived from carboxylic acids, it shows good spectrum of antibacterial action for gram-positive bacteria.

c. Substitutions on the aromatic ring phenyl that increase lipophilicity provide higher gram-positive activity and generally lower gram-negative activity.

d. The phenyl ring in the side chain can be replaced with other heterocycles with improved spectrum of activity and pharmacokinetic properties; these include thiophene, tetrazole, furan, pyridine, and aminothiazoles.

e. The L-isomer of an α-amino α1 -hydrogen derivative of cephalosphorins was 30–40 fold stable than D-isomer. Addition of methoxy oxime to α and α1increases the stability to nearly 100-fold. The presence of catechol grouping can also enhance activity, particularly, against Pseudomonas aeruginosa, and also retain some gram-positive activity, which is unused for a catechol cephalosporin.

These compounds penetrate into the cell by utilizing the bacterial ion β-dependent ion transport system. There is a reduction of Gram negative activity when the lipophilicity of this side chain is increased and effects of polar α-substituents are enhanced (OH, NH2, SO3H, COOH).

2. Modification in the C-3 substitution: The pharmacokinetic and pharmacodynamics depends on C-3 substituents. Modification at C-3 position has been made to reduce the degradation (lactone of desacetyl cephalosporin) of cephalosporins.

a.            The benzoyl ester displayers improved gram-positive activity, but lowered gram-negative activity.

b.           Pyridine, imidaozle replaced acetoxy group by azide ion yields derivative with relatively low gramnegative activity.

c.            Displacement with aromatic thiols of 3-acetoxy group results in an enhancement of activity against gram-negative bacteria with improved pharmacokinetic properties.

d.           Orally active compounds are produced by replacement of acetoxy group at C-3 position with CH3 and Cl.

3. Other modifications

a.            Methoxy group at C-7, shows higher resistance to hydrolysis by β-lactamase.

b.           Oxidation of ring spectrum to sulphoxide or sulphone greatly diminishes or destroys the antibacterial activity.

c.            Replacement of sulphur with oxygen leads to oxacepam (latamoxet) with increased antibacterial activity, because of its enhanced acylating power. Similarly, replacement of sulphur with methylene group (loracavet) has greater chemical stability and a longer half-life.

d.           The carboxyl group position-4 has been converted into ester prodrugs to increase bioavailability of cephalosporins, and these can be given orally as well.

e.            The antibacterial activity depends on the olefinic linkage at C-3 and C-4 position and their activity is lost due to the ionization of double bond to 2nd and 3rd positions.

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