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Silylation

Silylation. Grossman’s process. What is silylation ?. Silylation is the introduction of a (usually) substituted silyl group (R3Si) to a molecule. Steps . Silylating 6-aminopenicillanic acid, preferably with chlorotrimethylsilane (Highly flmmable ) (TMCS)

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Silylation

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  1. Silylation Grossman’s process

  2. What is silylation? Silylation is the introduction of a (usually) substituted silyl group (R3Si) to a molecule.

  3. Steps • Silylating 6-aminopenicillanic acid, preferably with chlorotrimethylsilane (Highly flmmable) (TMCS) • Acylating the silylated 6-aminopenicillanic acid formed in the previous step with in the presence of a weak base, preferablydimethylaniline. • Hydrolyzing and neutralizing the product of said acylation to produce amoxicillin trihydrate.

  4. Enzymatic synthesis We have already discussed the enzymatic synthesis of Amoxicillin. Parallel reactions less use of toxic solvents and waste of reagents It is a one step synthesis Equilibrium has to be shifted towards amoxicllin by decreasing its concentration in the aqueous medium by reducing its solubility – via pH or temperature

  5. B-lactamantbiotics The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by DD-transpeptidases which are penicillin-binding proteins (PBPs). PBPs vary in their affinity for binding penicillin or other β-lactam antibiotics. The amount of PBPs varies among bacterial species.

  6. β-Lactam antibiotics are analogues of d-alanyl-d-alanine This is one theory to explain the mechanism the terminal amino acid residues on the precursor NAM/NAG-peptide subunits of the nascent peptidoglycan layer. The structural similarity between β-lactam antibiotics and d-alanyl-d-alanine facilitates their binding to the active site of PBPs. T he β-lactam nucleus of the molecule irreversibly binds to the PBP active site.

  7. Potency of the B-lactams Woodward’s parameter – ‘h’ = the height of the pyramid formed by the nitrogen atom of the β-lactam as the apex and the three adjacent carbon atoms as the base Cohen’s parameter ‘c’, and is the distance between the carbon atom of the carboxylate and the oxygen atom of the β-lactam carbonyl. The best antibiotics are those with higher h values (more reactive to hydrolysis) and lower c values (better binding to PBPs).

  8. Resistance to the drug • Enzymatic hydrolysis of the β-lactam ring (by penicillinase or β-lactamase): enzyme β-lactamase or the enzyme penicillinase • Possession of altered penicillin-binding proteins: self explanatory. • The genes encoding these enzymes may be : • inherently present on the bacterial chromosome or .. • may be acquired via plasmid transfer (plasmid mediated resistance) • The β-lactamasegene expression may be induced by exposure to β-lactams, which is the main reason that resistance may develop.

  9. Augmentin The combination was invented around 1977/78 by British scientists working at Beecham (now part of GlaxoSmithKline). Clavulanate was added to amoxicillin to give the combination drug greater activity against those organisms that produce β-lactamases. The mechanisms of action of amoxicillin/clavulanate are interference with cell wall synthesis by attachment to penicillin-binding proteins (PBPs), inhibition of cell wall peptidoglycan synthesis and inactivation of inhibitors to autolytic enzymes

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