Option D - Medicinal Chemistry (SL)

how effective a drug is compared to its toxicity

lethal dose/effective dose

toxic dose/effective dose

range of dosages between the minimum amount of drug required to achieve the desired effect and a medically unacceptable adverse effect

drug is dangerous

• injected into the arm, leg, buttocks

• used for larger volumes of drugs

• when a vein cannot be found, or if the drug irritates the veins

• directly under the skin

• usually in small volumes

most effective as the drug enters the bloodstream directly

1. Dosage – amount of the drug that the person would be required to take, including the frequency of administration required to maintain the level needed to have a medicinal effect in the body based on the concentration in the bloodstream

2. Tolerance – when some drugs are taken for an extended period of time, the effective action of the drug on the body can decrease with each exposure

   1. This can be dangerous as more of the drug needs to be taken in order to have an effect and this amount may approach or exceed the toxic dose.

3. Addiction – when the body quickly adapts to the presence of the medication and experiences negative effects in its absence

4. Side-effects – unintentional physiological effects in the body that are not desired caused by the drug

1. Age

2. Weight

3. Gender

4. Method of administration

5. Polarity/solubility

6. Functional group

7. Stomach contents

8. Acidity of stomach

the degree and rate at which an administered drug is absorbed by the body’s circulatory system (ie. amount of medicine that reaches a target site)

• Intravenously administered drug = 100% bioavailability

1. Degree of ionisation

2. Solubility in lipids

3. Form of dosage (Eg. particle size)

4. Concentration of dosage

enables the correct dosage of drugs that are administered non-intravenously to be calculated correctly

occur when reducing or stopping the dosage of a drug which can lead to withdrawal symptoms (eg. sweating, tremors, etc)

uncontrollable or overwhelming need to use a drug; this compulsion is long-lasting and can return unexpectedly after a period of improvement

• Like dependence, addicts usually suffer from physical withdrawal symptoms if the dosage is removed or reduced

1. Identifying the need and structure

2. Synthesis

3. Yield and extraction

4. Consider the environment + make the process as green as possible

5. Changing the polarity of a drug can affect its bioavailability and effectiveness

6. All new drugs must undergo rigorous testing and clinical trials 

irreversibly binds itself to cyclooxygenase, an enzyme, and prevents the production of prostaglandins (a group of lipids which cause fever, swelling, and transmission of nerve impulses to the brain)

• ester

• carboxylic acid

• aromatic group

warming salicylic acid with ethanoic anhydride will produce aspirin

• Products: aspirin, in the form of precipitate, and ethanoic acid (when reacting with ethanoic anhydride)

• Catalyst: a few drops of concentrated sulphuric acid or concentrated phosphoric acid 

Salicylic acid + ethanoic anhydride → aspirin + ethanoic acid

C₇H₆O₃ + (CH₃CO)₂O → C₉H₈O₄ + CH₃COOH 

Recrystallization: using water, ethyl ethanoate or ethanol as the solvent to produce the pure product.

1. Find the amount of moles of salicylic acid (LR)

2. Use it to find the moles of aspirin (1:1 Molar Ratio)

3. Convert to grams → theoretical yield 

4. % yield = 100(actual yield/theoretical yield)

• Melting Point → presence of impurities lowers the melting point and also increases the range over which the sample melts

  • Pure aspirin melts between 138 and 140℃

• Thin layer chromatography → impurities will increase at a different rate to aspirin by performing thin layer chromatography with a suitable solvent the presence of any impurities is shown

• Infrared spectroscopy → the infrared spectrum of the prepared sample can be compared with that of pure aspirin to see whether any absorptions due to impurities are present 

Stomach ulcers and bleeding → caused by the aspirin’s acidic and anti-clotting properties affecting the stomach lining

Reye’s syndrome → rare, but serious illness in children which can fatally affect the liver and brain

Interaction with other drugs – synergistic effect → aspirin can interfere with or enhance the action of other drugs; taking aspirin and alcohol at the same time increases the likelihood of gastrointestinal bleeding occurring

Aspirin can be made soluble by reacting it with NaOH

Aspirin + NaOH → acetyl salicylate anion + H₂O

Effect: tends to reach the bloodstream faster although the overall bioavailability is not changed appreciably from the insoluble form

Paracetamol => less side effects than aspirin

Ibuprofen => works similarly to aspirin

Penicillin works by preventing the cross-linking from taking place in the cell walls of the bacteria. 

1. The 𝛃-lactam ring is considerably strained as the normal bond angles of 109.5 degrees and 120 degrees can not be achieved, so it breaks easily. 

2. When the ring opens, the two parts that are formed are very similar to the two amino acids, cysteine and valine. 

3. These two parts become covalently bonded to the enzyme DD-transpeptidase in the bacterium, inhibiting its cross-linking activity and preventing new cell wall formation. 

Without a cell wall, bacteria are vulnerable to outside water and osmotic pressure, and quickly die. Human cells have a cell membrane rather than a cell wall, so penicillin does not affect human cells. 

amide; carboxylic acid; ether; benzene ring + 𝛃-lactam ring

amide, carboxylic acid, ether + 𝛃-lactam ring

intravenously or intramuscularly as it is destroyed easily by stomach acid when taken orally

By replacing the benzyl, C₆H₅CH₂–side chain with other groups whilst still retaining the basic structure. This alters the chemical properties of the penicillin, making them more resistant to stomach acid, but still effective as an antibiotic.

Caused by:

1. The overuse/overprescription of penicillin

2. Addition of antibiotics in animal feed leads to bacteria in animals becoming resistant which is then shared to humans who consume meat

3. Not completing treatment → remaining bacteria will develop a resistance to it

enzyme developed by bacteria that can deactivate antiobiotics; it is either developed through genetic mutation or species pass it on to one another

• This was originally overcome through chemists changing the side chain in penicillin, but now there are several bacteria, known as ‘superbugs’ which are resistant to all-known antibiotics.

• Antibiotics should not be overprescribed (ie. they should only be used to treat serious bacterial infections)

• Antibiotics should not be used in animal feed or given to humans as a preventative

• Patient compliance – when a course of antibiotics is prescribed, it should be completed

As with aspirin, penicillin has a carboxyl group, meaning that it can be made much more soluble in aqueous solutions by converting it into a group 1 salt by reacting it with potassium or sodium hydroxide. 

Many other drugs are basic as they contain an amine group. These can be made soluble in aqueous solution by reacting them with HCl to convert them into soluble ionic salts.

natural narcotic analgesics that are derived from the opium poppy

• The main opiate present in opium is morphine with smaller amounts of codeine

Opiates are strong analgesics used to alleviate both chronic and acute pain. They work by:

1. Binding to opiate receptors in the brain → causes the transmission of pain signals in the brain and spinal cord to be blocked 

Syllabus states that they do this without stressing the central nervous system, but there are several studies disproving this

All opiates are made up of a benzene ring and a tertiary amine. They all contain the same active constituent as part of their structure: a six-membered ring (containing a nitrogen atom) bonded to a phenyl group (C₆H₅).

Morphine = two hydroxyl groups

Codeine = one ketone and a hydroxyl group

Heroine = two esters in the place of both groups

Reacting morphine with ethanoic acid with a sulphuric acid catalyst.

• Similar to aspirin, a better yield is obtained if ethanoic anhydride is used

Heating a solution of morphine dissolved in methanol with diazomethane, CH₂N₂, to give nitrogen as the inorganic product.

Opiates are addictive and due to tolerance, there is a danger of the dose reaching the lethal limit. They should not be administered for head injuries or when the patient is unconscious.

• Users who obtain opiates illegally also run the risks associated with using impure products and unknown products.

• cause euphoria

• slow heart & breathing rate

• May cause nausea & vomitting

• high dosage may cause coma or death

• addiction and dependence

• loss of sex drive

• social problems (theft, prostitution, etc…)

• risk of hepatitis, HIV, etc. through sharing needles

Heroin addicts feel compelled to continue using the drug both because of its euphoric and pain relieving effects and also because of fear of withdrawal symptoms they may experience within 6-24 hours if they stop.

• Withdrawal symptoms: craving for heroin, hot and cold sweats, nausea & vomiting, diarrhoea, anxiety, muscular cramps

Taking methadone, a synthetic drug.

• It is a strong analgesic, but does not produce euphoria.

Methadone treatment may be lifelong for heroin addicts who wish to avoid the illicit use of heroin or can be used to wean addicts off their addiction completely by progressively reducing the dosages given over a period of time.

The analgesic and addictive properties of opiates are due to their interaction with the opioid receptors in the brain. In order to interact, they must cross the blood-brain barrier.

• Their solubility in aqueous solution can be increased considerably by converting them into ionic salts.

This can be done by acidifying the tertiary amine group, so that they are often administered as their sulphate or chloride salt. Once they are transported to the brain, they revert to their undissociated form to cross the lipid-based blood-brain barrier.

Heroin is ~10  times more potent than morphine as its two ester groups make it a much less polar molecule than morphine, so it is more soluble in lipids, enabling it to pass more rapidly through the blood-brain barrier. 

They are bases that are used to remove excess acid in the stomach.

They work in a non-specific way by neutralizing the excess acid. They help prevent indigestion, inflammation of the stomach lining, and acid reflux.

• They relieve pain and discomfort (heartburn) and allow the mucous layer and stomach lining to mend.

MgO (s) + 2HCl (aq) → MgCl₂ (aq) + H₂O (l)

Mg(OH)₂ (s) + 2HCl (aq) → MgCl₂ (aq) + 2H₂O (l)

Al(OH)₃ (s) + 3HCl (aq) → AlCl₃ (aq) + 3H₂O (l)

Na₂CO₃ (s) + 2HCl (aq) → 2NaCl (aq) + CO₂ (g) + H₂O (l)

CaCO₃ (s) + 2HCl (aq) → CaCl₂ (aq) + CO₂ (g) + H₂O (l)

NaHCO₃ (s) + HCl (aq) → NaCl (aq) + CO₂ (g) + H₂O (l)

This is measured by how fast they react and by how much acid can be neutralised by a particular dose

Which can neutralise the most acid, 1.00 gram of NaHCO₃ or 1.00 gram of Al(OH)₃?

n of NaHCO₃ =1/(22.99+1.01+12.01+48)=0.01190 mol

NaHCO₃ (s) + HCl (aq) → NaCl (aq) + CO₂ (g) + H₂O (l)

1 mole of NaHCO₃ reacts with 1 mole of HCl

• Amount of HCl neutralised by 1.00g of NaHCO₃ is 0.01190 mol

n of Al(OH)₃ = 1/(26.98+ 3.03+48)=0.01282 mol

Al(OH)₃ (s) + 3HCl (aq) → AlCl₃ (aq) + 3H₂O (l) 

1 mole of Al(OH)₃  reacts with 3 mole of HCl

• Amount of HCl neutralised by 1.00g of Al(OH)₃ is 0.0385 mol

∴ Al(OH)₃ is able to neutralise more than three times as much stomach acid than sodium bicarbonate. 

They resist changes in pH when small amounts of acid or base are added.

• Importance in living organisms: changes in pH can alter the structure and, therefore, the efficiency of enzymes

consist of a weak acid together with the salt from that acid with a strong base

Mixture of ethanoic acid and sodium ethanoate

• Prepared by dissolving sodium ethanoate in a solution of ethanoic acid or by adding excess ethanoic acid to a sodium hydroxide solution

If H₃O⁺ ions are added, they are removed by combining with ethanoate ions to form undissociated ethanoic acid, so the pH remains constant.

If OH^- ions are added, they are removed by reacting with undissociated ethanoic acid to form ethanoate ions and water, so the pH remains constant.

consist of a weak base together with the salt formed from the base and a strong acid

Mixture of ammonia and ammonium chloride

• Prepared by dissolving ammonium chloride in a solution of ammonia or by adding excess ammonia solution to a hydrochloric acid solution

• Ammonia is a weak base, so it is only slightly dissociated in solution. Ammonium chloride is a salt, so it is completely dissociated into ions in solution.

If H₃O⁺ ions are added, they are removed by combining with hydroxide ions to form water and more of the ammonia will react with water water molecules to replace them, so the pH remains constant.

If OH^- ions are added, they are removed by reacting with ammonium ions to form ammonia and water, so the pH remains constant.

need to know the K_a of the acid

• base on top, acid on bottom

stimulates parietal cells (acid-producing cells) to release HCl in the stomach lining

block the release of stomach acid

prevent the ability of parietal cells to produce stomach acid and prevents stomach ulcers from forming by interacting with a cysteine residue in the proton pump

• it is not good as it prevents the digestion of proteins

PPIs have largely replaced H2-R antagonists as they cause a longer lasting reduction of stomach acid and are also more effective at preventing acid-reflux related symptoms

• active form of a drug after it has been processed by the body

• normally, their side effects are the same or weaker than those of the parent drug, although sometimes, it may be responsible for the main therapeutic effect of the parent drug

• CO₃/HCO₃ antacids → belching due to the release of CO₂

• Mg-containing antacids → diarrhoea

• Al-containing antacids → constipation

• Ranitidine & PPIs → diarrhoea, headaches, dizziness

  • long-term use of PPIs → osteoporosis, development of food and drug allergies

nonliving organisms consisting of a central core of RNA or DNA, surrounded by a capsid/capsomeres

• they can only reproduce inside the cells of living organisms

1. Inject DNA/RNA into the host cell’s cytoplasm

2. Forces the host cell to produce new DNA/RNA

3. Forms large numbers of new viruses

4. Host eventually bursts, releasing the new viruses into the bloodstream, airways, or other routes which can then go on to infect new cells

occurs when a virus undergoes a sudden change in genetic makeup, creating a new strain

occurs when a virus undergoes a gradual change in genetic makeup, causing a different, but somewhat similar genetic makeup to the parent virus

special immune system cells in humans that can recognize and kill cells containing viruses, since the surface of infected cells change when the virus begins to multiply

1. they lack a cell structure

2. they multiply very quickly

3. they continually evolve through mutation

1. altering the cell’s genetic material → virus cannot use it to multiply

2. blocking enzyme activity within the host cell → preventing the virus from multiplying

an effective antiviral drug for influenza

Functional Groups: ester; hydrolysed to its carboxylate anion in the liver

1. the carboxylate anion inhibits the enzyme neuraminidase present in all influenza viruses by blocking its active site

2. Prevents the influenza virus from acting on sialic acid, which is found in the proteins on the surface of the host cells

   1. This prevents the new viral particles from being released from the host cell, so they cannot infect other cells and multiply

another effective antiviral drug for influenza and a neuraminidase inhibitor

Functional Groups: hydroxyls, amines, carboxyl group

• much more soluble than oseltamivir due to its functional groups

both share structural properties with sialic acid

HIV - damages the cells in the immune system, weakening the ability to fight everyday infections and diseases

• This develops into AIDS

It is a retrovirus. There is no cure, but there is a treatment, composed of antiretroviral drugs.

1. NRTIs bond to the active site on reverse transcriptase, blocking its catalytic activity

2. Protease Inhibitors work by selectively binding to proteases in the virus, preventing them from breaking down protein precursors necessary for the production of new viruses

Radioactive isotopes are used in medicine both to target and treat tumours and for diagnostic purposes.

Damaging impact of radioactive depends on 2 factors:

• type & intensity of radiation → gamma rays are the most penetrating

• half-life → represents the time taken for a half of its radioactive atoms to decay

• not very dangerous

• Examples: syringes, gloves, paper towels, protective clothing, etc

• has a limited environmental impact:

It does not have to be stored long term. It is stored until it is below a safe limit and then buried in shallow landfill sites or incinerated.

• very dangerous (emit more radiation/have longer half-lives)

• Examples: nuclear reactors, medical equipment

• Some can be repurposed and recycled

Most HLW is vitrified, encased in steel/concrete, and buried deep underground in geologically stable conditions where (in theory) it cannot leak into the groundwater.

1. it can cause cellular and genetic damage → leading to cancer, birth defects, problems with fertility

2. it can weaken the immune system → leading to an increase in contracting infectious diseases

They can often be purified by distillation and reused; however, much can escape as vapour or be discarded as aste.

• Vapour of solvents contributes to the greenhouse effect and/or the destruction of the ozone layer

They need to be categorized, segregated, and stored in labelled containers.

• Innocuous solvents → disposed of in rivers or the sea

• Organic solvents + those containg heavy metals → not allowed to pollute water

• Non-chlorinated solvents → can be combusted

• efficient at dissolving organic materials

• can be absorbed through inhalation and/or skin contact

Effects: short-term (dizziness, fatigue, headache, skin rashes); long-term (damage to the liver, kidney, nervous system)

• Not easily biodegraded + can accumulate in ground water and damage ecosystems→ must be incinerated in special furnaces at very high temperatures

  • they produce toxic gasses when burned at lower temps.

Comes from: the disposal of unused antibiotics, through the urine of people taking antibiotics, from animals who have been fed antibiotics

• it is eventually discharged into rivers which leads to organisms building up antibiotic resistance

• large use of antibiotics → weakened humans/animals immune systems + made them more susceptible to bacterial infections

Solution: access to antibiotics should be limited + banned completely in animals

seeks to minimize the production and release of hazardous substances to the envrionment, including any solvents used

What should be taken into account: atom economy,

e-factor, and the toxicity of waste products

a way to assess the “greenness“ of a process

• the greater the atom economy, the greener it is

this should be taken into account when assessing the greenness of a process

Traditionally, oseltamivir is synthesised using shikimic acid, traditionally found in the Chinese star anise plant, as the precursor. However, the plant does not produce it in sufficient quantities to support the pharmaceutical industry.

• Oseltamivir has been synthesised with lithium nitride and other molecules, making it more sustainable.

Greenest method = biotechnology

• Enzyme-catalysed reactions are highly selective, efficient, and can take place in aqueous solution removing the need for organic solvents

• Shikimic acid can now be produced synthetically using genetically modified E.coli bacteria → increased the atom economy and decreased the environmental factor considerably