Organic Chemistry | Question Paper

Background for Questions 3 and 4
Ritonavir is a potent CYP3A4 inhibitor used in anti-HIV therapy. It is co-
administered with anti-HIV drugs to enhance their pharmacokinetics as these drugs
would otherwise be rapidly metabolised by CYP3A4. It has been proposed that
ritonavir acts in this role by binding to the haem iron, blocking the enzyme active site
and hence preventing access to the active site for other substrate molecules.
A group of researchers has proposed a so-called ‘pharmacophore’ model for the
inhibitor/enzyme interaction for CYP3A4. This is a model of the molecular (steric
and electronic) features present in an inhibitor that are necessary for optimal
interaction with a biological target such as a protein, to trigger (or block) its
biological response, and was based on structure/inhibition studies of ritonavir and a
number of its derivatives.
Compounds with the greatest inhibitory effects have been found to have the
following structural attributes:
● the presence of a strong haem-ligating nitrogen donor that binds to the haem Fe
atom,
● a flexible backbone to enable a good fit into the CYP3A4 active site,

● hydrophobic side groups that can interact with hydrophobic pockets in the active
site, including through the use of π-interactions,
● a hydrogen acceptor/donor capable of hydrogen bonding interactions with
protein residues near the active site.
The researchers synthesised a series of ritonavir-like compounds to evaluate this
model. The general structure of the compounds is shown below.
In this study, the researchers made a series of modifications to the groups at the R1
and R2 positions. Four of these structures from this range of compounds are shown
below. The researchers probed how stepwise changes to the structure contributed to
the binding affinity and inhibition properties of the molecules, as well as their effects
on the crystal structure of the CYP3A4 enzyme on binding.
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Question 3
This question carries 29 marks for this assignment and tests learning outcomes KU1,
KU2–KU4, CS1, CS2, KS1, KS3, PS1 and PS2.,
(a) The following scheme shows two steps for the synthesis of a phenyl substituent at the
R1 position in compound 4. The experimental procedure for the first step of the
synthesis involves reactants A and B, and product C as given below.
2-Bromoacrylic acid (7.3 mmol), compound B, was added to a solution of
thioacetanilide (6.6 mmol), compound A, in dry toluene (20 ml) where the mixture
was stirred at 90 °C for 1 h, and then allowed to cool to room temperature. The
intermediate compound C precipitated out of solution and was filtered, washed with
acetone, and recrystallized from MeOH:EtOAc:hexane (1:1:2) to afford the pure
thiazolinium bromide intermediate (compound C).
Prior to completing an experimental procedure such as this it is necessary to carry out
a risk assessment.
Discuss in your own words for the experimental procedure of the first step of the
synthesis, giving your reasons, any safety precautions that you would take when
performing this reaction. You do NOT need to consider the recrystallization of this
product (i.e. the steps following the washing of the filtrate) or the second reaction step
in your answer.
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