Higher 3 Pharmaceutical Chemistry Concept Test

Answer all questions. Question one is worth 20 marks and question two and three are worth 15 marks each.

Time: 1 hour and 15 minutes

Acknowledgements

Question 1 diagrams http://faculty.smu.edu/jbuynak/Medicinal_Outline_11_9_04.pdf

Suicide inhibitors Organic Chemistry 4th edition by Paula Yurkanis Bruice

Q2 spectra http://webbook.nist.gov/cgi/cbook.cgi?ID=C56860&Units=SI&Mask=1E9F

50

Question one

One way to kill bacterial cells is via the use of translational inhibitor which inhibits protein synthesis in bacterial cells.

Oxazolidinones bind to the 50S large subunit while tetracyclines bind to the 30S small subunit of the ribosomes.

An outline of translation is given below:

(a) The transfer step can be illustrated by a nucleophilic acyl addition mechanism. Copy the diagram on the next page and use it to draw the mechanism. [2]

(b) Erythromycin A is a macrolide antibiotic. They are bacteriostatic agents that inhibit protein synthesis by binding reversibly to 50S protein ribosomal subunits. State what is meant by ‘bacteriostatic’ and name another drug that has similar property. [1]

Some of the hydrogen bondings between erythromycin A and 23S RNA bases are given above. Complete the diagram by drawing 4 more hydrogen bonds that are possible. Name the other significant bonding present in the diagram. [3]

(c) Penicilllinase knocks out penicillins before they can act on bacterial cell wall.

Clavulanic acid is used to inhibit penicilllinase. Complete the mechanism. [4]

Chemists have developed other drugs that inhibit penicillase. This involves forming a sulphone as shown below.

(i) What is the reagent and condition for this synthesis? [1]

(ii) Because the sulphone is rather similar to the original antibiotic, penicillase accepts it as a substrate forming an ester. But if this ester is hydrolysed, penicillinase would then be free again to break down penicillins. However, the chemistry involving sulphone provides an alternative pathway to hydrolysis that form a stable imine (C=N). As imines are susceptible to nucleophilic attacks, an amine group on penicillinase’s active site can form a second covalent bond, forming an inactivated enzyme and product shown below.

These kinds of inhibitors are known as “suicide inhibitors”.

What is meant by the “chemistry involving sulphone” in this context?Draw a mechanism to show how the suicide inhibitor forms the inactive enzyme above. [5]

(d) Recently it has been discovered that some bacteria found in a lake in the United States are able to use arsenic instead of phosphorous to live. Arsenic is a well-known poison.

(i) Name two molecules that are essential to any living organism which contain phosphorous. [1]

(ii) Suggest why arsenic can replace phosphorous in the incorporation of DNA. [1]

(iii) Discuss the paradigm shift when it was found out that arsenic could be a building block of life. [2]

Question two

Explain the origin of the IR spectrum. [2]

Discuss the basis of mass spectrometry [2]

The spectra above shows that of L-Glutamic acid, an alpha-amino acid, Mr=147 (M+ is negligible in the mass spectrum).

Deduce the structure of glutamic acid (stereochemistry is not important), given that it is a diacid. [5]

Explain why drugs like morphine have difficulty crossing the blood-brain barrier. Your explanation should include how it could cross the barrier, the binding of morphine to the opiate receptors, as well as the various relevant processes involved. [3]

It is well-known that glucose is the only substrate absorbed and used for cellular respiration in the brain.

D-Mannitol is polar and yet it is able to cross the blood-brain barrier. Propose an explanation why. [3]

D-Mannitol.

Glucose.

Question three

This question is about insomnia. Insomnia can be classified as primary and secondary insomnia. Secondary insomnia is caused by external factors or illnesses, such as excessive caffeine usage or depression.

Write down the mode of action of caffeine. [2]

Explain why a person feels that he needs more caffeine to stay awake than before. [2]

Explain why a person experiences headaches if he suddenly withdraws from caffeine. [2]

One treatment of insomnia is the use of benzodiazepines (BZD):

BZD enhance the effect of neurotransmitter GABA, resulting in release of Cl- in the post-synaptic neuron which results in hyponotic effect. BZDs indirectly result in the release of Cl-.

GABAA receptor

Triazolam is one such example. Using the information and diagrams given suggest how BZDs like triazolam enhance the effect of GABA. [3]

Suggest what types of bonds are formed between BZDs and the GABA receptor. [2]

BZDs have extremely short half-lifes of 2-5 hours. Assume triazolam has a half-life of 3 hours and a effective concentration of 2.625 moldm-3, explain how you would work out the time require to reach effective concentration if 2 moldm-3 is administered every 6 hours. [2]

BZDs are also prone to abuse. Suggest a way to treat BZD overdose. [1]

The use of BZDs and morphine or alcohol can cause increased sedation, more euphoria and even lethal side-effects. What is the term for this drug interaction? [1]