Now, we may be getting a little ahead of ourselves
since we will be talking about beta-lactam
antibiotics in the final slide for this module.
However, it is important in the context of
prodrugs and the context of the pharmacokinetic
pathway. Here we have benzylpenicillin. This
is a characteristic beta-lactam with a thiazolidine
ring attached to it, characteristic of all
penicillins. And the crucial part of this
molecule, without which there is no antibiotic
activity whatsoever is the beta-lactam ring.
The beta-lactam ring is the cyclic amide following
the square shape within that structure.
One of the reasons why bioavailability is
an issue with the early penicillins, such
as benzylpenicillin, is that it was prone
to acid catalysed, intra molecular hydrolysis
facilitated by the tautomerism of that
amide group so that you get the aminium ion
shown there with the O- in the 6 position
of the penicillin structure. This is highly
What it then does, as we appreciate, is that
nucleophilic attack on the strained beta-lactam
ring, shown by the green arrows, which carries
out an addition elimination reaction which
you should remember from Module III, when
we talked about carboxylic acid derivatives.
And what this does is it forms an intermediate,
which then opens up that beta-lactam ring,
interestingly converting it from a strained
amide to an ester.
Now, I know that flies in the face of that
which we discussed before when we were talking
about amides being hydrolysed and converted
into esters, but the reality here is that
that four membered ring is highly strained.
It wants to break open and via acid hydrolysis,
which, in this case, takes place in the stomach
which has a low pH. What effectively happens
is that most of the benzylpenicillin that
would be taken orally is broken down before
it even has a chance to be absorbed through
the gastrointestinal tract. The absence of
the beta-lactam ring doesn’t just actually
reduce the activity, it destroys it. There
is no antibiotic activity associated with
the final compound in the bottom left hand
So, the solution. As we’ll see a little
later on, but I’ll briefly lead to you here,
incorporating an R group within the 6 position
on that amide which is electron-withdrawing.
So, for example, a phenoxymethyl group, such
as first made in the case of penicillin V,
pulls the electron density away from that
amide carbonyl. By pulling the density away
from that carbonyl, it reduces its nucleophilicity
and therefore, it does not attack the amide.
And penicillin V is far more stable to acids
than benzyl penicillin and was one of the
first penicillins to be already bioavailable
and therefore, to be given as an oral dose.
Okay. Now, I’d like to talk to you about
another element of drug distribution, which
is trying to get a molecule into the brain.
Now, the brain or around the brain, you have
the Blood Brain Barrier or BBB, for short,
which is a layer of tightly packed endothelial
cells that only allow small molecules in,
less than 500 daltons, or to put it in another
way, molecules which have a molecular weight
of less than 500 grams per mole. And they
have to be lipophilic in order to cross by
As you can see, the difference between a general
capillary, where you have an intercellular
cleft passage and you have passive diffusion,
is that you have a tight junction in a brain
capillary with these astrocyctic processes
surrounding it. This means that it must be
small and highly lipophilic to pass through
the brain or else be taken up via active transport.